Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[CH:10]=O)[CH2:4][CH2:3]1.Cl.CNC.[F-].[K+].[N+:22]([CH3:25])([O-:24])=[O:23]>C1(C)C=CC=CC=1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[CH:10]=[CH:25][N+:22]([O-:24])=[O:23])[CH2:4][CH2:3]1
Reactant: C[N+](=O)[O-]
Reactant: CN1CCN(c2ccccc2C=O)CC1
Agent: CNC
Agent: Cl
Agent: [F-]
Solvent: Cc1ccccc1
Product: CN1CCN(c2ccccc2C=C[N+](=O)[O-])CC1
Reaction time: 2 h

Procedure:
A mixture of 2-(4-methylpiperazin-1-yl)benzaldehyde (5 grams, 24.5 mmol, prepared according to the method of D. Reinhoudt et al., Synthesis, 1987, 641), dimethylamine hydrochoride (4 grams, 49 mmol), potassium fluoride (0.213 grams, 3.7 mmol) and nitromethane (100 mL) in anhydrous toluene (100 mL) was refluxed under nitrogen using a Dean Stark trap to collect the azeotroped water. After 2 hour the reaction was determined to be completed by thin layer chromatography using triethylamine: methanol: ethyl acetate (5:10:85). The solvents were removed in vacuo and the residue was partitioned between methylene chloride and saturated aqueous sodium carbonate. The organic layer was then washed with saturated sodium chloride, dried and concentrated to a red oil, 5.69 grams. Chromatography using silica gel on a 4×1.75 inch column, eluting with 100% ethyl acetate followed by increasing percentages of methanol, produced 4.03 grams of 1-methyl-4-[2-(2-nitrovinyl)-phenyl]-piperazine as a light orange solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[CH2:10][CH:11]([C:16]([F:19])([F:18])[F:17])[CH2:12][C:13]([OH:15])=O)=[CH:4][CH:3]=1.NC1C=CC=CC=1.C1(=O)OC(=O)CCC1.C(Cl)(=O)C>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9](=[O:20])[CH2:10][CH:11]([C:16]([F:19])([F:18])[F:17])[CH2:12][C:13]2=[O:15])=[CH:4][CH:3]=1
Reactant: O=C(O)CC(CC(=O)Nc1ccc(Br)cc1)C(F)(F)F
Agent: O=C1CCCC(=O)O1
Solvent: CC(=O)Cl
Solvent: Nc1ccccc1
Product: O=C1CC(C(F)(F)F)CC(=O)N1c1ccc(Br)cc1
Yield: 78.5 %

Procedure:
Into a 50 ml 1-necked, round-bottomed flask containing a stir bar were placed 2.50 g (7.96 mmol) N-(4'-bromophenyl)-3-(trifluoromethyl)glutaramic acid (prepared as described in Example 1 from the appropriate aniline and glutaric anhydride) and acetyl chloride (15 ml). The mixture was heated to reflux for 6 hours resulting in a clear, light grey solution. The acetyl chloride was removed via atmospheric distillation through a short path distillation head. The resulting light grey crystalline solid was triturated with hexanes, filtered and washed with hexanes to yield an off-white crystalline solid which was dried in vacuo at 50° C. to yield 2.10 g (89% yield) of product, m.p. 163°-4° C.
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C@H:12]([NH2:14])[CH3:13])=[CH:9][CH:10]=2)[CH:5]=[N:4]1.[F:15][C:16]([F:34])([F:33])[C:17]([C:20]1[CH:29]=[CH:28][C:27]2[CH2:26][C@H:25]([C:30](O)=[O:31])[CH2:24][CH2:23][C:22]=2[N:21]=1)([CH3:19])[CH3:18].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1>CN1C(=O)CCC1>[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C@H:12]([NH:14][C:30]([CH:25]3[CH2:24][CH2:23][C:22]4[N:21]=[C:20]([C:17]([CH3:19])([CH3:18])[C:16]([F:34])([F:33])[F:15])[CH:29]=[CH:28][C:27]=4[CH2:26]3)=[O:31])[CH3:13])=[CH:9][CH:10]=2)[CH:5]=[N:4]1
Reactant: CC(C)(c1ccc2c(n1)CC[C@@H](C(=O)O)C2)C(F)(F)F
Reactant: C[C@@H](N)c1ccc2[nH]ncc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: C[C@@H](NC(=O)C1CCc2nc(C(C)(C)C(F)(F)F)ccc2C1)c1ccc2[nH]ncc2c1
Temperature: 25 °C
Yield: 78.6 %

