Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]#[N:28])=[CH:17][CH:16]=2)[C:7](=[O:13])[N:8]([CH:10]2[CH2:12][CH2:11]2)[N:9]=1)[CH2:2][CH2:3][CH3:4].[NH:29]1C=N[N:31]=[N:30]1>C(Cl)Cl>[CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[NH:31][N:30]=[N:29][N:28]=3)=[CH:19][CH:20]=2)[C:7](=[O:13])[N:8]([CH:10]2[CH2:12][CH2:11]2)[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: c1nnn[nH]1
Reactant: CCCCc1nn(C2CC2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Solvent: ClCCl
Product: CCCCc1nn(C2CC2)c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 120 °C
Reaction time: 48 h
Yield: 34 %

Procedure:
The conversion of 5-n-butyl-2-cyclopropyl-4-[(2'-cyanobiphenyl-4-yl)methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one to the corresponding tetrazole was accomplished by the procedure of Example 9, Step E, except that it was stirred at 120° C. for 2 days. After work-up, the residue was taken up in CH2Cl2 and flash chromatographed over silica gel (5 mL for 0.091 mmole, gradient elution using 2-10% MeOH/CH2Cl2) to give the desired compound as an oil in 34% yield, homogeneous by TLC in 10% MeOH/CH2Cl2, mass spectrum (FAB) 416 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[NH:6][CH:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:3]=1.[H-].[Na+].FS([C:19](C(O)=O)([F:21])[F:20])(=O)=O.O>CC#N>[Cl:1][C:2]1[C:7]([O:8][CH:19]([F:21])[F:20])=[N:6][CH:5]=[C:4]([CH:3]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)c1c[nH]c(=O)c(Cl)c1
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1cnc(OC(F)F)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of methyl 5-chloro-6-oxo-1,6-dihydropyridine-3-carboxylate (3.810 g; 20.31 mmol) in anh. MeCN (400 ml) was treated portionwise with NaH (60% dispersion in mineral oil; 2.193 g; 54.84 mmol), and stirring at rt, under nitrogen, was continued for 20 min. FSO2CF2CO2H (6.149 g; 34.52 mmol) was then added dropwise, and the resulting heterogeneous mixture was further stirred at rt, under nitrogen, for 45 min. Water (10 ml) was slowly added, and MeCN was removed under reduced pressure. Water (150 ml) and AcOEt (150 ml) were added, and the separated aq. layer was further extracted with AcOEt (3×100 ml). The mixed organic layers were dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM) afforded methyl 5-chloro-6-(difluoromethoxy)nicotinate as an off-white solid. LC-MS (conditions A): tR=0.81 min.; no ionisation.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]([CH2:11][CH3:12])[C:9]#[N:10])[CH:3]=1.I[CH2:14][CH3:15].NC1N=CC(C2C=CN=C(C3(C#N)CCOCC3)C=2)=NC=1C1ON=C(C2C=CC(CNC)=CC=2)C=1>C1(C)C=CC=CC=1.O>[CH2:11]([C:8]([C:4]1[CH:3]=[C:2]([I:1])[CH:7]=[CH:6][N:5]=1)([CH2:14][CH3:15])[C:9]#[N:10])[CH3:12]
Reactant: CCC(C#N)c1cc(I)ccn1
Reactant: CCI
Agent: CNCc1ccc(-c2cc(-c3nc(-c4ccnc(C5(C#N)CCOCC5)c4)cnc3N)on2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCC(C#N)(CC)c1cc(I)ccn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
Crude 2-(4-iodo-2-pyridyl)butanenitrile (270 mg, 0.9923 mmol) was added to a solution of iodoethane (309.6 mg, 158.8 μL, 1.985 mmol) and bis(trimethylsilyl)azanide (sodium ion (1)) (992.3 μL of 1 M, 0.9923 mmol) in toluene (2 mL) at 0° C. The solution was stirred at 0° C. for 10 minutes. Reaction mixture was diluted with water and the product extracted with dichloromethane (×3). Organic extracts were combined, dried over MgSO4, filtered and concentrated in vacuo. (297.8 mg, assumed 100% yield). LC/MS m/z 301.02 [M+H]+
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C@H:8]([CH2:16]O)[CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].[C:19]1(=[O:29])[NH:23][C:22](=[O:24])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]12.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.O1CCCC1>>[CH:10]1([CH2:9][C@H:8]([NH:7][C:6](=[O:18])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:16][N:23]2[C:19](=[O:29])[C:20]3[C:21](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:22]2=[O:24])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CC1CCCCC1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.7 %

