Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([OH:24])=O)[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6].[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:24])[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6]
Reactant: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)O)c(Cl)c1
Reactant: C1CCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)N2CCCC2)c(Cl)c1

Procedure:
Prepared analogously to Example 1d from 3-chloro-N-(5-chloro-1H-benzimidazol-2ylmethyl)-4-carboxybenzamide, pyrrolidine, TBTU, and triethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.43 minutes; C20H18Cl2N4O2 (417.29); mass spectrum: (M+H)+=417.2.
Reaction SMILES: [Cl:1][C@H:2]1[C@@H:7]([NH:8][C:9]([C:11]2[NH:12][C:13]([CH2:17][CH3:18])=[C:14]([Cl:16])[N:15]=2)=[O:10])[CH2:6][CH2:5][N:4]([C:19]2[S:20][C:21]([C:25]([O:27]CC)=[O:26])=[C:22]([CH3:24])[N:23]=2)[CH2:3]1.[OH-].[Li+]>>[Cl:1][C@H:2]1[C@@H:7]([NH:8][C:9]([C:11]2[NH:12][C:13]([CH2:17][CH3:18])=[C:14]([Cl:16])[N:15]=2)=[O:10])[CH2:6][CH2:5][N:4]([C:19]2[S:20][C:21]([C:25]([OH:27])=[O:26])=[C:22]([CH3:24])[N:23]=2)[CH2:3]1
Reactant: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](Cl)C2)nc1C
Agent: [Li+]
Agent: [OH-]
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3nc(C)c(C(=O)O)s3)C[C@H]2Cl)nc1Cl
Yield: 34.2 %

Procedure:
The same operation as in Example (2652d) was performed using ethyl cis(±)-2-(3-chloro-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}piperidin-1-yl)-4-methyl-1,3-thiazole-5-carboxylate obtained in Example (198c) (78 mg, 0.169 mmol) and a 2 N aqueous lithium hydroxide solution (848 μL). The resulting pale yellow solid was purified by thin layer silica gel chromatography (eluent: chloroform:tetrahydrofuran=3:2 v/v) to obtain 25 mg of the title compound (34%) as a colorless solid from the more polar elution fraction.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27](=[O:40])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)[CH:29]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27](=[O:40])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)[CH:29]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccccn2)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2ccccn2)c1

Procedure:
The title compound was prepared from (2-amino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J3) (207 mg, 0.75 mmol) and 3-oxo-3-(3-pyridin-2-yl-phenyl)-propionic acid tert-butyl ester (Example K3) (223 mg, 0.75 mmol) according to the general procedure M. Obtained as a white solid (284 mg).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].I[CH2:19][CH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>CC(C)=O>[CH3:11][O:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[O:1][CH2:19][CH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)[C:6]#[N:7]
Reactant: COc1cc(C#N)ccc1O
Reactant: ICC1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(C#N)ccc1OCC1CCOCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.0 g 4-Hydroxy-3-methoxybenzonitrile, 1.1 g potassium carbonate and 2.0 g 4-(iodomethyl)-tetrahydropyran were placed in 20 mL acetone and heated to reflux overnight. After this time, 1.1 g potassium carbonate was added and the reaction was heated at reflux for a further 2 h before more 0.93 g potassium carbonate was introduced and reflux was continued for a further 3 h. The mixture was then cooled to ambient temperature and concentrated under reduced pressure. The material that remained was partitioned between diethyl ether and water and the aqueous phase was removed and extracted with additional diethyl ether. The combined organic fractions were dried, filtered and the filtrate was concentrated under reduced pressure. Purification by silica gel chromatography (SiO2: ethyl acetate/heptanes: 10% to 30%) provided the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:71]=[CH:70][C:67]([C:68]#[N:69])=[CH:66][C:65]=1[O:72][C:73]([F:76])([F:75])[F:74]>>[C:68]([C:67]1[CH:70]=[CH:71][C:64]([NH:63][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:36])([CH3:37])[CH3:35])[C:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])=[C:65]([O:72][C:73]([F:74])([F:75])[F:76])[CH:66]=1)#[N:69]
Reactant: N#Cc1ccc(N)c(OC(F)(F)F)c1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(C#N)cc2OC(F)(F)F)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.4 g, 0.69 mmol), was reacted with diisopropylethylamine (0.46 g, 3.6 mmol), diphenylphosphinic chloride (0.34 g, 1.4 mmol), then reacted with 4-amino-3-(trifluoromethoxy)benzonitrile (Matrix) (0.14 g, 0.71 mmol) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-cyano-2-trifluoromethoxy-phenyl)-amide as a yellow solid (Yield, 40 mg, 9%).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH2:22])=[NH:21])=[CH:18][CH:17]=2)=[O:15])[CH2:10][CH2:9]1)=[O:7])C(C)C.[C:25]([O-])(=O)[CH3:26]>>[NH2:11][C:14]1[CH:16]=[C:17]([CH:18]=[CH:25][CH:26]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH2:22])=[NH:21])=[CH:18][CH:17]=2)=[O:15])[CH2:10][CH2:9]1)=[O:7]
Reactant: CC(=O)[O-]
Reactant: CC(C)COC(=O)N1CCN(C(=O)c2ccc(C(=N)N)cc2)CC1
Product: N=C(N)c1ccc(C(=O)N2CCN(C(=O)c3cccc(N)c3)CC2)cc1