Procedure:
A 2 mL vial was charged sequentially with a solution of (R)-1-(1H-indazol-5-yl)ethanamine dihydrochloride (34 mg, 0.15 mmol) in NMP (0.2 mL, 2 mmol), a solution of (R)-2-(1,1,1-trifluoro-2-methylpropan-2-yl)-5,6,7,8-tetrahydroquinoline-6-carboxylic acid (38 mg, 0.13 mmol) and N,N-diisopropylethylamine (93 μL, 0.53 mmol) in NMP (0.1 mL). A solution of N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (61 mg, 0.16 mmol) in NMP (0.3 mL) was added to the resulting mixture and the solution stirred at room temperature. After 30 min the mixture was filtered and purified by reverse-phase HPLC (20-75% MeCN in 10 mM Et2NH/H2O) to afford the amide as a solid (44 mg, 76%). 1H NMR (400 MHz, DMSO-d6) δ 12.98 (br s, 1H), 8.38 (d, J=8.1 Hz, 1H), 8.04 (d, J=0.4 Hz, 1H), 7.66 (s, 1H), 7.50 (t, J=8.1 Hz, 1H), 7.34 (d, J=8.1 Hz, 1H), 5.06 (app pentet, J=7.3 Hz, 1H), 2.94-2.76 (m, 4H), 2.68-2.57 (m, 1H), 2.11-2.03 (m, 1H), 1.90-1.78 (m, 1H), 1.54 (s, 6H), 1.43 (d, J=7.0 Hz, 3H); m/z=431.3 (M+1)+.
Reaction SMILES: F[C:2]1[CH:3]=C(C=C(F)[CH:39]=1)C[C@H](C(N1[C@@H](CC2C=CC=CC=2)COC1=O)=O)[C@@H](C1COCCN1C(OC(C)(C)C)=O)O.Br[C:42]1[CH:43]=[C:44]([CH:83]=[C:84]([C:86]([O:88]C)=[O:87])[CH:85]=1)[C:45]([NH:47][C@@H:48]([CH2:74][C:75]1C=C(F)C=C(F)C=1)[C@@H]([C@H]1C[C@@H](OCCC)CN1C(OC(C)(C)C)=O)O[Si](C(C)(C)C)(C)C)=[O:46].C(O[C@H]1CN(C(OC(C)(C)C)=O)[C@@H](C(O)=O)C1)C=C.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N[C@@H](CC1C=C(F)C=C(F)C=1)[C@@H]([C@H]1C[C@@H](OCCC)CN1C(OC(C)(C)C)=O)O[Si](C(C)(C)C)(C)C>ClCCl>[CH2:39]([N:47]([CH2:48][CH2:74][CH3:75])[C:45]([C:44]1[CH:83]=[C:84]([CH:85]=[CH:42][CH:43]=1)[C:86]([OH:88])=[O:87])=[O:46])[CH2:2][CH3:3]
Reactant: CCCO[C@@H]1C[C@H]([C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(Br)cc(C(=O)OC)c2)N(C(=O)OC(C)(C)C)C1
Reactant: CC(C)(C)OC(=O)N1CCOCC1[C@@H](O)[C@H](Cc1cc(F)cc(F)c1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: C=CCO[C@@H]1C[C@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Agent: CCCO[C@@H]1C[C@H]([C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](N)Cc2cc(F)cc(F)c2)N(C(=O)OC(C)(C)C)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCN(CCC)C(=O)c1cccc(C(=O)O)c1
Reaction time: 0.33 h
Yield: 79 %