Procedure:
A mixture of tert-butyl[(1S)-2-cyclohexyl-1-(hydroxymethyl)ethyl]carbamate (3.3 g, 13 mmol), phthalimide (2.10 g, 14.3 mmol), triphenylphosphine (3.75 g, 14.3 mmol), diisopropyl azodicarboxylate (3.58 mL, 18.2 mmol) in tetrahydrofuran (30 mL, 400 mmol) was stirred at room temperature overnight. Direct purification by combi-flash chromatography afforded 2.8 g (56% yield) of the desired product. LC-MS found: 287.1 (M−Boc)+.
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([CH:21]=O)[C:17]=3[CH:23]=2)[C:3]1=[O:24].[CH2:25]([NH:29][CH2:30][CH2:31][SH:32])[CH2:26][CH2:27][CH3:28].C(O)C>O1CCCC1>[CH2:25]([N:29]1[CH2:30][CH2:31][S:32][CH:21]1[C:18]1[C:17]2[CH:23]=[C:13]([N:4]3[C:5](=[O:12])[CH:6]=[C:7]([C:8]([F:9])([F:11])[F:10])[N:2]([CH3:1])[C:3]3=[O:24])[CH:14]=[CH:15][C:16]=2[S:20][N:19]=1)[CH2:26][CH2:27][CH3:28]
Reactant: CCCCNCCS
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C=O)c3c2)c1=O
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCN1CCSC1c1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.7 %

Procedure:
A mixture of 5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-1,2-benzisothiazole-3-carboxaldehyde (0.500 g, 1.41 mmol), 2-(butylamino)ethanethiol (0.250 ml, 1.69 mmol), ethanol and tetrahydrofuran is stirred overnight at room temperature and concentrated in vacuo. The residue is chromatographed on silica gel with ethyl acetate-hexanes to afford the title compound as a light yellow solid (0.210 g, 31.7%, mp 78-82° C.) which is identified by NMR spectral analysis.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Br)[N:3]=1.[CH3:9][S-:10].[Na+]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:10][CH3:9])[N:3]=1
Reactant: C[S-]
Reactant: Brc1cccc(Br)n1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSc1cccc(Br)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2,6-dibromopyridine (200 mg, 0.844 mmol) in DMF (2 mL), was added sodium methanethiolate (65.1 mg, 0.929 mmol). The mixture was stirred at rt for 16 h, then was diluted with EtOAc. The organic phase was washed with water (2×) and brine, dried (Na2SO4) and concentrated. The crude residue was purified by flash chromatography (0 to 20% EtOAc/hexanes gradient) to afford Intermediate 165.1.
Reaction SMILES: [N:1]1([CH2:5][C@H:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([C:15]([F:18])([F:17])[F:16])[CH:9]=2)[NH2:7])[CH2:4][CH2:3][CH2:2]1.O[C:20]1[C:21]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([NH2:32])=[O:31])[C:22]=2[N:23]=[N:24][N:25]=1>>[N:1]1([CH2:5][C@@H:6]([NH:7][C:20]2[C:21]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([NH2:32])=[O:31])[C:22]=3[N:23]=[N:24][N:25]=2)[C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([C:15]([F:18])([F:16])[F:17])[CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: NC(=O)c1cccc2c(O)nnnc12
Reactant: N[C@H](CN1CCC1)c1ccc(Cl)c(C(F)(F)F)c1
Product: NC(=O)c1cccc2c(N[C@H](CN3CCC3)c3ccc(Cl)c(C(F)(F)F)c3)nnnc12

Procedure:
Compound 14 was prepared following general synthetic scheme 7 wherein (S)-2-(Azetidin-1-yl)-1-(4-chloro-3-(trifluoromethyl)phenyl)ethan-1-amine was reacted with 4-hydroxybenzo[d][1,2,3]-triazine-8-carboxamide to give the title compound. LC-MS [451 (M+1)], 1H NMR (400 MHz, DMSO-d6): δ 9.30 (s, 1H), 8.87 (d, 1H), 8.63 (d, 1H), 8.54 (d, 1H), 8.05-8.01 (m, 3H), 7.81 (d, 1H), 7.70 (d, 1H), 5.59 (d, 1H), 3.21-3.14 (m, 4H), 3.02 (t, 1H), 2.99-2.78 (m, 1H), 1.92 (t, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH3:20])=[CH:14][C:13]=2[OH:21])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[Na+].[I-].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CC(C)=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH3:20])=[CH:14][C:13]=2[O:21][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCCc1ccc(OS(=O)(=O)c2ccc(C)cc2)c(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1ccc(OS(=O)(=O)c2ccc(C)cc2)c(OCc2ccccc2)c1
Temperature: 40 °C
Reaction time: 5 h
Yield: 63.6 %

