Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[C:7](=[O:12])[N:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1)[CH2:5]2.CN[C@@H]1CCCC[C@H]1NC.[I-:35].[Na+]>C(O)CCC.C(OCC)(=O)C.[Cu]I>[I:35][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[C:7](=[O:12])[N:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1)[CH2:5]2
Reactant: [I-]
Reactant: Cc1cc(Br)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: [Na+]
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: Cc1cc(I)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Temperature: 120 °C
Reaction time: 8 h
Yield: 85.9 %

Procedure:
To a solution of 5-Bromo-7-methyl-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (300 mg, 0.713 mmol) in butanol (3 ml), (1R,2R)—N,N′-dimethylcyclohexane-1,2-diamine (20 mg, 0.142 mmol), copper(I) iodide (13.6 mg, 0.07 mmol) and sodium iodide (214 mg, 1.43 mmol) were added. The resulting mixture was stirred at 120° C. overnight. After cooling, the mixture was diluted with ethyl acetate, washed with water, brine, dried over anhydrous sodium sulphate, filtered, concentrated. Column chromatography (30% EtOAc/Hexanes) provided the title compound as a yellow oil (274 mg, 85%). 1H NMR (300 MHz, CDCl3): δ 7.55-7.57 (m, 2H), 7.30-7.35 (m, 2H), 7.16-7.20 (m, 2H), 4.74 (s, 2H), 4.318 (s, 2H), 2.69 (s, 3H).
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=1.CON(C)[C:11](=[O:22])[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[N:14][CH:13]=1>C1COCC1>[CH3:7][N:6]1[C:2]([C:11]([C:12]2[CH:13]=[N:14][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:16][CH:17]=2)=[O:22])=[CH:3][N:4]=[CH:5]1
Reactant: CON(C)C(=O)c1ccc(C(F)(F)F)nc1
Reactant: Cn1cncc1Br
Solvent: C1CCOC1
Product: Cn1cncc1C(=O)c1ccc(C(F)(F)F)nc1
Temperature: 5.300000190734863 °C
Reaction time: 1 h