Procedure:
Step G (3): Preparation of (2R,4R)-tert-butyl 2-((1S,2S)-2-(3-bromo-5-(methoxycarbonyl)benzamido)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)propyl)-4-propoxypyrrolidine-1-carboxylate. To a solution of 3-bromo-5-(methoxycarbonyl)benzoic acid (Step G (2), 111 mg, 0.43 mmol) in dichloromethane (10 mL) and was added Hunig's base (108 mg, 0.84 mmol) to make a clear solution and HATU (167 mg, 0.44 mmol) was then added. After stirring for 20 min, the reaction mixture was added (2R,4R)-tert-butyl 2-((1S,2S)-2-amino-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)propyl)-4-propoxypyrrolidine-1-carboxylate (Example 1, Step 1 (A), 150 mg, 0.28 mmol) and the reaction mixture was stirred at rt overnight. The crude mixture was purified by silica gel flash Chromatography (0% to 10% to 20% EtOAc/Hexane step gradient) to give 170 mg of the title compound (79% yield): 1H NMR (CDCl3, 500 MHz) δ ppm 0.03 (3H, s), 0.06 (3H, s), 0.83 (9H, s), 0.88 (3H, m), 1.45-1.54 (11H, m), 1.96-2.02 (1H, m), 2.20 (1H, d, J=10 Hz), 2.67 (1H, dd, J=5, 15 Hz), 2.84 (1H, m), 3.27-3.38 (3H, m), 3.76 (1H, dd, J=5, 10 Hz), 3.91 (3H, s), 4.00 (1H, m), 4.05-4.11 (2H, m), 4.63 (1H, m), 6.61 (1H, m), 6.76 (2H, d, J=5 Hz), 8.25 (1H, m), 8.32 (1H, s), 8.53 (1H, s), 8.74 (1H, d, J=5 Hz). MS (ESI) (M+H)+ 771.32.
Reaction SMILES: C([O-])(C)(C)C.[K+].[C:7]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[C:12]2([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH2:27][CH3:28])[OH:19])#[N:8].[N:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][C:37]=2[S:39](Cl)(=[O:41])=[O:40])[CH:32]=[CH:31][CH:30]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(Cl)Cl>[CH2:27]([O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:12]1([OH:19])[C:11]2[C:15](=[CH:16][CH:17]=[C:9]([C:7]#[N:8])[CH:10]=2)[N:14]([S:39]([C:37]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:38]=2[N:29]=[CH:30][CH:31]=[CH:32]3)(=[O:40])=[O:41])[C:13]1=[O:18])[CH3:28]
Reactant: CCOc1ccccc1C1(O)C(=O)Nc2ccc(C#N)cc21
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOc1ccccc1C1(O)C(=O)N(S(=O)(=O)c2cccc3cccnc23)c2ccc(C#N)cc21
Reaction time: 1 h
Yield: 68.3 %

Procedure:
2.3 g (10.6 mMol) of potassium tert-butanolate are added to 5.5 g (18.7 mMol) of the intermediate 1b in 40 ml of DMF at 0° C. The reaction mixture was stirred for 1 h. Then 4.25 g (18.7 mMol) of 8-quinolinesulfonyl chloride were added at 0° C. The reaction solution was stirred at 0° C. for three hours and then at room temperature for 16 h. This reaction solution was poured into aqueous K2CO3 solution, resulting in a precipitate which was isolated. This solid was dissolved in methylene chloride, dried and concentrated in vacuo. The resulting residue was recrystallized from ethanol. 6.2 g of the product were obtained.
Reaction SMILES: [NH2:1][C:2]1([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>ClCCl>[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:1][C:2]2([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:4][CH2:3]2)=[O:25])=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)C1(N)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(NC(=O)c2ccc(Cl)cc2)CC1
Reaction time: 2 h
Yield: 98.2 %