Procedure:
To a solution of 2-hydroxy-4-propylphenyl 4-methylbenzenesulfonate (0.11 mmol; 33 mg) under argon, in acetone (0.2 mL), were added K2CO3 (0.13 mmol; 18 mg), NaI (0.02 mmol; 3 mg), and benzylbromide (0.12 mmol; 0.015 mL). The reaction was stirred at 40° C. for 5 hr. The reaction mixture was then hydrolysed with NH4Cl sat. (3 mL) and extracted with ethyl acetate (3*5 mL). Combined organic phases were washed with saturated NaHCO3 (3 mL), dried over MgSO4, concentrated. The residue was purified by preparative TLC (dichlorométhane) to yield the title compound as a clear oil (28 mg; 0.07 mmol; 64%).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:13]3[C:14](=[O:32])[NH:15][C:16](=[O:31])[C:17]=3[C:18]3[C:26]4[C:21](=[CH:22][C:23]([N+:27]([O-])=O)=[CH:24][CH:25]=4)[N:20]([CH3:30])[CH:19]=3)=[CH:8][N:9]2[CH3:12])=[CH:5][CH:4]=1)#[N:2].O.O.[Sn](Cl)Cl.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>C(O)C>[NH2:27][C:23]1[CH:22]=[C:21]2[C:26]([C:18]([C:17]3[C:16](=[O:31])[NH:15][C:14](=[O:32])[C:13]=3[C:7]3[C:6]4[C:10](=[CH:11][C:3]([C:1]#[N:2])=[CH:4][CH:5]=4)[N:9]([CH3:12])[CH:8]=3)=[CH:19][N:20]2[CH3:30])=[CH:25][CH:24]=1
Reactant: Cn1cc(C2=C(c3cn(C)c4cc([N+](=O)[O-])ccc34)C(=O)NC2=O)c2ccc(C#N)cc21
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: Cn1cc(C2=C(c3cn(C)c4cc(C#N)ccc34)C(=O)NC2=O)c2ccc(N)cc21
Reaction time: 16 h
Yield: 78.3 %

Procedure:
3-(6-cyano-1-methyl-1H-indol-3-yl)-4-(1-methyl-6-nitro-1H-indol-3-yl)-pyrrole-2,5-dione (9.0 g, 21 mmole) was suspended in ethanol (1.8 L) and treated with tin (II) chloride dihydrate (35 g, 156 mmole). This was mechanically stirred for 16 h at reflux. The reaction was cooled and reduced in volume to 1L. This was poured into a mixture of ethyl acetate (2 L) and saturated sodium bicarbonate solution (1 L) and well mixed. The organic layer was decanted and washed with saturated sodium bicarbonate solution, dried over magnesium sulfate, filtered, evaporated, and then purified by flash column chromatography (ethyl acetate). The product was further purified by crystalization from tetrahydrofuran/hexane to provide 6.5 g of 3-[4-(6-amino-1-methyl-1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl]-1-methyl-1H-indole-6-carbonitrile; mp 255-260° C.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Cl.[CH2:11]([O:15][C:16](=[O:20])[CH:17]([CH3:19])[NH2:18])[CH:12]([CH3:14])[CH3:13]>>[CH2:11]([O:15][C:16](=[O:20])[C@H:17]([CH3:19])[NH:18][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)[CH:12]([CH3:14])[CH3:13]
Reactant: N#Cc1ccc(F)cc1
Reactant: CC(C)COC(=O)C(C)N
Agent: Cl
Product: CC(C)COC(=O)[C@H](C)Nc1ccc(C#N)cc1