Procedure:
To a 3 L 4-neck flask equipped with an overhead stirrer, nitrogen bubbler, and thermocouple was added 5-bromo-1-methyl-1H-imidazole (47.96 g, 297.9 mmol), followed by THF (537 mL). To this room temperature solution was added isopropylmagnesium chloride/lithium chloride complex [1.3 M] (246.8 mL, 320.8 mmol) (addition temperature maintained between 16.6 and 25° C.) to afford a milky suspension and the reaction was stirred for 60 minutes and then cooled to 5.3° C. in an ice bath. To this mixture was added a solution of N-methoxy-N-methyl-6-(trifluoromethyl)nicotinamide (53.66 g, 229.14 mmol, Intermediate 15, step b) in THF (268.3 mL) (addition temperature between 5.3 and 5.6° C.) to afford an orange mixture. After addition, the reaction was warmed to room temperature over 2 hours. After stirring at room temperature for 18 hours, THF (200 mL) was added and the reaction was stirred for 2 hours. The reaction was then cooled to 4° C. with an ice bath and carefully quenched with 2N HCl to a pH=7, quenching temperature reached 12° C. The mixture was diluted with ethyl acetate (500 mL), phase split and the organic layer was washed with brine (2×200 mL) and dried over sodium sulfate, filtered, and the solvent was removed. Hot ether was added and then filtered to give the title compound as a solid.
Reaction SMILES: N#N.[C:3]([C:6]1[O:10][C:9]([CH2:11][N:12]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]3[N:21]=[CH:22][O:23][C:24]=3[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][CH2:32]O)[CH:26]=3)=[O:19])=[N:13]2)=[CH:8][CH:7]=1)(=[O:5])[CH3:4].C[CH2:35][N:36](C(C)C)[CH:37](C)C.CS(Cl)(=O)=O.CNC.C([O-])(O)=O.[Na+]>C(Cl)Cl.C1COCC1.CC(=O)OCC>[C:3]([C:6]1[O:10][C:9]([CH2:11][N:12]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]3[N:21]=[CH:22][O:23][C:24]=3[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][CH2:32][N:36]([CH3:37])[CH3:35])[CH:26]=3)=[O:19])=[N:13]2)=[CH:8][CH:7]=1)(=[O:5])[CH3:4]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(=O)c1ccc(Cn2ccc(NC(=O)c3ncoc3-c3cccc(CCO)c3)n2)o1
Agent: CNC
Agent: CS(=O)(=O)Cl
Agent: N#N
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)c3ncoc3-c3cccc(CCN(C)C)c3)n2)o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 5-[3-(2-hydroxy-ethyl)-phenyl]-oxazole-4-carboxylic acid [1-(5-acetyl-furan-2-ylmethyl)-1H-pyrazol-3-yl]-amide (51 mg, 0.12 mmol) in CH2Cl2 (1.0 mL) was treated with DIPEA (0.03 mL, 0.18 mmol) followed by methanesulfonyl chloride (0.01 mL, 0.15 mmol). The reaction mixture was stirred at rt for 2.5 h before dimethylamine (0.9 mL of a 2N solution in THF, 1.8 mmol) was and the reaction mixture was further stirred at rt for 2 h. EA (10 mL) and sat. aq. NaHCO3 (10 mL) were added and the aqueous layer was extracted with EA (10 mL). The combined organic extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by HPLC gave the title compound as a pale yellow oil. LC-MS-conditions 02: tR=0.76 min; [M+H]+=448.25.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]([C:15]([CH3:19])([CH3:18])[CH2:16][CH3:17])[CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)=[O:7])=[CH:4][CH:3]=1.[CH2:22]([C:24]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][CH3:40])[C:25]=1[NH:26][CH2:27][CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])[CH3:23].[OH-].[K+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([C:15]([CH3:19])([CH3:18])[CH2:16][CH3:17])[CH2:9][CH2:10][CH2:11][C:12]([N:26]([CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])[C:25]2[C:35]([CH2:39][CH3:40])=[CH:36][CH:37]=[CH:38][C:24]=2[CH2:22][CH3:23])=[O:14])=[O:7])=[CH:20][CH:21]=1
Reactant: CCC(C)(C)N(CCCC(=O)O)C(=O)c1ccc(Cl)cc1
Reactant: CCOC(=O)CCCNc1c(CC)cccc1CC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCc1cccc(CC)c1N(CCCC(=O)O)C(=O)CCCN(C(=O)c1ccc(Cl)cc1)C(C)(C)CC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-(p-chlorobenzoyl)-4-[(1,1-dimethylpropyl)amino]butyric acid and ethyl γ-(2,6-diethylanilino)butyrate and suitable processing, dissolving the evaporation residue in ethanol, adding an ethanolic solution of potassium hydroxide, stirring for 12 hours at room temperature and further processing yields N-[N-(p-chlorobenzoyl)-4-(1,1-dimethylpropylamino)butyryl]-4-(2,6-diethylanilino)butyric acid.
Reaction SMILES: C([C:3]1[C:4]([C:26]#[CH:27])=[C:5]([CH:9]=[CH:10][C:11]=1[C:12]1[CH:21]=[C:20]2[C:15]([C:16]([CH3:25])([CH3:24])[CH2:17][C:18]([CH3:23])([CH3:22])[O:19]2)=[CH:14][CH:13]=1)[C:6]([O-:8])=[O:7])C.[OH-].[K+]>>[CH3:22][C:18]1([CH3:23])[CH2:17][C:16]([CH3:24])([CH3:25])[C:15]2[C:20](=[CH:21][C:12]([C:11]3[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([C:26]#[CH:27])[CH:3]=3)=[CH:13][CH:14]=2)[O:19]1
Reactant: C#Cc1c(C(=O)[O-])ccc(-c2ccc3c(c2)OC(C)(C)CC3(C)C)c1CC
Agent: [K+]
Agent: [OH-]
Product: C#Cc1cc(-c2ccc3c(c2)OC(C)(C)CC3(C)C)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To 207.2 mg (0.572 mmol) of ethyl-4-(2,2,4,4-tetramethyl-7-chromanyl) ethynyl-benzoate (Compound 4) was added 5 ml of ethanolic KOH solution. The reaction mixture was stirred at room temperature for 48 hours and the solvent was then removed in vacuo. The residue was taken up with water and ether and the layers were separated. The aqueous layer was acidified to Ph~2 with 1N HCl and extracted with ether. The ether layer was then washed with water and saturated sodium chloride and then dried (MgSO4). The solvent was removed in vacuo to give the title compound as a pale yellow solid.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C([C:13]1[CH:18]=[C:17]([C:19]2[CH:27]=[C:26]3[C:22]([CH:23]=[CH:24][N:25]3[C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)=[CH:21][CH:20]=2)[CH:16]=[CH:15][C:14]=1[OH:34])(C)(C)C.N1C=CC=CC=1.O>C1COCC1>[Br:1][C:23]1[C:22]2[C:26](=[CH:27][C:19]([C:17]3[CH:18]=[CH:13][C:14]([OH:34])=[CH:15][CH:16]=3)=[CH:20][CH:21]=2)[N:25]([C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)[CH:24]=1
Reactant: CC(C)(C)c1cc(-c2ccc3ccn(-c4ccncc4)c3c2)ccc1O
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: O
Solvent: c1ccncc1
Product: Oc1ccc(-c2ccc3c(Br)cn(-c4ccncc4)c3c2)cc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
N-Bromosuccinimide (8.1 mg, 0.046 mmol) was added to a mixture solution of tert-butyl 4-(1-(pyridin-4-yl)-1H-indol-6-yl)phenol (10 mg, 0.035 mmol) in THF (0.5 mL) mixture solution at −78° C. After stirring at −78° C. for 2 hours, the mixture was further stirred at 0° C. for 1 hour and then pyridine (8.5 μL, 0.105 mmol) was added. After stirring at room temperature for 30 minutes, water was added and the mixture was extracted with ethyl acetate. The collected organic layer was washed with saturated sodium bicarbonate solution and brine, and then concentrated under reduced pressure by drying with anhydrous magnesium sulfate. The target compound was obtained as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][C@H:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH2:57]([O:59][C:60]([CH2:62][C@H:63]1[CH2:67][CH2:66][CH2:65][NH:64]1)=[O:61])[CH3:58].ClCl>O1CCCC1.ClCCl.C(O)C>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:64]1[CH2:65][CH2:66][CH2:67][C@@H:63]1[CH2:62][C:60]([O:59][CH2:57][CH3:58])=[O:61])=[O:5])[C:11]([NH:13][C@H:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: CCOC(=O)C[C@H]1CCCN1
Reactant: C[C@H](NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)C[C@H]1CCCN1C(=O)c1ccc(C(=O)N[C@@H](C)c2nc3cc(Cl)ccc3[nH]2)cc1Cl
Yield: 59 %