Procedure:
Add ethyl 1-aminocyclopropanecarboxylate (89.2 g, 0.54 mol) to diisopropylethylamine (187.86 mL, 1.08 mol) in dichloromethane (900 mL) Immerse the flask in a cold water bath and slowly add 4-chlorobenzoic acid chloride (75.46 mL, 0.59 moles). After addition is complete, remove the bath, allow the reaction to equilibrate to 20° C., and stir for approximately 2 hours. Wash with 1N hydrochloric acid (HCl), followed by saturated sodium bicarbonate (NaHCO3), water, and then brine. Dry the organic layer over sodium sulfate (Na2SO4), filter, and concentrate under reduced pressure. Slurry the residue with heptane, filter, and rinse with heptane to give the title compound (142 g, 98%) as a white powder: MS (m/z): 268 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)(=[O:10])=[O:9].Br[CH2:20][C:21]([O:23]C(C)(C)C)=[O:22]>>[C:2]1([CH3:1])[C:3]([S:8]([N:11]([CH2:20][C:21]([OH:23])=[O:22])[C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=2)(=[O:9])=[O:10])=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1ccc(NS(=O)(=O)c2ccccc2C)cc1
Product: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccccc2C)cc1

Procedure:
prepared by reaction of 2-methyl-N-p-tolyl-benzenesulfonamide with tert-butyl bromoacetate
Reaction SMILES: [K].[C:2]([C:4](=[N:8][OH:9])[C:5]([NH2:7])=[O:6])#[N:3].C1(C)C=CC(S(O[CH2:20][CH2:21][N:22]2[CH:26]=[N:25][CH:24]=[N:23]2)(=O)=O)=CC=1>C(#N)C>[C:2]([C:4](=[N:8][O:9][CH2:20][CH2:21][N:22]1[CH:26]=[N:25][CH:24]=[N:23]1)[C:5]([NH2:7])=[O:6])#[N:3]
Reactant: Cc1ccc(S(=O)(=O)OCCn2cncn2)cc1
Reactant: N#CC(=NO)C(N)=O
Agent: [K]
Solvent: CC#N
Product: N#CC(=NOCCn1cncn1)C(N)=O

