Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Br[C:36]1[C:49]([CH3:50])=[CH:48][C:39]([O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])=[CH:38][C:37]=1[CH3:51]>>[Si:41]([O:40][C:39]1[CH:48]=[C:49]([CH3:50])[C:36]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[C:10]3[C:6]=2[CH2:7][CH2:8][C@H:9]3[O:11][C:12]2[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=2)=[C:37]([CH3:51])[CH:38]=1)([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42]
Reactant: Cc1cc(O[Si](C)(C)C(C)(C)C)cc(C)c1Br
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(O[Si](C)(C)C(C)(C)C)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzo-furan-3-yl)acetate and (4-bromo-3,5-dimethylphenoxy)(tert-butyl)dimethylsilane following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 4): tR=2.09 min; Mass spectrum (ESI+): m/z=599 [M+Na]+.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[N:7]2.O1CCC[CH2:23]1.[H-].[Na+].IC>C(OCC)(=O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([N:14]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH3:23])=[N:7]2
Reactant: COc1ccc(Br)c2ccc(NC(=O)OC(C)(C)C)nc12
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CCOC(C)=O
Product: COc1ccc(Br)c2ccc(N(C)C(=O)OC(C)(C)C)nc12
Reaction time: 2 h

Procedure:
5-Bromo-2-t-butyloxycarbonylamino-8-Methoxyquinoline (1.21 g) and tetrahydrofuran (20 ml) were combined at room temperature under a nitrogen atmosphere. Sodium hydride (60% dispersion in oil) (164 mg) was added and the reaction mixture stirred for 2 h whilst effervescence occurred and a yellow colour appeared. Iodomethane (0.43 ml) was then added and stirring was continued for 2 h after which time the reaction was diluted with ethyl acetate (100 ml), washed successively with water, saturated aqueous sodium bicarbonate and brine, then dried (magnesium sulphate) and evaporated in vacuo to give the title compound (1.1 g) as a yellow solid.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.O[C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=1[N:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[CH2:29][OH:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C>O1CCCC1.O>[CH3:21][O:20][C:18]([C:17]1[CH:22]=[CH:23][C:14]2[O:30][CH2:29][C:25]3=[CH:26][CH:27]=[CH:28][N:24]3[C:15]=2[CH:16]=1)=[O:19]
Reactant: COC(=O)c1ccc(O)c(-n2cccc2CO)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(c1)-n1cccc1CO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.3 %

Procedure:
Diethyl azodicarboxylate (2.3 ml) was added dropwise to the mixture of methyl 4-hydroxy-3-(2-hydroxymethylpyrrol-1-yl)benzoate (2.5 g) and triphenylphosphine (4.0 g) in tetrahydrofuran (50 ml) under ice-cooling and the mixture was stirred for 2 hours at ambient temperature. The mixture was poured into the mixture of ethyl acetate and water. The separated organic layer was washed with brine and dried over magnesium sulfate. Evaporation of the solvent gave the residue, which was purified by column chromatography on silica gel eluting with chloroform. The eluted fractions containing the desired product were collected and evaporated in vacuo to give 8-methoxycarbonyl 4H-pyrrolo[2,1-c][1,4]-benzoxazine (0.61 g).
Reaction SMILES: BrC1C=CC(C(N2CCN(C3C(C)=CC(CC)=CN=3)CC2)=O)=CC=1.COC1C=CC(CN2CC(C)NC2=O)=CC=1.[CH2:41]([C:43]1[CH:44]=[C:45]([CH3:79])[C:46]([N:49]2[CH2:54][CH2:53][N:52]([C:55]([C:57]3[CH:62]=[CH:61][C:60]([N:63]4[CH:67]([CH3:68])[CH2:66][N:65](CC5C=CC(OC)=CC=5)[C:64]4=[O:78])=[CH:59][CH:58]=3)=[O:56])[CH2:51][CH2:50]2)=[N:47][CH:48]=1)[CH3:42]>>[CH2:41]([C:43]1[CH:44]=[C:45]([CH3:79])[C:46]([N:49]2[CH2:50][CH2:51][N:52]([C:55]([C:57]3[CH:58]=[CH:59][C:60]([N:63]4[CH:67]([CH3:68])[CH2:66][NH:65][C:64]4=[O:78])=[CH:61][CH:62]=3)=[O:56])[CH2:53][CH2:54]2)=[N:47][CH:48]=1)[CH3:42]
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)N(Cc5ccc(OC)cc5)CC4C)cc3)CC2)c(C)c1
Agent: CCc1cnc(N2CCN(C(=O)c3ccc(Br)cc3)CC2)c(C)c1
Agent: COc1ccc(CN2CC(C)NC2=O)cc1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)NCC4C)cc3)CC2)c(C)c1