Procedure:
Prepared analogously to Example 1g from (1S)-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, TBTU, diisopropylethylamine, and (2R)-2-(ethoxy-carbonylmethyl)pyrrolidine in tetrahydrofuran. Yield: 59%; Rf value: 0.42 (silica gel: dichloromethane/ethanol=9:1); C25H26Cl2N4O4 (517.271); mass spectrum: (M+H)+=517/519/521 (chlorine isotope).
Reaction SMILES: [CH3:1][C:2]([NH:5][S:6]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])[CH3:3].[H-].[Na+].Br[CH2:21][CH2:22][O:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][O:25]1.[NH4+].[Cl-]>CN(C=O)C.O>[CH3:4][C:2]([NH:5][S:6]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:21][CH2:22][O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)[CH:10]=1)(=[O:8])=[O:7])([CH3:1])[CH3:3]
Reactant: CC(C)(C)NS(=O)(=O)c1c[nH]c2ccccc12
Reactant: BrCCOC1CCCCO1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)NS(=O)(=O)c1cn(CCOC2CCCCO2)c2ccccc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 86.9 %

Procedure:
A solution of 5.0 g (0.020 mol) of N-(1,1-dimethylethyl)-1H-indole-3-sulfonamide in 30 mL anhydrous DMF was cooled to 10° C. under nitrogen atmosphere and was treated slowly with 0.87 g (0.022 mol) 60% sodium hydride (oil dispersion). The mixture was stirred for 20 minutes at room temperature then recooled to 10° C., whereupon 5.0 g (0.024 mol) of 2-(2'-bromoethoxy)tetrahydropyran (J. Org. Chem., Vol. 50, p. 4243, 1985) was added followed by heating to 70° C. for 3 hours. After cooling in an ice bath, 20 mL of saturated NH4Cl solution plus 20 mL of water was added and the mixture was extracted twice with ethyl acetate. The organic extract was washed twice with dilute HCl solution, then brine followed by drying (MgSO4) and evaporation in vacuo. The residue was triturated and collected by filtration with n-butyl chloride to afford 6.61 g of the title compound, m.p. 125°-132° C.
Reaction SMILES: CC(P(C(C)(C)C)C1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][CH:9]=[CH:8][CH:7]=1)(C)C.C(N(CC)CC)C.[C:29]1([C:35]#[C:36][P:37](=[O:42])([OH:41])[O:38][CH2:39][CH3:40])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(C1C=CC=CC=1)CCC#C>[Au].ClC(Cl)C>[C:29]1([C:35]#[C:36][P:37](=[O:41])([O:42][C:8]([CH2:9][CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH2:7])[O:38][CH2:39][CH3:40])[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Reactant: CCOP(=O)(O)C#Cc1ccccc1
Agent: [Au]
Agent: C#CCCCc1ccccc1
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: C=C(CCCc1ccccc1)OP(=O)(C#Cc1ccccc1)OCC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 74 %