Procedure:
4-[4-(isobutyloxycarbonyl)piperazine-1-carbonyl]benzamidine, acetate, FAB 333.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[O:12]C(=O)[NH:9][C:7](=[O:8])[C:5]=2[CH:6]=1.O[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[OH-].[Na+]>O1CCCC1>[N:20]1([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C:2]2[CH:3]=[C:4]([OH:12])[C:5](=[CH:6][CH:1]=2)[C:7]([NH2:9])=[O:8])[CH2:21][CH2:22][O:23][CH2:24][CH2:25]1
Reactant: OCCCCCCN1CCOCC1
Reactant: O=c1[nH]c(=O)c2ccccc2o1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)c1ccc(CCCCCCN2CCOCC2)cc1O
Temperature: 25 °C
Reaction time: 60 h
Yield: 37.2 %

Procedure:
A slurry of carsalam (6.13 g, 37.6 mmol), 4-(6-hydroxyhexyl)morpholine (7.0 g, 37.4 mmol), triphenylphosphine (9.97 g, 35.0 mmol), and tetrahydrofuran (40 mL) was treated with a solution of diisopropyl azodicarboxylate (7.40 mL, 7.60 g, 37.6 mmol) and tetrahydrofuran (10 mL), added dropwise over 15 minutes. The reaction mixture was stirred at 25° C. for 60 hours. The solution was treated with aqueous 2N NaOH (50 mL, 100 mmol) and warmed to 60° C. for 180 minutes. The cooled reaction mixture was concentrated to remove the tetrahydrofuran. The aqueous residue was washed with ethyl acetate (2×40 mL), and was acidified with 4% aqueous HCl to a pH of 0.84 (causing carbon dioxide gas to evolve). The pH of the aqueous phase was raised to 7.8 with 2N aqueous NaOH. Solid sodium bicarbonate was added. Extraction with ethyl acetate (8×40 mL), drying over sodium sulfate and concentration gave an oil which solidified upon standing. A total of 4.26 g of 4-(6-morpholin-4-ylhexyl)-salicylamide was isolated.
Reaction SMILES: [CH2:1]([N:3]1[C:8]2[CH:9]=[C:10]([C:14]3[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=3[O:22][C:23]([F:26])([F:25])[F:24])[CH:17]=[O:18])[C:11]([CH3:13])=[CH:12][C:7]=2[O:6][C:5]([CH3:28])([CH3:27])[C:4]1=[O:29])[CH3:2].[CH3:30][Mg]Br.C(OCC)C.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C1COCC1>[C:17]([C:16]1[CH:19]=[CH:20][C:21]([O:22][C:23]([F:25])([F:24])[F:26])=[C:14]([C:10]2[C:11]([CH3:13])=[CH:12][C:7]3[O:6][C:5]([CH3:28])([CH3:27])[C:4](=[O:29])[N:3]([CH2:1][CH3:2])[C:8]=3[CH:9]=2)[CH:15]=1)(=[O:18])[CH3:30]
Reactant: CCN1C(=O)C(C)(C)Oc2cc(C)c(-c3cc(C=O)ccc3OC(F)(F)F)cc21
Reactant: C[Mg]Br
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCN1C(=O)C(C)(C)Oc2cc(C)c(-c3cc(C(C)=O)ccc3OC(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