Procedure:
Following General Procedure AP above and using 4-fluorobenzonitrile (Aldrich) and D,L-alanine iso-butyl ester hydrochloride (from Example AA above), the title compound was prepared as an oil. The product was recovered by column chromotography on silica gel using 1:5 EtOAc/hexanes as the eluent.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:43])[CH2:9][C@@H:10]([NH:18][C:19]([N:21]1[CH2:26][CH2:25][CH2:24][C@@H:23]([C@H:27]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)[O:28][CH2:29][CH2:30][CH2:31][C:32]([O:34]C)=O)[CH2:22]1)=[O:20])[CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:44][NH2:45].C(O)C>>[Cl:42][C:38]1[CH:37]=[C:36]([C@H:27]([O:28][CH2:29][CH2:30][CH2:31][C:32]([NH:45][CH3:44])=[O:34])[C@@H:23]2[CH2:24][CH2:25][CH2:26][N:21]([C:19]([NH:18][C@@H:10]([CH2:11][CH:12]3[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]3)[CH2:9][N:8]([CH3:43])[C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:20])[CH2:22]2)[CH:41]=[CH:40][CH:39]=1
Reactant: CN
Reactant: COC(=O)CCCO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)N[C@@H](CC2CCCCC2)CN(C)C(=O)OC(C)(C)C)C1
Solvent: CCO
Product: CNC(=O)CCCO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)N[C@@H](CC2CCCCC2)CN(C)C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
methyl 4-((R)—((R)-1-((S)-1-(tert-butoxycarbonyl(methyl)amino)-3-cyclohexylpropan-2-ylcarbamoyl)piperidin-3-yl)(3-chlorophenyl)methoxy)butanoate (70 mg, 0.11 mmol) was dissolved in the CH3NH2/C2H5OH (20 mL), which was stirred at rt overnight. After the reaction was completed, the solvent was removed in vacuo. The product was purified via preparative TLC to afford tert-butyl (S)-2-((R)-3-((R)-(3-chlorophenyl)(4-(methylamino)-4-oxobutoxy)methyl)piperidine-1-carboxamido)-3-cyclohexylpropyl(methyl)carbamate (50 mg, 71% yield), which was used immediately in the next step.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[C:5]([N:7]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]2[O:27][CH:26]=[C:25](Br)[C:24]=2[CH:29]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)=[O:6])[CH3:2].[CH:31]#[C:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]>>[CH2:1]([O:3][C:4](=[O:30])[C:5]([N:7]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]2[O:27][CH:26]=[C:25]([C:31]#[C:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:24]=2[CH:29]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)=[O:6])[CH3:2]
Reactant: CCOC(=O)C(=O)N(Cc1ccc(C(F)(F)F)cc1)Cc1ccc2occ(Br)c2c1
Reactant: C#CCCCCCCCC
Product: CCCCCCCCC#Cc1coc2ccc(CN(Cc3ccc(C(F)(F)F)cc3)C(=O)C(=O)OCC)cc12
Yield: 40 %

Procedure:
The same procedure as employed in the preparation of Example 226 (step c) but using ethyl{[(3-bromo-1-benzofuran-5-yl)methyl][4-(trifluoromethyl)benzyl]amino}(oxo)acetate and 1-decyne gave the title compound as a yellow oil (40%). 1H NMR (CDCl3, 300 MHz) δ 7.78 (s, 0.5H), 7.76 (s, 0.5H), 7.65 (d, 1H, J=7.9 Hz), 7.61 (d, 1H, J=7.9 Hz), 7.52-7.33 (m, 4H), 7.22 (m, 1H), 4.64 (s, 1H), 4.56 (s, 1H), 4.47 (s, 1H), 4.41 (s, 1H), 4.39 (q, 1H, J=7.2 Hz), 4.34 (q, 1H, J=7.2 Hz), 2.49 (m, 2H), 1.66 (m, 2H), 1.49 (m, 2H), 1.40-1.26 (m, 11H), 0.89 (t, 3H, J=6.8 Hz). M−(LC/MS(ESI)): 540.5; M+(LC/MS(ESI)): 542.7. HPLC (Condition A), Rt: 6.07 min (HPLC purity: 98.0%).
Reaction SMILES: [CH3:1][C@:2]12[C:10](=[O:11])[CH2:9][C@H:5]([C:6]1([CH3:8])[CH3:7])[CH2:4][CH2:3]2.[Br:12]Br.Br>C(O)C>[CH3:8][C:6]1([CH3:7])[C:2]2([CH3:1])[C:10]([CH:9]([Br:12])[CH:5]1[CH2:4][CH2:3]2)=[O:11]
Reactant: BrBr
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)C(=O)C2
Agent: Br
Solvent: CCO
Product: CC12CCC(C(Br)C1=O)C2(C)C
Reaction time: 3 h