Procedure:
A gold (Ag(I)) catalyst {[Au(JohnPhos)NCCH3]|SbF6—} [JohnPhos:(2-biphenyl)di-tert-butylphosphine] (11.3 mg, 0.015 mmol) and triethylamine (Et3N) (3.0 mg, 0.03 mmol) were put into a reaction container, and dichloroethane (0.4 mL) was put thereinto. After stirring at room temperature for 5 minutes, ethyl hydrogen phenylethynylphosphonate) (63.0 mg, 0.3 mmol) diluted with 0.5 mL of dichloroethane was added thereto, and finally, pent-4-ynylbenzene (86.5 mg, 0.6 mmol) was put thereinto. Then, when all of the starting materials disappeared in the TLC, the reaction was allowed to be completed. After the solvent was removed under low atmospheric pressure, the product was separated by chromatography to obtain ethyl 5-phenylpent-1-en-2-yl phenylethynylphosphonate (78.7 mg, 74%) which is a title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:12]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[F:20])[N:11]=[C:10]([C:21]3[CH:22]=[N:23][NH:24][CH:25]=3)[C:4]=2[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[O:26]1[CH2:31][CH2:30][CH:29](O)[CH2:28][CH2:27]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(/C(OC(C)(C)C)=O)=N\C(OC(C)(C)C)=O>O1CCCC1.O>[Cl:1][C:2]1[C:3]2[N:12]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[F:20])[N:11]=[C:10]([C:21]3[CH:25]=[N:24][N:23]([CH:29]4[CH2:30][CH2:31][O:26][CH2:27][CH2:28]4)[CH:22]=3)[C:4]=2[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncc(Cl)c2c1c(-c1cn[nH]c1)nn2-c1c(F)cccc1F
Reactant: OC1CCOCC1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COc1ncc(Cl)c2c1c(-c1cnn(C3CCOCC3)c1)nn2-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 7-chloro-1-(2,6-difluorophenyl)-4-methoxy-3-(1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine in tetrahydrofuran (3 mL) were added tetrahydro-2H-pyran-4-ol (0.160 ml), triphenylphosphine (527 mg) and di-tert-butyl (E)-diazene-1,2-dicarboxylate (2.505 ml) at room temperature, and the mixture was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (140 mg).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:33]([CH:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[C:6]=1[CH3:39])=[O:4].[OH-].[Li+]>CO.O.C(Cl)Cl.O>[C:29]([O:28][C:26]([N:23]1[CH2:24][CH2:25][N:20]([C:17]2[CH:18]=[CH:19][C:14]([NH:13][C:10]3[N:11]=[CH:12][C:7]4[C:6]([CH3:39])=[C:5]([C:3]([OH:4])=[O:2])[N:33]([CH:34]5[CH2:35][CH2:36][CH2:37][CH2:38]5)[C:8]=4[N:9]=3)=[N:15][CH:16]=2)[CH2:21][CH2:22]1)=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: COC(=O)c1c(C)c2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n1C1CCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: Cc1c(C(=O)O)n(C2CCCC2)c2nc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)ncc12
Temperature: 25 °C
Yield: 43.1 %