A solution of Compound 1D (200 mg, 0.49 mmol) in dry 3 mL of dry THF is cooled to −78° C. and treated with a 3M solution of methyl magnesium bromide in diethyl ether (0.17 mL, 0.54 mmol). The reaction was allowed to warm to room temperature, the reaction turned blue when it was complete. The mixture was quenched with 5 mL of a saturated aqueous solution of NH4Cl and passed through a SPE. The crude product was eluted with EtOAc. After removing excess solvent the crude alcohol was then dissolved in 2 mL of dichloromethane and treated with Dess-Martin reagent (250 mg, 0.59 mmol) and stirred at room temperature overnight. The reaction was quenched with 4 mL of saturated sodium thiosulfate solution and 4 mL of saturated sodium bicarbonate solution, the reaction mixture was stirred until clear. The reaction mixture was passed through another SPE and eluted with dichloromethane, removal of solvent yielded crude ketone which was purified with flash chromatography (25% EtOAc/hexane) to yield 95 mg (46%) of the desired product and a white solid. MS (electrospray): mass calculated for C22H22F3NO4, 421.15; m/z found 422.1 [M+H]+.
Reaction SMILES: Cl.[I:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH:13]3[CH2:15][CH:10]2[CH2:11][NH:12]3)=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:23](OC(=O)C)(=[O:25])[CH3:24]>ClCCl>[C:23]([N:12]1[CH2:11][CH:10]2[CH2:15][CH:13]1[CH2:14][N:9]2[C:6]1[CH:5]=[CH:4][C:3]([I:2])=[CH:8][CH:7]=1)(=[O:25])[CH3:24]
Reactant: Ic1ccc(N2CC3CC2CN3)cc1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CC2CC1CN2c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
5-(4-Iodophenyl)-2,5-diazabicyclo[2.2.1]heptane hydrochloride (269 mg, 0.80 mmol) was suspended in dichloromethane (0.3 ml), and triethylamine (0.2 ml) and acetic anhydride (0.09 ml, 0.96 mmol) were added. After stirring at room temperature for 1 hr, dichloromethane was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 2-acetyl-5-(4-iodophenyl)-2,5-diazabicyclo[2.2.1]heptane (255 mg, yield 93%).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([NH:11][C:12](=[O:26])[C:13]([NH:16][C:17](=[O:25])[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)([CH3:15])[CH3:14])=[N:8][C:7]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:5])C.[OH-].[K+]>C1COCC1.C(O)C>[F:24][C:21]1[CH:20]=[CH:19][C:18]([C:17]([NH:16][C:13]([CH3:14])([CH3:15])[C:12]([NH:11][C:9]2[S:10][C:6]([C:4]([OH:5])=[O:3])=[C:7]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:8]=2)=[O:26])=[O:25])=[CH:23][CH:22]=1
Reactant: CCOC(=O)c1sc(NC(=O)C(C)(C)NC(=O)c2ccc(F)cc2)nc1-c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(NC(=O)c1ccc(F)cc1)C(=O)Nc1nc(-c2ccccc2)c(C(=O)O)s1
Temperature: 65 °C