Procedure:
15.1 g (0.1 mol) of the potassium salt of 2-cyano-2-oximinoacetamide and 28.3 g (0.106 mol) of 1-(2-(p-toluenesulphonyloxy)-ethyl)-1,2,4-triazole in 100 ml of acetonitrile are heated at 80° C. for 10 hours. The solid product is separated off, and the acetonitrile solution is evaporated down in vacuo. The residue is recrystallized from boiling diethyl ketone. 13.4 g of 2-cyano-2-[2-(1,2,4-triazol-1-yl)-ethyl-oximino]-acetamide of melting point 137° C. are obtained: this is 64% of theory.
Reaction SMILES: [C:1]([C@@H:4]([C@H:8]1[C:12](=[O:13])[O:11][C:10]([CH3:15])([CH3:14])[O:9]1)[CH2:5][CH:6]=[CH2:7])([OH:3])=O.ON1C2N=CC=CC=2N=N1.Cl.CN(CCCN=C=NCC)C.Cl.[NH2:39][C@@H:40]([C:52]([CH3:55])([CH3:54])[CH3:53])[C:41]([NH:43][C@@H:44]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[CH3:45])=[O:42].C(N(C(C)C)CC)(C)C>ClCCl>[CH3:14][C:10]1([CH3:15])[O:9][C@@H:8]([C@@H:4]([CH2:5][CH:6]=[CH2:7])[C:1]([NH:39][C@H:40]([C:41]([NH:43][C@@H:44]([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH3:45])=[O:42])[C:52]([CH3:53])([CH3:54])[CH3:55])=[O:3])[C:12](=[O:13])[O:11]1
Reactant: C=CC[C@@H](C(=O)O)[C@@H]1OC(C)(C)OC1=O
Reactant: C[C@@H](NC(=O)[C@@H](N)C(C)(C)C)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC[C@@H](C(=O)N[C@H](C(=O)N[C@H](C)c1ccccc1)C(C)(C)C)[C@@H]1OC(C)(C)OC1=O
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A portion of the crude (4S)-4-[(1R)-1-carboxy-but-3-enyl]-2,2-dimethyl-1,3-dioxolan-5-one from b) above (calculated from the NMR to contain 1.54 g, 7.19 mmol) and 1-hydroxy-7-aza-1H-1,2,3-benzotriazole (1.09 g, 7.55 mmol) in anhydrous dichloromethane (30 mL) were mixed and cooled to 0° C. under nitrogen. N-(Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.60 g, 8.27 mmol) was added, and the mixture was stirred for 1.5 h at 0° C. (2S)-Amino-3,3-dimethyl-N-[(1R)-1-phenylethyl]butanamide hydrochloride (Preparation 1)(2.15 g, 7.55 mmol) was added, followed by diisopropylethylamine (1.37 mL, 7.55 mmol). After another 45 min, the mixture was allowed to warm to room temperature. After 3 h at room temperature, the mixture was partitioned between ethyl acetate (200 mL) and pH 7 aqueous phosphate buffer (100 mL). The organic layer was washed with sodium bicarbonate, brine, dried (Na2SO4), and concentrated under reduced pressure. The resulting foam crystallised upon addition of ether, and the white solid (1.89 g) was filtered off. Recystallisation from ethyl acetate/hexane gave (2R)-2-[(4S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]-N-[(1S)-2,2-dimethyl-1-({[(1R)-1-phenylethyl]amino}carbonyl)propyl]pent-4-enamide as a white solid (1.30 g, 42%, as a single diastereomer).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([CH:12]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]1)=[CH:5]2.[Li]CCCC.CON(C)[C:32](=[O:36])[CH2:33][CH2:34][CH3:35]>C1COCC1>[C:32]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([CH:12]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]1)=[CH:5]2)(=[O:36])[CH2:33][CH2:34][CH3:35]
Reactant: Cn1c(C2CCN(C(=O)OC(C)(C)C)C2)cc2cc(Br)ccc21
Reactant: CCCC(=O)N(C)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC(=O)c1ccc2c(c1)cc(C1CCN(C(=O)OC(C)(C)C)C1)n2C
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 69.9 %

Procedure:
To solution of tert-butyl 3-(5-bromo-1-methyl-1H-indol-2-yl)pyrrolidine-1-carboxylate (1.207 g, 3.18 mmol) in THF (13 mL) at −78° C. was added solution of n-BuLi (2.5M hexanes, 1.50 mL, 3.75 mmol) dropwise over 10 min. The reaction was stirred at −78° C. for 10 min, then a solution of N-methoxy-N-methylbutyramide (0.50 g, 3.81 mmol) in THF (2.0 mL) was added dropwise. The reaction was slowly allowed to warm to −50° C. before it was quenched with NH4Cl (aqueous saturated, 10 mL). Once ambient temperature was reached in the reaction mixture, the product was extracted with EtOAc (3×20 mL). Combined organics were washed with NaCl (aqueous saturated) and dried over Na2SO4. Upon solvent removal residue was purified by column chromatography using EtOAc/hexanes (gradient 0-60%) to afford tert-butyl 3-(5-butyryl-1-methyl-1H-indol-2-yl)pyrrolidine-1-carboxylate (0.823 g) in 70% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:49]=[CH:48][C:6]([CH2:7][N:8]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34]([OH:36])=O)=[CH:32][CH:31]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[CH2:50]([N:52]1[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1)[CH3:51]>>[CH3:47][O:46][C:43]1[CH:42]=[CH:41][C:40]([CH2:39][N:8]([CH2:7][C:6]2[CH:48]=[CH:49][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:31]=[CH:32][C:33]([C:34]([N:55]6[CH2:56][CH2:57][N:52]([CH2:50][CH3:51])[CH2:53][CH2:54]6)=[O:36])=[CH:37][CH:38]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:45][CH:44]=1
Reactant: CCN1CCNCC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)O)cc3)cn2)cc1
Product: CCN1CCN(C(=O)c2ccc(N3CCc4c(-c5cnc(N(Cc6ccc(OC)cc6)Cc6ccc(OC)cc6)nc5)nc(N5CCOCC5)nc43)cc2)CC1
Yield: 67.2 %