Procedure:
To a suspension of 2-[5-(4-tert-Butoxycarbonyl-piperazin-1-yl)-pyridin-2-ylamino]-7-cyclopentyl-5-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid methyl ester (250 mg, 0.467 mmol) (prepared as described in the procedure for the synthesis of Example 384), in MeOH/H2O/DCM (70 mL) is added a solution of lithium hydroxide (39.2 mg, 0.93 mmol) in water (15 mL). The reaction mixture is heated to reflux for 4 hours. The reaction mixture is allowed to cool to room temperature and concentrated in vacuo. The resulting solution is acidified to pH˜3 using saturated aqueous citric acid solution. The solution is evaporated and the residue is purified by preparative HPLC to give 2-[5-(4-tert-Butoxycarbonyl-piperazin-1-yl)-pyridin-2-ylamino]-7-cyclopentyl-5-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid as a yellow solid (105 mg, 53%). [M+H]+=522.3
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[Cu][C:13]#[N:14]>CN1C(=O)CCC1.O>[NH2:4][C:3]1[CH:5]=[CH:6][C:7]([CH:9]([CH3:11])[CH3:10])=[CH:8][C:2]=1[C:13]#[N:14]
Reactant: CC(C)c1ccc(N)c(Br)c1
Reactant: N#C[Cu]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)c1ccc(N)c(C#N)c1
Temperature: 25 °C
Yield: 57.1 %

Procedure:
Combine 2-bromo-4-isopropyl aniline (7.5 g, 35 mmol) and copper (I) cyanide (3.76 g, 42 mmol) in NMP (30.0 mL) and heat at 200° C. for 2 hours. Cool to ambient temperature and dilute with water (300 mL). Extract with ethyl acetate to give 4.58 g of the crude product. Silica gel chromatography, eluting with methylene chloride, gives 3.20 g of the title compound as a red oil: mass spectrum (ion spray): m/z=161 (M+1); 1H NMR (300 MHz, DMSO-d6): δ 7.21 (m, 2H), 6.73 (d, 1H), 5.79 (s, 2H), 2.73 (quintet, 1H), 1.12 (d, 6H).
Reaction SMILES: ClC(Cl)C.[NH2:5][CH2:6][C@@H:7]1[C@@H:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:10][N:9]([C:18]([O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([O:29][CH3:30])=[O:28])=[CH:23][CH:22]=2)=[O:19])[CH2:8]1.[C:31]([C:34]1[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[S:36][CH:35]=1)(=O)[CH3:32].[BH4-].[Na+]>CO.C(O[Ti](OC(C)C)(OC(C)C)OC(C)C)(C)C>[S:36]1[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[C:34]([CH:31]([NH:5][CH2:6][C@@H:7]2[C@@H:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:10][N:9]([C:18]([O:20][C:21]3[CH:22]=[CH:23][C:24]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:26]=3)=[O:19])[CH2:8]2)[CH3:32])=[CH:35]1
Reactant: COC(=O)c1ccc(OC(=O)N2C[C@H](CN)[C@@H](c3ccccc3)C2)cc1
Reactant: CC(=O)c1csc2ccccc12
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CO
Product: COC(=O)c1ccc(OC(=O)N2C[C@H](CNC(C)c3csc4ccccc34)[C@@H](c3ccccc3)C2)cc1
Reaction time: 2 h
Yield: 55 %

Procedure:
A 1.0 ml dichloroethane solution of 119 mg of 4-(methoxycarbonyl)phenyl(3S,4S)-3-(aminomethyl)-4-phenylpyrrolidine-1-carboxylate and 62 mg of 3-acetylbenzothiophene was mixed with 0.12 ml of tetraisopropoxy titanium and stirred for 2 hours. The reaction solution was diluted with 1.0 ml of methanol, mixed with 38 mg of sodium borohydride, further stirred for 1 hour and then concentrated under a reduced pressure, and the thus obtained was purified by a silica gel chromatography (chloroform-methanol) to obtain 95 mg of 4-(methoxycarbonyl)phenyl(3S,4S)-3-({[1-(1-benzothien-3-yl)ethyl]amino}methyl)-4-phenylpyrrolidine-1-carboxylate as a yellow amorphous substance. EP: 515.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([C:18]([O:20]CC)=[O:19])=[C:5]2[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(C(C)C)CC)(C)C.[F:38][C:39]([F:52])([F:51])[O:40][C:41]1[CH:46]=[CH:45][C:44]([S:47](Cl)(=[O:49])=[O:48])=[CH:43][CH:42]=1.O.[OH-].[Li+]>C(Cl)Cl>[CH2:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][S:47]([C:44]3[CH:43]=[CH:42][C:41]([O:40][C:39]([F:38])([F:51])[F:52])=[CH:46][CH:45]=3)(=[O:49])=[O:48])=[CH:10][CH:9]=2)[C:5]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[C:6]1[C:18]([OH:20])=[O:19])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1c(-c2ccccc2)c2cc(N)ccc2n1Cc1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: O=C(O)c1c(-c2ccccc2)c2cc(NS(=O)(=O)c3ccc(OC(F)(F)F)cc3)ccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.5 %