Procedure:
Using (4-bromophenyl)[4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (155 mg) described in Preparation Example 212 and 1-(4-methoxybenzyl)-4-methylimidazolidin-2-one (88 mg) described in Preparation Example 52 and by the reaction and treatment in the same manner as in Example 506, the title compound (117 mg) was obtained via 3-{4-[4-(5-ethyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]phenyl}-1-(4-methoxybenzyl)-4-methylimidazolidin-2-one.
Reaction SMILES: ClC1N=C2C(C3C=C(Cl)C=CC=3OCCC)=CC=CN2N=1.[C:22]([O:26][C:27]([N:29]1[CH2:35][CH2:34][C:33]2[CH:36]=[CH:37][C:38](N)=[CH:39][C:32]=2[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[C:22]([O:26][C:27]([N:29]1[CH2:35][CH2:34][C:33]2[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=2[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(N)cc2CC1
Agent: CCCOc1ccc(Cl)cc1-c1cccn2nc(Cl)nc12
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CC(C)(C)OC(=O)N1CCc2ccccc2CC1

Procedure:
748-(5-Chloro-2-propoxy-phenyl]-[1,2,4]triazolo[1,5a]pyridine-2-ylamino]1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylic acid tert-butyl ester was prepared from 2-chloro-8-(5-chloro-2-propoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridine and 7-amino-1,2,4,5-tetrahydro-3-benzazepin-3-carboxylic acid tert-butyl ester with 2,2′-bis-dicyclohexylphosphanyl-biphenyl as the ligand in a manner analogous to Example 2d (0.14 g, 46%). MP=127-129° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.60 (s, 1H), 8.76 (d, 1H), 7.72 (s, 1H), 7.65 (m, 1H), 7.42 (m, 3H), 7.20 (m, 1H), 7.05 (m, 2H), 3.97 (m, 2H), 3.43 (m, 4H), 2.77 (m, 4H), 1.59 (m, 2H), 1.41 (s, 9H), 0.78 (m, 3H). MS=549 (MH)+.
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:4][C:3](=[O:11])[NH:2]1.[ClH:12].CC(C)=[O:15]>O>[ClH:12].[NH2:2][CH2:1][C:5]1([CH2:4][C:3]([OH:11])=[O:15])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: CC(C)=O
Reactant: O=C1CC2(CCCCC2)CN1
Agent: Cl
Solvent: O
Product: NCC1(CC(=O)O)CCCCC1
Temperature: 25 °C

Procedure:
89 g (0.581 mole) 2-Aza-spiro[4,5]decan-3-one are stirred under reflux for 4 hours with semiconcentrated hydrochloric acid. The reaction mixture is cooled to ambient temperature, diluted with water and extracted with methylene chloride for the removal of the starting material. The aqueous phase is evaporated to dryness in a vacuum and the residue obtained is mixed with acetone. Upon standing, 79.85 g, 1-aminomethyl-1-cyclohexaneacetic acid hydrochloride (64.7% of theory) crystallize out; content 99%; m.p. 123° to 127° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: COc1ccc([N+](=O)[O-])c(F)c1
Solvent: CCO
Product: COc1ccc(N)c(F)c1
Yield: 94.7 %

Procedure:
30 g (0.175 mole) of 3-fluoro-4-nitroanisole was dissolved in 100 mL of ethanol and degassed several times from alternating vacuum/N2. 1.5 g of Pd/C was added and the contents were hydrogenated using a Parr shaker (35 psi). After 30 min. the pressure had dropped to 5 psi, so it was increased to 35 psi and allowed to react for another 2 hrs. No further pressure drop was experienced. Contents were degassed, filtered through Celite and rotoary-evaporated to dryness to give 23.4 g (95%) of desired product. No purification was necessary. 1H NMR (CDCl3, 400 MHz) 6.71 (dd, 1H), 6.62 (d, 1H), 6.53 (d, 1H) 3.73 (s, 3H), 3.43 (bs, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[NH:11][C@H:12]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH3:13])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:27][O:26][C:23]1[CH:22]=[CH:21][C:20]([CH:10]([NH:11][C@H:12]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH3:13])[C:6]2[CH:5]=[C:4]([NH2:1])[CH:9]=[CH:8][CH:7]=2)=[CH:25][CH:24]=1
Reactant: COc1ccc(C(N[C@@H](C)C2CCCCC2)c2cccc([N+](=O)[O-])c2)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc(C(N[C@@H](C)C2CCCCC2)c2cccc(N)c2)cc1
Yield: 100.2 %