Procedure:
D-camphor ([a]D20 -44.0°, c=7.5), in ethanol is prepared as follows Bromine (320 g) is added dropwise to d-camphor (304 g) at 80° C. over a period of three hours under stirring and the liquified reaction mixture is kept at the same condition for 3 hours. After hydrogen bromide is released by bubbling, the reaction mixture is poured into ice water (3 liters) and the resulting precipitate is recrystallized from ethanol (230 mol) to give d-3-bromocamphor (302 g), mp 76° C. [a]D20 -134° (c=10, EtOH). d-3-bromocamphor (231 g) is dissolved in chloroform (400 ml) and chlorosulfonic acid (233 g) are added dropwise to this solution over 1 hour at 50° C. The reaction mixture is refluxed for 12 hours and poured into iced water (1 liter). The layer and washings are neutralized with Ca(OH)2 (120 g), and precipitated CaSO4 is filtered off. To the filtrate (NH4)2CO3 (128 g) are added and the precipitated CaCO2 is removed. The filtrate is concentrated and crystallized crude ammonium d-bromocamphor sulfonic acid (152 g) is recrystallized from water (270 ml) to give ammonium d-bromocamphor sulfonic acid (102 g), mp. 270°-272° C.(dec), [a]D20 -85.3° (c=2, water), lit.[a]D22 -85.3° (c=4, water), [a]D20 -84.5° (c=1.6, water). Calculated for NH4C10H14O2 4SBr: C, 36.59: H, 5.53: N, 4.27. Ammonium d-bromocamphor sulfonic acid obtained above is passed through Amberlite IR-120, and the effluent is concentrated to dryness and used as free d-bromocamphor sulfonic acid monohydrate. Analysis: All samples are dried overnight in vacuo at 40° C. Melting points are measured with a Yamato MP-21 melting point apparatus in an unsealed capillary tube and are uncorrected. Optical rotations are measured with a Perkin-Elmer 141 automatic polarimeter.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:46][S:47]([CH3:50])(=[O:49])=[O:48])[CH:6]=[C:7]([C:9]2[C:17]3[C:16]([NH:18][C@H:19]([C:21]4[N:26]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[C:25](=[O:33])[C:24]5=[C:34]([CH3:37])[CH:35]=[CH:36][N:23]5[N:22]=4)[CH3:20])=[N:15][CH:14]=[N:13][C:12]=3[N:11](COCC[Si](C)(C)C)[CH:10]=2)[CH:8]=1.FC(F)(F)C(O)=O.N>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:46][S:47]([CH3:50])(=[O:49])=[O:48])[CH:6]=[C:7]([C:9]2[C:17]3[C:16]([NH:18][C@H:19]([C:21]4[N:26]([C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=5)[C:25](=[O:33])[C:24]5=[C:34]([CH3:37])[CH:35]=[CH:36][N:23]5[N:22]=4)[CH3:20])=[N:15][CH:14]=[N:13][C:12]=3[NH:11][CH:10]=2)[CH:8]=1
Reactant: COc1cc(NS(C)(=O)=O)cc(-c2cn(COCC[Si](C)(C)C)c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)c1
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(NS(C)(=O)=O)cc(-c2c[nH]c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)c1
Yield: 95.8 %

Procedure:
(S)—N-(3-Methoxy-5-(4-((1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)methanesulfonamide (42 mg, 0.05 mmol) was treated with trifluoroacetic acid (840 μl, 10.80 mmol) and a solution of ammonia (7N in methanol, 840 μl, 5.88 mmol) according to the method described in Example 27. The residue was purified using SP1® Purification System (0% to 15% dichloromethane-2-propanol) to obtain 28 mg (87% yield) of the title compound.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:13][CH2:14][C:15](Cl)=[O:16].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[Cl:13][CH2:14][C:15]([C:4]1[CH:5]=[CH:6][C:1]([CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:2][CH:3]=1)=[O:16]
Reactant: O=C(Cl)CCl
Reactant: COC(=O)CCc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)CCc1ccc(C(=O)CCl)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 72.9 %

