Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[C:7]([CH2:12]Br)[CH:6]=1)[CH3:2].[CH2:15]([O:22][C:23](=[O:27])[NH:24][CH2:25][CH3:26])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[H-].[Na+]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[C:7]([CH2:12][N:24]([C:23]([O:22][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:27])[CH2:25][CH3:26])[CH:6]=1)[CH3:2]
Reactant: CCNC(=O)OCc1ccccc1
Reactant: CCOC(=O)c1ccc(Br)c(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(Br)c(CN(CC)C(=O)OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
4-Bromo-3-bromomethyl-benzoic acid ethyl ester (2.95 g, 9.2 mmol) and ethyl-carbamic acid benzyl ester (3.30 g, 18.4 mmol) were combined in DMF (100 mL) and cooled to 0° C. Sodium hydride (60% in mineral oil; 0.772 g, 19.3 mmol) was added slowly, and the reaction was stirred at room temperature for 10 minutes. The mixture was quenched with H2O and 1N aqueous HCl (20 mL), and then extracted with 1:1 EtOAc:hexanes three times. The organic layer was washed with brine, and then dried and concentrated. The residue was purified by silica gel chromatography (0-100% EtOAc in hexanes) to give the title compound, as well as the hydrolyzed product, which was combined with the product from the next step.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:15]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[C:22]([NH2:26])(=[O:25])[CH:23]=[CH2:24].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CC#N>CCOC(C)=O.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:15]1(=[C:8]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:5]2[CH:6]=[CH:7][C:2](/[CH:24]=[CH:23]/[C:22]([NH2:26])=[O:25])=[CH:3][CH:4]=2)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: C=CC(N)=O
Reactant: Brc1ccc(C(=C2CCCCCC2)c2ccccc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: NC(=O)/C=C/c1ccc(C(=C2CCCCCC2)c2ccccc2)cc1
Yield: 33.7 %

Procedure:
A suspension of [(4-Bromophenyl)(phenyl)methylene]cycloheptane (1) (0.50 g, 1.47 mmol), TEA (1.21 mL, 8.71 mmol), acrylamide (0.62 g, 8.73 mmol), Pd(OAc)2 (0.080 g, 0.36 mmol), P(o-tolyl)3) (0.19 g, 0.63 mmol) and CH3CN was stirred at reflux under N2. After 2 h heating was discontinued and the reaction diluted with EtOAc (50 mL) and water (50 mL). The mixture was filtered through a celite pad and the filtrate transferred to a separatory funnel. The organic fraction was washed with brine (50 mL), dried (MgSO4), filtered and concentrated to an amber oil. This oil was purified by column chromatography on silica gel (50 g) using a hexanes to 25% EtOAc:hexanes to 100% EtOAc gradient to afford a pale yellow solid. Trituration of the solid with EtOAc (25 mL) yielded 164 mg (33%) of the title compound (4) as a white solid. 1H NMR (300 MHz, DMSO-d6): δ 1.54 (s, 8H), 2.24 (br s, 4H), 6.55 (d, J=15.9 Hz, 1H), 7.07 (br, 1H), 7.14-7.20 (m, 7H), 7.25 (d, J=15.9 Hz, 1H), 7.49 (d, J=8.1 Hz, 2H), 7.50 (br, 1H). LRMS (APCI): m/z 332 (M+H)+. Anal. Calcd for C23H25NO.0.1H2O: C, 82.67; H, 7.63; N, 4.19. Found: C, 82.75; H, 7.56; N, 4.20.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.O1CCOCC1.[CH3:26][NH:27][CH3:28]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]([N:27]([CH3:28])[CH3:26])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(-c2ccc(Cl)cc2)o1
Reactant: CNC
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: C1COCCO1
Product: CN(C)C(=O)c1ccc(-c2ccc(Cl)cc2)o1
Reaction time: 4 h