Procedure:
In a similar manner to that described in Example (1b), a solution of N-[(3-nitrophenyl)-(4-methoxyphenyl)methyl]-N-[(S)-1-cyclohexylethyl]amine (2.63 g) [prepared as described in step (a) above] in methanol (50 ml), nickel chloride hexahydrate (3.39 g) and sodium borohydride (1.14 g) were reacted, to afford the title compound (2.42 g) as a yellow oil.
Reaction SMILES: [CH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH:13][CH:14]2[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)[CH:6]=[N:5][CH:4]=1)=[CH2:2].[ClH:27].CO>>[ClH:27].[CH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH:6]=[N:5][CH:4]=1)=[CH2:2]
Reactant: C=Cc1cncc2cccc(NC3CCN(C(=O)OC(C)(C)C)CC3)c12
Agent: Cl
Solvent: CO
Product: C=Cc1cncc2cccc(NC3CCNCC3)c12
Temperature: 25 °C

Procedure:
According to the method of Example 1, Step C, deprotection was performed (50° C., 2 hours) by using Intermediate 81 (46.6 mg) and 10% hydrogen chloride/methanol solution (2 ml). The reaction mixture was cooled to room temperature, and then the solvent was evaporated under reduced pressure. The residue was added with methanol (2 ml) and diethyl ether (6 ml). The deposited precipitates were collected by filtration and washed with diethyl ether to obtain the title compound (25.3 mg).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH:8]([CH:11]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[S:21][CH:22]=[C:23]([C:25]([O:27]CC)=[O:26])[N:24]=3)[CH2:16][CH2:15]2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].CS(N1CCC(C(C2C=CC=CC=2)CC=O)CC1)(=O)=O.N1CCC(C2SC=C(C(OCC)=O)N=2)CC1>>[CH3:1][S:2]([N:5]1[CH2:6][CH2:7][CH:8]([CH:11]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:12][CH2:13][N:14]2[CH2:15][CH2:16][CH:17]([C:20]3[S:21][CH:22]=[C:23]([C:25]([OH:27])=[O:26])[N:24]=3)[CH2:18][CH2:19]2)[CH2:9][CH2:10]1)(=[O:4])=[O:3]
Reactant: CCOC(=O)c1csc(C2CCN(CCC(c3ccccc3)C3CCN(S(C)(=O)=O)CC3)CC2)n1
Agent: CCOC(=O)c1csc(C2CCNCC2)n1
Agent: CS(=O)(=O)N1CCC(C(CC=O)c2ccccc2)CC1
Product: CS(=O)(=O)N1CCC(C(CCN2CCC(c3nc(C(=O)O)cs3)CC2)c2ccccc2)CC1

Procedure:
The ethyl 2-(1-{3-[1-(methylsulfonyl)piperidin-4-yl]-3-phenylpropyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate used as starting material was prepared by reductive amination of 3-[1-(methylsulfonyl)piperidin-4-yl]-3-phenylpropanal (prepared following Method I using 4-benzoyl-N-methanesulphonylpiperidine as starting material) with ethyl 2-piperidin-4-yl-1,3-thiazole-4-carboxylate (Method K) as the amine component.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=2)[CH:7]=1.[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:20]1([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]4[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=4)[N:10]=3)[CH:7]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C(Nc1nc2ccc(Br)cn2n1)c1cccnc1
Product: O=C(Nc1nc2ccc(-c3ccccc3)cn2n1)c1cccnc1
Yield: 55.5 %

Procedure:
The title compound was prepared following procedure described for intermediate A1 step a), but starting from N-(6-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide ((B6), 75 mg; 0.24 mmol; 1.0 eq.) and phenylboronic acid (57 mg; 0.47 mmol; 2.0 eq.). Purification by flash chromatography on silica (MeOH/EtOAc, 5:95) gave the title compound as a beige powder (42 mg, 56%). HPLC, Rt: 2.26 min. (purity 98.7%).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[F:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][NH:25][CH2:26]2>CN(C=O)C>[F:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][N:25]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[CH:9][C:10]=1[F:16])[CH2:26]2
Reactant: Fc1cccc2c1CNC2
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Solvent: CN(C)C=O
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3Cc4cccc(F)c4C3)c(F)cc2c1=O
Yield: 66.1 %