Procedure:
Ethyl 5-amino-1-benzyl-3-phenyl-1H-indole-2-carboxylate (0.23 g, 0.67 mmol) was dissolved in 7 mL of methylene chloride. To the solution was added diisopropylethylamine (0.5 mL, 2.9 mmol) and 4-trifluoromethoxy-benzenesulfonyl chloride (0.13 g, 0.5 mmol). After being stirred at room temperature overnight the reaction was concentrated and the residue was re-dissolved in 10 mL of 2:1:1 THF/MeOH/water. Lithium hydroxide monohydrate (0.15 g, 3.6 mmol) was added and the mixture was stirred at 40° C. overnight. Most of the organic solvents was removed and the reaction mixture was made acidic (pH 6) with glacial acetic acid, and the solid was collected and purified by semi-preparative HPLC (Column: Phenomenex C18 Luna 21.6 mm×60 mm, 5 μM; Solvent A: Water (0.1% TFA buffer); Solvent B: Acetonitrile (0.1% TFA buffer); Solvent Gradient: Time 0: 0% B; 10 min: 100% B; Hold 100% B 5 min. Flow Rate: 22.5 mL/min). The product was collected based on UV absorption and concentrated to give the title compound as a pale yellow solid (0.16 g, 45%):
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[F:16][C:17]1[CH:33]=[CH:32][C:20]([O:21][C:22]2[N:27]=[CH:26][C:25]([CH:28]([NH2:30])[CH3:29])=[CH:24][C:23]=2[CH3:31])=[CH:19][CH:18]=1>>[Cl:14][C:13]1[C:3]2[CH2:2][N:30]([CH:28]([C:25]3[CH:26]=[N:27][C:22]([O:21][C:20]4[CH:19]=[CH:18][C:17]([F:16])=[CH:33][CH:32]=4)=[C:23]([CH3:31])[CH:24]=3)[CH3:29])[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: Cc1cc(C(C)N)cnc1Oc1ccc(F)cc1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Agent: Cl
Product: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)cnc1Oc1ccc(F)cc1
Yield: 84 %

Procedure:
The title compound is prepared in 84% yield (120 mg, brown solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (100 mg, 0.36 mmol, Step-1 of Intermediate-1) and 1-(6-(4-fluorophenoxy)-5-methylpyridin-3-yl)ethanamine hydrochloride (120 mg, 0.43 mmol, Amine-39, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[N:6]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:7](=[O:18])[C:8]2[C:13]([C:14]([F:17])([F:16])[F:15])=[N:12][O:11][C:9]=2[N:10]=1)[CH2:3][CH3:4].[C:26]([O:30][C:31](=[O:37])[NH:32][CH2:33][CH2:34][CH:35]=O)([CH3:29])([CH3:28])[CH3:27].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].O>CO>[C:26]([O:30][C:31](=[O:37])[NH:32][CH2:33][CH2:34][CH2:35][NH:1][CH:2]([C:5]1[N:6]([CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:7](=[O:18])[C:8]2[C:13]([C:14]([F:16])([F:15])[F:17])=[N:12][O:11][C:9]=2[N:10]=1)[CH2:3][CH3:4])([CH3:29])([CH3:28])[CH3:27]
Reactant: CCC(N)c1nc2onc(C(F)(F)F)c2c(=O)n1Cc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCC(NCCCNC(=O)OC(C)(C)C)c1nc2onc(C(F)(F)F)c2c(=O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.8 %

Procedure:
To a solution of 10 (0.358 mmol) in MeOH (5.0 mL) was added (3-oxo-propyl)-carbamic acid tert-butyl ester (116 mg, 0.671 mmol), followed by NaBH(OAc)3 (142 mg, 0.671 mmol). The reaction mixture was stirred at room temperature for 3 h. Water was added to quench the reaction, the aqueous phase was extracted with EtOAc three times. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by SiO2 chromatography (EtOAc:heaxanes/1:2) to give 11 (120 mg, 53%). 1H NMR (CDCl3): δ 7.35–7.18 (m, 5H), 5.67 (d, J=15.9 Hz, 1H), 5.18 (d, J=15.9 Hz, 1H), 7.47–7.34 (m, 5H), 5.73–5.66 (m, 2H), 5.48–5.46 (m, 1H), 4.92–4.91 (m, 1H), 2.02–1.80 (m, 2H), 1.46 (s, 9H), 0.92 (t, J=7.14 Hz, 3H).