Procedure:
A mixture of 50 g of methyl 3-phenylpropionate, 51.6 g of chloroacetyl chloride and 250 ml of dichloromethane was cooled to 0° C. The mixture was stirred at 0° to 10° C. and 122 g of aluminum chloride was added gradually into the mixture. The reaction mixture was then stirred at a room temperature for 2 hours. The reaction mixture was allowed to stand overnight, then the reaction mixture was poured into a mixture of ice-concentrated hydrochloric acid and was extracted with chloroform. The chloroform layer was washed with water, dried then chloroform was removed from the reaction mixture by distillation. The residue thus obtained was crystallized by adding isopropyl ether, and the crystals formed were collected by filtration, then recrystallized from ethanol to obtain 53.4 g of methyl 3-(4-chloroacetylphenyl)propionate in the form of needle-like crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@:5]1([CH2:19][C:20]([CH3:22])=[CH2:21])[CH2:9][C:8](=[O:10])[N:7]([C:11]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:18])[CH2:6]1)=[O:4]>CO.CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3]([C@@:5]1([CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:9][C:8](=[O:10])[N:7]([C:11]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:18])[CH2:6]1)=[O:4]
Reactant: C=C(C)C[C@]1(C(=O)OC)CC(=O)N(c2c(C)cccc2C)C1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)[C@@]1(CC(C)C)CC(=O)N(c2c(C)cccc2C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.5 %

Procedure:
10% Pd/C (120 mg) was added to a solution of (S)-1-(2,6-dimethyl-phenyl)-3-(2-methyl-allyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester (prepared from step d, 474 mg, 1.57 mmol) in MeOH (5 mL) and resulting black suspension was stirred at room temperature overnight under H2 gas using a balloon. The reaction mixture was then diluted with EtOAc (25 mL) and filtered through celite, washed with MeOH (25 mL) and volatiles from filtrate were evaporated to obtain crude product which was purified by flash chromatography (SiO2, 20→60% EtOAc/hexanes) to obtain (S)-1-(2,6-dimethyl-phenyl)-3-isobutyl-5-oxo-pyrrolidine-3-carboxylic acid methyl ester (450 mg, 94% yield). LC-MS: Rt (retention time): 2.55 min, MS: (ES) m/z 304.1 (M+H+).
Reaction SMILES: Br.[NH2:2][CH:3]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]=2[NH:5][C:4]1=[O:20].[NH4+].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[Ce+4].C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[K+].Br.C(O)(=O)C.[NH:65]1[C:69](=[O:70])[CH2:68][CH2:67][C@H:66]1[C:71](O)=[O:72].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(#N)C>[O:70]=[C:69]1[NH:65][C@H:66]([C:71]([NH:2][CH:3]2[N:9]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:7]3[CH:16]=[CH:17][CH:18]=[CH:19][C:6]=3[NH:5][C:4]2=[O:20])=[O:72])[CH2:67][CH2:68]1
Reactant: O=C1CC[C@@H](C(=O)O)N1
Reactant: NC1N=C(c2ccccc2)c2ccccc2NC1=O
Agent: Br
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: O=[N+]([O-])[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CC(=O)O
Product: O=C1CC[C@@H](C(=O)NC2N=C(c3ccccc3)c3ccccc3NC2=O)N1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 3-amino-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine hydrogen bromide (142 mg, 0.426 mmol), prepared by sequential treatment of an aqueous acetonitrile solution of the 4-methoxybenzyl derivative from example 5 with ammonium cerium IV nitrate, potassium tartrate solution and HBr/acetic acid-(L)-pyroglutamic acid (60.2 mg, 0.466 mmol), EDC (91 mg, 0.473 mmol), HOBT (63.5 mg, 0.473 mmol), and diisopropylethylamine (0.082 ml, 0.473 mmol) in DMF (5 ml) was stirred at room temperature for 18 hours. The resultant solution was concentrated in vacuo, and the residue partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The organic extract was washed with brine, dried, (MgSO4), filtered, and concentrated. The residue was purified by preparative HPLC (C18, eluted with a 5:95 to 40:60 water:acetonitrile). Lyophilization provided the titled compound as a 1:1 mixture of diastereomers.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[C:3]=1[NH2:9].C(OC([N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[CH2:23][C:24](O)=O)=O)(C)(C)C>>[Br:1][C:2]1[C:3]2[N:9]=[C:24]([CH2:23][CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22][NH:17]3)[NH:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(Br)c1N
Reactant: CC(C)(C)OC(=O)N1CCCCC1CC(=O)O
Product: Brc1cccc2[nH]c(CC3CCCCN3)nc12

Procedure:
The title compound was prepared using the method of Description 18 from 3-bromobenzene-1,2-diamine (0.50 g, 2.7 mmol) and 2-carboxymethyl-piperidine-1-carboxylic acid tert-butyl ester (0.65 g, 2.7 mmol), as a pale brown amorphous solid (0.70 g, 88%)