Procedure:
Using 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-benzoic acid (48.0 mg, 0.0728 mmol) obtained in Step A in Example 1-D-19 and N-ethylpiperazine (37.0 μl, 0.291 mmol) instead of 3-(aminomethyl)pyridine, in the same manner as Step B in Example 1-D-19, amidation was carried out, to obtain a crude product of {4-[4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl]-phenyl}-(4-ethyl-piperazin-1-yl)-methanone as a brown solid (37 mg), and then the PMB groups were removed according to the above Deprotection method 2, to obtain the desired compound (D-83) as a yellow powder (25.0 mg, 67%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N1C=CN=C1)([N:16]1[CH:20]=[CH:19]N=C1)=O.C(N(CC)CC)C.C(N)C>C1COCC1>[CH2:20]([NH:16][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:2]=1[Cl:1])[CH3:19]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CCN
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCNC(=O)c1cc([N+](=O)[O-])ccc1Cl
Reaction time: 1 h
Yield: 45.5 %

Procedure:
2-Chloro-5-nitrobenzoic acid (20 g, 100 mmol) in THF (200 mL) was treated with carbonyldiimidazole (CDI) (17.8 g, 110 mmol) and triethylamine (16 mL, 110 mmol) at room temperature. After 1 hr, a solution of ethylamine (70% in water, 10 mL) was added and the mixture was stirred for 18 h. Solvent was removed by evaporation and the residue was dissolved in methylene chloride, washed with 3% KOH solution followed by water (three times) until the aqueous phase extracts were colorless. The organic phase was dried over MgSO4, filtered, and the filtrate was concentrated to provide 10.4 g of N-ethyl-2-chloro-5-nitrobenzamide as light yellow crystals.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[NH2:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12]([CH3:21])([CH3:20])[C:13](=O)[NH:14][C:15]2=O)=[CH:10][CH:9]=1.[OH-].[Na+]>C1COCC1>[CH3:20][C:12]1([CH3:21])[C:11]2[C:16](=[CH:17][C:8]([NH2:7])=[CH:9][CH:10]=2)[CH2:15][NH:14][CH2:13]1
Reactant: CC1(C)C(=O)NC(=O)c2cc(N)ccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(C)CNCc2cc(N)ccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 61.3 %

Procedure:
To a stirred mixture of LiAlH4 (800 mg, 21 mmol) and anhydrous THF (30 mL) was added at 0° C. a solution of 7-amino-4,4-dimethylisoquinoline-1,3(2H,4H)-dione (500 mg, 2.5 mmol) in THF (5 mL). The mixture was stirred at room temperature under N2 for 24 h, and then carefully treated with wet THF, 10% aq. NaOH, and filtered through Celite. The filtrate was concentrated and the residue was dissolved in EtOAc (150 mL). The organic phase was washed with brine, dried (Na2SO4), and evaporated. The residue was purified by chromatography to give the title compound (270 mg, 63%).
Reaction SMILES: I.I.[N:3]1([C:10]2[N:14]([CH2:15][CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])[C:13]3[CH:22]=[CH:23][CH:24]=[CH:25][C:12]=3[N:11]=2)[CH2:9][CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH:38]=[N:37][N:36]=[N:35]2)=[CH:30][C:29]=1[C:39]([N:41]1[CH2:45][CH2:44][C@:43]([CH2:52][CH2:53]OS(C)(=O)=O)([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH2:42]1)=[O:40].C(N(CC)CC)C>C(#N)C>[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH:38]=[N:37][N:36]=[N:35]2)=[CH:30][C:29]=1[C:39]([N:41]1[CH2:45][CH2:44][C@@:43]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)([CH2:52][CH2:53][N:6]2[CH2:7][CH2:8][CH2:9][N:3]([C:10]3[N:14]([CH2:15][CH2:16][CH2:17][C:18]([F:21])([F:19])[F:20])[C:13]4[CH:22]=[CH:23][CH:24]=[CH:25][C:12]=4[N:11]=3)[CH2:4][CH2:5]2)[CH2:42]1)=[O:40]
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)N1CC[C@](CCOS(C)(=O)=O)(c2ccccc2)C1
Reactant: FC(F)(F)CCCn1c(N2CCCNCC2)nc2ccccc21
Agent: I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(-n2cnnn2)cc1C(=O)N1CC[C@](CCN2CCCN(c3nc4ccccc4n3CCCC(F)(F)F)CC2)(c2ccccc2)C1
Yield: 106.2 %