Procedure:
A mixture of 2-[2-(4-Fluoro-benzoylamino)-2-methyl-propionylamino]-4-phenyl-thiazole-5-carboxylic acid ethyl ester (357 mg, 0.785 mmol) and concentrated aqueous KOH (2 mL) in a mixture of THF (3 mL) and ethanol (5 mL) was heated at 65° C. for 2 h, cooled to RT and partitioned between ethyl acetate and 3 M HCl. The combined organic extract was dried and concentrated to give the title compound. m/z 428.1 (MH+).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH3:28])[CH:25]=3)[O:20][C:19](=O)[C:18]=2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:13][CH:12]=1)(=O)[CH3:8].Cl.C(=O)([O-])[O-].[K+].[K+].Cl.ClCC[N:47]1[CH2:51][CH2:50][CH2:49][CH2:48]1.[I-].[Na+]>O1CCCC1.O.C(O)C.[Pd]>[CH3:28][O:27][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[O:20][CH2:19][C@@H:18]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C@H:17]2[C:14]1[CH:13]=[CH:12][C:11]([O:10][CH2:7][CH2:8][N:47]2[CH2:51][CH2:50][CH2:49][CH2:48]2)=[CH:16][CH:15]=1
Reactant: COc1ccc2oc(=O)c(-c3ccccc3)c(-c3ccc(OC(C)=O)cc3)c2c1
Reactant: ClCCN1CCCC1
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: COc1ccc2c(c1)[C@H](c1ccc(OCCN3CCCC3)cc1)[C@H](c1ccccc1)CO2
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
Lithium aluminium hydride (0.96 g, 2.54 mmol) was added in small portions to a stirred solution of 4-(4-acetoxyphenyl)-3-phenyl-6-methoxy-coumarin (0.49 g, 1.27 mmol) in tetrahydrofuran (75 ml). The resulting mixture was stirred for 30 min., 6M hydrochloric acid (4 ml) added dropwise, and the mixture heated to 65° C. for 3 h. The mixture was cooled to room temperature, diluted with 100 ml water, and the product extracted into ethyl acetate (2×100 ml). The extracts were washed with brine, dried over sodium sulfate and evaporated to give a yellow gum. This gum was dissolved in ethanol (100 ml), and palladium on carbon (5%, 0.045 g, 0.02 mmol) added, then the mixture was hydrogenated for 18 h. The catalyst was removed by filtration and the solvents evaporated to give an orange gum, which was vacuum dried. The gum was dissolved in dry acetone (20 ml) then potassium carbonate (1.87 g, 13.50 mmol), 1-(2-chloroethyl)pyrrolidine hydrochloride (0.257 g, 1.51 mmol) and sodium iodide (0.01 g, catalyst) were added and the mixture heated to 60° C. for 20 h. The inorganic solids were removed by filtration and the solvent removed to give an orange gum, which was purified by column chromatography on silica gel 60 with 9:1 dichloromethane/methanol eluent. This gave the product as a pale orange gum, which was vacuum dried.
Reaction SMILES: [Br:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1[O:11][CH2:12][CH:13]1[CH2:15][CH2:14]1.[CH:16]([Mg]Br)=[CH2:17].[Cl-].[NH4+]>O1CCCC1>[Br:1][C:2]1[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)=[CH:4][CH:5]=[C:6]2[C:7]=1[NH:8][CH:17]=[CH:16]2
Reactant: O=[N+]([O-])c1cccc(OCC2CC2)c1Br
Reactant: C=C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Brc1c(OCC2CC2)ccc2cc[nH]c12
Temperature: -45 °C
Reaction time: 0.5 h
Yield: 51 %