Procedure:
136 mg of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4- oxoquinoline-3-carboxylic acid, 206 mg of 4-fluoroisoindoline, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 127 mg of the target compound.
Reaction SMILES: [O-2].[Zn+2:2].[C:3]1([P:9](=[O:12])([OH:11])[OH:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CO.O>[C:3]1([P:9](=[O:10])([O-:12])[O-:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Zn+2:2]
Reactant: O=P(O)(O)c1ccccc1
Agent: [O-2]
Agent: [Zn+2]
Solvent: O
Solvent: CO
Product: O=P([O-])([O-])c1ccccc1

Procedure:
A slurry in methanol-water of zinc oxide was prepared by charging a 300 mL reaction flask equipped with a stirrer with 10.0 g (123 mmol) of zinc oxide (JIS grade 2, available from HakusuiTech Ltd.) and 90.0 g of 50% by mass methanol-water. A solution of 1.9 g (12 mmol) of phenylphosphonic acid (Nissan Chemical Industries, Ltd.) dissolved in 11.0 g of 50% by mass methanol-water was gradually added dropwise at room temperature (about 25° C.) to this slurry with stirring, thereby effecting a reaction for one hour. The slurry was then filtered and the wet cake was thoroughly rinsed with methanol. The wet cake was subsequently dried at 120° C. for at least 12 hours, yielding a white powder of zinc phenylphosphonate-containing zinc oxide.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[C@@H:3]([CH3:5])[OH:4].Cl.CCN(C(C)C)C(C)C.[NH:23]([C:35]([O:37][CH2:38][CH:39]=[CH2:40])=[O:36])[C@H:24]([C:32](O)=[O:33])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(Cl)CCl>C(Cl)Cl>[NH:23]([C:35]([O:37][CH2:38][CH:39]=[CH2:40])=[O:36])[C@H:24]([C:32]([NH:1][C@H:2]([C:6]([O:8][C:9]([CH3:11])([CH3:10])[CH3:12])=[O:7])[C@@H:3]([CH3:5])[OH:4])=[O:33])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: C=CCOC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: C[C@@H](O)[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@H](C(=O)OC(C)(C)C)[C@@H](C)O
Reaction time: 0.5 h
Yield: 72.7 %

Procedure:
H-Thr-OtBu-HCl (3.1 g, 15 mmol, 1.3 equiv) was dissolved in CH2Cl2 (30 mL) and DIEA (2.9 mL, 17 mmol, 1.5 equiv) was added and the mixture allowed to stir for 30 min. Alloc-Phe-OH (2.8 g, 11 mmol, 1 equiv) and EDC (2.8 g, 15 mmol, 1.3 equiv) in CH2Cl2 (35 mL) was then added and the reaction was stirred for 18 h. The organic reaction mixture was washed with H2O (3×25 mL), dried (MgSO4) and concentrated in vacuo. The resultant oil (4.12 g) was purified by flash chromatography [CHCl3-MeOH—HOAc (9:1:0.2)] to give the title product (3.25 g, 8 mmol, 71% yield), which was characterized by analytical HPLC (tR 20.9 min, >98% purity; Condition C); ESMS, calcd for C21H30N2O6, 406.2. Found: m/z 408.0 [M+H]+; 1H-NMR (200 MHz, CDCl3): 7.1-7.3 (5H, m, Ar); 6.89 (1H, d, J=8.8 Hz, NH); 5.7-5.9 (1H, m, CH allyl); 5.56 (1H, d, J=8.0 Hz, OH); 5.2-5.3 (2H, m, CH2 g-allyl); 4.52 (2H, d, J=5.4 Hz, CH2 a-allyl); 4.45 (1H, dd, J=8.4 Hz, 2.8 Hz, a-CH Thr); 4.22 (1H, dq, J=6.2 Hz, J=3.0 Hz, b-CH Thr); 3.0-3.2 (2H, m, b-CH2 Phe); 1.47 (9H, s, tBu); 1.15 (3H, d, J=6.6 Hz, g-CH3 Thr); 13C-NMR (50 MHz, CDCl3): 172.2 (CO), 169.5 (CO); 156.0 (CO); 136.1 (Cq, Ar); 132.5 (CH, allyl); 129.3 (CH, Ar); 128.5 (CH, Ar); 126.9 (CH, Ar); 117.7 (CH2, allyl); 82.7 (Cq, tBu); 68.5 (b-CH Thr); 65.9 (CH2, allyl); 58.0 (a-CH Thr); 56.2 (a-CH Phe); 38.3 (b-CH2 Phe); 28.0 (CH3, tBu); 20.8 (g-CH3 Thr).
Reaction SMILES: Cl.Cl.[N:3]1([CH2:9][CH2:10][CH2:11][N:12]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:15](=[O:16])[C:13]2=[O:14])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.[C:35]1([N:41]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:42](Cl)=[O:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(Cl)Cl>[C:35]1([N:41]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:42]([N:6]2[CH2:7][CH2:8][N:3]([CH2:9][CH2:10][CH2:11][N:12]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:15](=[O:16])[C:13]3=[O:14])[CH2:4][CH2:5]2)=[O:43])[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Reactant: O=C1C(=O)N(CCCN2CCNCC2)c2ccccc21
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C1C(=O)N(CCCN2CCN(C(=O)N(c3ccccc3)c3ccccc3)CC2)c2ccccc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 33 %