Procedure:
Reflux a solution of 2-[1,4]diazepan-1-yl-1-(4,4,4-trifluoro-butyl)-1H-benzoimidazole dihydroiodide (0.65 g, 1.12 immol), methanesulfonic acid 2-{(S)-1-[1-(2-methoxy-5-tetrazol-1-yl-phenyl)-methanoyl]-3-phenyl-pyrrolidin-3-yl}-ethyl ester (0.50 g, 1.06 mmol, example 47.2), triethylamine (3.58 mmol) and acetonitrile (15 mL) for 20 hours. Cool and concentrate in vacuo. Dilute with dichloromethane (150 mL), wash the organic phase with NaHCO3 solution (3×30 mL), dry (Na2SO4) the organic phase, filter and evaporate. Purify the residue by flash chromatography (silica gel, 7×15 cm) eluting with 10% methanol/0.1% ammonium hydroxide solution in dichloromethane and concentrate the appropriate fractions to afford 0.79 g of the title compound as a cream colored foam, Rf=0.46 (silica gel, 1.0% methanol/0.1% ammonium hydroxide solution in dichloromethane). The compound may be converted to the dihydrochloride salt by methods well known in the art.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=2[OH:18])[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:25][C:26]1[C:27](F)=[CH:28][C:29]([F:54])=[C:30]([S:32]([N:35]([CH2:43][C:44]2[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][C:45]=2[O:52][CH3:53])[C:36]2[N:41]=[CH:40][C:39]([F:42])=[CH:38][N:37]=2)(=[O:34])=[O:33])[CH:31]=1>CS(C)=O.O>[NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]([F:15])([F:17])[F:16])[CH:11]=[CH:10][C:9]=2[O:18][C:27]2[C:26]([Cl:25])=[CH:31][C:30]([S:32]([N:35]([CH2:43][C:44]3[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][C:45]=3[O:52][CH3:53])[C:36]3[N:37]=[CH:38][C:39]([F:42])=[CH:40][N:41]=3)(=[O:33])=[O:34])=[C:29]([F:54])[CH:28]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COc1ccc(CN(c2ncc(F)cn2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Reactant: Nc1cc(-c2cc(C(F)(F)F)ccc2O)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(CN(c2ncc(F)cn2)S(=O)(=O)c2cc(Cl)c(Oc3ccc(C(F)(F)F)cc3-c3ccnc(N)c3)cc2F)c(OC)c1
Reaction time: 18 h
Yield: 87.9 %

Procedure:
2-(2-Aminopyridin-4-yl)-4-(trifluoromethyl)phenol (Preparation 17, 0.93 g, 3.6 mmol) was taken up in dimethylsulfoxide (40 mL) and potassium carbonate (0.95 g, 6.9 mmol) was added followed by 5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(5-fluoropyrimidin-2-yl)benzenesulfonamide (Preparation 19, 1.73 g, 3.64 mmol). The reaction mixture was stirred for 18 hours then diluted with water (120 mL) and the solid collected by filtration. The filtrate was extracted with ethyl ether. The solid was dissolved in dichloromethane and combined with the ether extract. The combined organic solution was dried over anhydrous magnesium sulfate, treated with activated carbon and filtered through a pad of diatomaceous earth. The solvent was concentrated in vacuo to give a thick oil. The oil was purified by silica gel column chromatography (0 to 5% methanol in dichloromethane gradient elution) and concentrated in vacuo to afford the title compound as a glass (2.24 g).