Procedure:
A 250 mL roundbottom flask with stirbar was charged with a solution of Example 98A (6.18 g, 22.7 mmol) in tetrahydrofuran (80 mL) and cooled to −45° C. under nitrogen. A solution of 0.7 M vinylmagnesium bromide in tetrahydrofuran (100 mL, 70.0 mmol) was added over 20 minutes and the mixture stirred at −45° C. for 30 minutes. The mixture was then poured into aqueous ammonium chloride and extracted with 3×150 mL of ether. The combined organics were dried over anhydrous magnesium sulfate. After filtration and solvent removal the residues were adsorbed on silica gel and chromatographed on a 150 g silica cartridge eluting with 0-10-100% ethyl acetate/heptane to provide 3.087 g, (51%) of the title compound.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[CH:9][NH:8][C:7]=12.C(=O)([O-])[O-].[Cs+].[Cs+].[CH:17]1([C:21]([NH2:23])=[O:22])[CH2:20][CH2:19]C1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[NH:8]1[C:7]2=[C:2]([NH:23][C:21]([CH:17]3[CH2:20][CH2:19]3)=[O:22])[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[CH:9]1
Reactant: NC(=O)C1CCC1
Reactant: Brc1nccc2cc[nH]c12
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: Cc1ccccc1
Product: O=C(Nc1nccc2cc[nH]c12)C1CC1
Temperature: 120 °C
Reaction time: 8 h
Yield: 39.3 %

Procedure:
To a solution of 7-bromo-1H-pyrrolo[2,3-c]pyridine (500 mg, 2.53 mmol) in toluene were added tris (dibenzylidene acetone) dipalladium (116.20 mg, 0.126 mmol), Xantphos (32.98 mg, 0.057 mmol), cesium carbonate (896 mg, 2.75 mmol), and cyclobutanecarboxamide (251 mg, 2.96 mmol, Intermediate 4). The resulting reaction mixture was heated to 120° C. and stirred for 8 hours. After cooling to room temperature a saturated aqueous sodium bicarbonate solution (20 mL) was added to the reaction mixture and extracted with ethyl acetate (3×50 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel (100-200) column chromatography to afford N-(1H-pyrrolo[2,3-c]pyridin-7-yl)cyclopropane carboxamide (200 mg, 36% yield).
Reaction SMILES: NC1C=CC=CC=1.[C:8]1([CH3:15])[C:13]([OH:14])=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:16]([C:19]1[CH:20]=[C:21]([CH3:26])[C:22]([OH:25])=[CH:23][CH:24]=1)([CH3:18])=[CH2:17]>>[OH:14][C:13]1[CH:12]=[CH:11][C:10]([C:16]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([CH3:26])[CH:20]=2)([CH3:18])[CH3:17])=[CH:9][C:8]=1[CH3:15]
Reactant: Cc1ccccc1O
Reactant: C=C(C)c1ccc(O)c(C)c1
Solvent: Nc1ccccc1
Product: Cc1cc(C(C)(C)c2ccc(O)c(C)c2)ccc1O