Procedure:
To a suspension of 1-[3-(1-piperazinyl)propyl]isatin dihydrochloride (1.39 g) in methylene chloride (40 ml) was added bis(trimethylsilyl)acetamide (3.44 g), and the mixture was stirred for 10 minutes. After N,N-diphenylcarbamoyl chloride (1.16 g) was added thereto, the stirring was continued at the ambient temperature for 5 hours. The reaction mixture was poured into ice-water and the methylene chloride layer was separated, washed with water and then dried over anhydrous magnesium sulfate. After removal of the solvent, the residue was crystallized from diethyl ether to obtain N,N-diphenyl-4-[3-(isatin-1-yl)propyl]piperazine-1-carboxamide (0.62 g), mp. 163° to 164.5° C.
Reaction SMILES: [C:1]1([NH:7][CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O-:12][C:13]#[N:14].[K+].Cl>O.C(O)(=O)C>[C:1]1([N:7]2[CH2:8][C:9](=[O:11])[NH:14][C:13]2=[O:12])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#C[O-]
Reactant: O=C(O)CNc1ccccc1
Agent: Cl
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: O=C1CN(c2ccccc2)C(=O)N1
Temperature: 90 °C
Yield: 24.5 %

Procedure:
A solution of N-phenylglycine (Fluka) (30.2 g, 0.2 moles) in 900 ml of water and 1 ml of acetic acid was heated to 60° C. After thirty minutes potassium cyanate (16.2 g, 0.2 moles) in 100 ml of water was added. Heating was continued for 90', then 25 ml of 37% hydrochloric acid were added and the reaction mixture was heated for 15 h at 90° C. After cooling the precipitate was filtered and crystallized from 95% ethanol. 8.65 g of 1-phenylhydantoin were obtained, m.p. 197°-198°.
Reaction SMILES: [Cl:1][C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[F:10].Cl[C:12]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][CH:15]=[CH:14][N:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.O>[Cl:1][C:2]1[C:8]([F:9])=[CH:7][C:5]([NH:6][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:4][C:3]=1[F:10]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: Nc1cc(F)c(Cl)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cccnc1Nc1cc(F)c(Cl)c(F)c1
Temperature: 80 °C
Reaction time: 36 h