Procedure:
Aniline (25 g; 1.39 moles of aniline per mole of p-isopropenyl-o-cresol) was added to 50 g of a mixture of o-cresol and p-isopropenyl-o-cresol (1:1 mole ratio) obtained by the alkali cleavage of 2,2-bis(4'-hydroxy-3'-methylphenyl)-propane. The mixture was stirred at 170° C., and 1.5 g of the catalyst solution prepared in Example 1 (0.0029 mole of catalyst per mole of p-isopropenyl-o-cresol) was added. The reaction was performed for 3 hours. Gas-chromatographic analysis of the resulting reaction mixture showed that 42.7 g (yield 91%) of 2-(4'-hydroxy-3'-methylphenyl)-2-(4'-aminophenyl)-propane having a melting point of 152.5 to 153.5° C. was formed.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[F:29][C:30]1[CH:35]=[C:34]([OH:36])[CH:33]=[CH:32][C:31]=1[S:37]([N:40]1[C:48]2[C:43](=[C:44]([OH:52])[CH:45]=[C:46](B(O)O)[CH:47]=2)[CH:42]=[CH:41]1)(=[O:39])=[O:38].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:46]1[CH:47]=[C:48]2[C:43]([CH:42]=[CH:41][N:40]2[S:37]([C:31]2[CH:32]=[CH:33][C:34]([OH:36])=[CH:35][C:30]=2[F:29])(=[O:38])=[O:39])=[C:44]([OH:52])[CH:45]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Reactant: O=S(=O)(c1ccc(O)cc1F)n1ccc2c(O)cc(B(O)O)cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3cc(O)c4ccn(S(=O)(=O)c5ccc(O)cc5F)c4c3)n(-c3ccccc3)c(=O)c12
Temperature: 100 °C
Reaction time: 18 h
Yield: 19 %

Procedure:
To a solution of (S)-2-(1-((6-amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (28 mg, 0.06 mmol) were added (1-((2-fluoro-4-hydroxyphenyl)sulfonyl)-4-hydroxy-1H-indol-6-yl)boronic acid (22 mg, 0.06 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (5 mg, 0.01 mmol) and 63 μl of a 2M aqueous solution of cesium carbonate in dioxane (2 ml). The mixture was stirred under argon atmosphere at 100° C. for 18 hours and then diluted with ethyl acetate. The resulting solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The product was purified by reverse phase using SP1® Purification System to give 8 mg (19% yield) as a white solid. Purity 99%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C@@H:11]([C:13]([OH:15])=[O:14])[CH3:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].N[C@H](C(O)=O)CC1C=CC=CC=1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C@H:11]([C:13]([OH:15])=[O:14])[CH3:12])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: C[C@@H](Nc1ccc([N+](=O)[O-])cc1)C(=O)O
Agent: N[C@@H](Cc1ccccc1)C(=O)O
Product: C[C@H](Nc1ccc([N+](=O)[O-])cc1)C(=O)O
Yield: 77 %

Procedure:
The reaction described above for 4-nitrophenyl-D-alanine was repeated for the L isomer. About 125 grams of L-Phe was nitrated as described above and resulted in about 124 grams of 4-nitrophenyl-L-alanine (about 77% yield). [α]D =+6.8° (c=1.0 in 1N HCl).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:15])[CH:11]=2)[CH2:6]1)=[O:4].[C:16]([C@H:20]1[CH2:25][CH2:24][C@H:23](O)[CH2:22][CH2:21]1)([CH3:19])([CH3:18])[CH3:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[C:16]([C@H:20]1[CH2:25][CH2:24][C@H:23]([O:15][C:10]2[CH:11]=[C:12]3[C:7](=[CH:8][CH:9]=2)[CH2:6][CH:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:14][CH2:13]3)[CH2:22][CH2:21]1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[C@H]1CC[C@H](O)CC1
Reactant: COC(=O)C1CCc2cc(O)ccc2C1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)C1CCc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2C1
Reaction time: 0.33 h

Procedure:
To a mixture of 6-hydroxy-1,2,3,4-tetrahydro-naphthalene-2-carboxylic acid methyl ester (0.280 g, 1.36 mmol), trans-4-tert-butylcyclohexanol (0.2338 g, 1.496 mmol) and triphenylphosphine (0.7122 g, 2.715 mmol) in toluene (5 mL, 50 mmol) was stirred for 20 min, then, diisopropyl azodicarboxylate (0.34 mL, 1.6 mmol) was added dropwise at 0° C. The solution was stirred at reflux overnight. The reaction was added silica gel and the solvent was concentrated. The residue was purified with silica gel eluted with EtOAc in hexanes from 0 to 20% to give the product as a white precipitate (73 mg, 16%). LCMS Rt=1.50 min, m/z=450.10 [M+H].