Procedure:
A mixture of 4-chloro-3,5-difluoroaniline (1.64 g, 10.0 mmol), 2-chloro-3-nitropyridine (1.56 g, 9.84 mmol) and cesium carbonate (6.56 g, 20.1 mmol) in N,N-dimethylformamide (30 mL) was stirred at 80° C. for 36 hours. The reaction mixture was cooled to room temperature, diluted with water (200 mL) and extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (5×50 mL), dried over sodium sulfate, filtered, concentrated in vacuo and purified by chromatography on silica gel (Gradient: 0% to 5% ethyl acetate in petroleum ether) to provide the product as a yellow solid. Yield: 200 mg, 0.70 mmol, 7%. 1H NMR (400 MHz, CDCl3) δ 10.23 (br s, 1H), 8.55-8.61 (m, 2H), 7.52 (br d, J=9 Hz, 2H), 6.96-7.01 (m, 1H).
Reaction SMILES: [Cl-].[NH4+:2].C[Al](C)C.[F:7][C:8]1[C:9]([NH:34][CH:35]([C:41]([CH3:44])([CH3:43])[CH3:42])[CH2:36][C:37](OC)=O)=[N:10][C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([F:23])[CH:21]=3)[N:16]([S:24]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[CH:15]=2)=[N:12][CH:13]=1>C1(C)C=CC=CC=1>[F:7][C:8]1[C:9]([NH:34][CH:35]([C:41]([CH3:44])([CH3:43])[CH3:42])[CH2:36][C:37]#[N:2])=[N:10][C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([F:23])[CH:21]=3)[N:16]([S:24]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[CH:15]=2)=[N:12][CH:13]=1
Reactant: COC(=O)CC(Nc1nc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(F)cc23)ncc1F)C(C)(C)C
Reactant: [NH4+]
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC(CC#N)C(C)(C)C)n3)c3cc(F)cnc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ammonium chloride (0.12 g, 2.30 mmol) was suspended in toluene (4.5 mL). The mixture was cooled in an ice bath and AlMe3 (1.15 mL of a 2 M solution in toluene, 2.30 mmol) was added dropwise. The mixture was stirred 30 minutes and another 30 min at room temperature. A solution of racemic methyl 3-[[5-fluoro-2-[5-fluoro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-4-yl]amino]-4,4-dimethyl-pentanoate (0.25 g, 0.46 mmol) in 4.5 mL toluene was added and the resulting mixture was stirred 60° C. overnight. The reaction mixture was cooled in an ice bath and quenched with 1N HCl. The mixture was extracted with dichloromethane and filtered through a phase separator. The residue was purified on silica gel (EA/Hex): LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT=2.04 minutes (M+H) 511.42.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[C@H:5]([CH3:29])[CH2:6][C@H:7]([NH:21][C:22](=[O:28])[CH2:23][CH2:24][C:25](O)=[O:26])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[CH3:2].CCN=C=NCCCN(C)C.Cl.C1C=NC2N(O)N=NC=2C=1.[NH2:53][CH2:54][CH2:55][C:56]#[N:57].C(N(CC)CC)C.NC(C)C#N>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:30])[C@H:5]([CH3:29])[CH2:6][C@H:7]([NH:21][C:22](=[O:28])[CH2:23][CH2:24][C:25](=[O:26])[NH:57][CH2:56][CH2:55][C:54]#[N:53])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)CCC(=O)O
Reactant: N#CCCN
Agent: CC(N)C#N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)CCC(=O)NCCC#N
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
To a solution of (2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methyl-pentanoic acid ethyl ester (prepared by using the procedure described in US005217996) (200 mg, 0.486 mmol) in DMF (3 mL) are added EDC-HCl (112 mg, 0.583 mmol) and HOAt (79 mg, 0.583 mmol) at room temperature. After stirring for 10 minutes, 3-aminopropionitrile (41 mg, 0.583 mmol) and triethylamine (0.081 mL, 0.583 mmol) is added and stirred overnight. Additional EDC-HCl (66 mg, 0.292 mmol), HOAt (40 mg, 0.292 mmol), aminopropionitrile (21 mg, 0.292 mmol), and triethylamine (0.081 mL, 0.583 mmol) are added. After stirring for 1 hour, the reaction mixture is heated to 50° C. and stirred for 5 hours. The reaction mixture is diluted with ethyl acetate and washed with H2O and brine. The organic layer is dried over Na2SO4 and concentrated. The residue is purified by silica gel column chromatography to give (2R,4S)-5-biphenyl-4-yl-4-[3-(2-cyano-ethylcarbamoyl)-propionylamino]-2-methyl pentanoic acid ethyl ester. HPLC Retention time 1.37 minutes (condition B); MS 464 (M+1); 1H NMR (400 MHz, CDCl3) δ ppm 1.17 (d, J=7.33 Hz, 3H), 1.25 (t, J=7.07 Hz, 3H), 1.51 (ddd, J=4.29, 0.85, 14.14 Hz, 1H), 1.95 (ddd, J=4.29, 9.60, 13.89 Hz, 1H), 2.41-2.59 (m, 5H), 2.58 (t, J=6.57 Hz, 2H), 2.83 (d, J=6.57 Hz, 2H), 3.45 (ddd, J=2.53, 8.00, 12.0 Hz, 2H), 4.14 (ddd, J=2.53, 8.00, 14.01 Hz, 2H), 4.21-4.31 (m, 1H), 5.64 (d, J=9.09 Hz, 1H), 6.60-6.67 (m, 1H), 7.24 (d, J=8.34 Hz, 2H), 7.34 (t, J=7.33 Hz, 1H), 7.43 (t, J=7.83 Hz, 2H), 7.53 (d, J=8.34 Hz, 2H), 7.58 (d, J=7.07 Hz, 2H).