Procedure:
A mixture of 58 g (0.26 mole) of 5-(4-chlorophenyl)-2-furoic acid and 120 ml of thionyl chloride was heated under reflux for 3 hrs. The thionyl chloride was removed on a rotary evaporator. A small amount of benzene was added to the residual solid and then removed on a rotary evaporator. The furoyl chloride was dissolved in 300 ml of dioxane with stirring and treated dropwise with a solution of 300 ml of dioxane containing 26 g (0.58 mole) of dimethylamine, while maintaining the temperature between 15°-25°. The reaction solution was stirred at room temperature overnight and then at 80° for 4 hrs. with a small amount of solid forming. The mixture was added to 2000 ml of water and resulting solid was filtered and dried at 60° to yield 58 g (77%). An analytical sample was prepared by recrystallizing a sample from hexane, m.p. 101°-102°.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[C:3](=[O:20])[CH2:4][O:5][C:6]1[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:9]=[C:8]([C:17]([OH:19])=O)[CH:7]=1.[CH2:23]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:34](=[O:46])[C@@H:35]([NH2:45])[CH2:36][NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:30][CH2:29]1)=[O:27])[CH3:24].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.O>[CH2:23]([O:25][C:26]([N:28]1[CH2:29][CH2:30][N:31]([C:34](=[O:46])[C@@H:35]([NH:45][C:17]([C:8]2[CH:7]=[C:6]([O:5][CH2:4][C:3](=[O:20])[C:2]([CH3:1])([CH3:22])[CH3:21])[N:10]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:9]=2)=[O:19])[CH2:36][NH:37][C:38]([O:40][C:41]([CH3:43])([CH3:42])[CH3:44])=[O:39])[CH2:32][CH2:33]1)=[O:27])[CH3:24]
Reactant: CCOC(=O)N1CCN(C(=O)[C@@H](N)CNC(=O)OC(C)(C)C)CC1
Reactant: CC(C)(C)C(=O)COc1cc(C(=O)O)nn1-c1ccccc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CNC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)C(C)(C)C)n(-c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1.7 g of 5-(3,3-Dimethyl-2-oxo-butoxy)-1-phenyl-1H-pyrazole-3-carboxylic acid and 2.0 g of 4-((S)-2-Amino-3-tert-butoxycarbonylamino-propionyl)-piperazine-1-carboxylic acid ethyl ester in 10 ml of DMF, 0.9 g of HOBT and 1.1 g of EDC was added and the reaction mixture was stirred for 2 h at RT. Then, the reaction mixture was diluted with water and extracted with DCM. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 3.8 g.
Reaction SMILES: ON1C(=O)CCC1=O.[NH:9]([C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42])[C@@H:10]([C:38](O)=[O:39])[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[NH:37])[N:16]([C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18].[NH2:51][CH2:52][C:53]([OH:55])=[O:54]>>[NH:9]([C:41]([O:43][CH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)=[O:42])[C@@H:10]([C:38]([NH:51][CH2:52][C:53]([OH:55])=[O:54])=[O:39])[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[NH:37])[N:16]([C:27]([O:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:28])[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]
Reactant: N=C(NCCC[C@@H](NC(=O)OCc1ccccc1)C(=O)O)N(C(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reactant: NCC(=O)O
Agent: O=C1CCC(=O)N1O
Product: N=C(NCCC[C@@H](NC(=O)OCc1ccccc1)C(=O)NCC(=O)O)N(C(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Yield: 87 %

Procedure:
Cbz-D-Arg(Cbz)2-Gly-OH is prepared according to Example 1 by coupling the N-hydroxysuccinimide active ester of Cbz-D-Arg(Cbz)2-OH to glycine in a yield of 87%.
Reaction SMILES: [C:1]([C:4]1[C:8]([O:9][CH3:10])=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[N:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[N:5]=1)(O)=[O:2].[NH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.O.ON1C2C=CC=CC=2N=N1.C(=O)([O-])O.[Na+]>C(Cl)Cl.O>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[N:6]1[C:7]([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)=[C:8]([O:9][CH3:10])[C:4]([C:1](=[O:2])[NH:25][N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[N:5]1
Reactant: COc1c(C(=O)O)nn(-c2ccccc2Cl)c1-c1ccc(Cl)cc1
Reactant: NN1CCOCC1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COc1c(C(=O)NN2CCOCC2)nn(-c2ccccc2Cl)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a solution of 3-carboxy-1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-methoxy-1H-pyrazole (3.5 g, compound obtained in Reference Example 1(6)) in methylene chloride (100 mL) was added N-aminomorpholine (1.47 g), water-soluble carbodiimide HCl (2.76 g) and 1-hydroxybenzotriazole hydrate (2.21 g), and the mixture was stirred at room temperature overnight. To the reaction mixture was added an aqueous sodium hydrogencarbonate solution and the mixture was stirred and extracted with chloroform. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the crude product was purified by column chromatography on silica gel (solvent: hexane/ethyl acetate=40/60 to 20/80) to obtain 1-(2-chloro-phenyl)-5-(4-chlorophenyl)-4-methoxy-3-(N-morpholinocarbamoyl)-1H-pyrazole (3.49 g; yield: 81%) as a powder.
Reaction SMILES: C([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[NH:13][C:14]([C:16]1[CH:17]=[CH:18][C:19]([C:26]2[C:31]([Cl:32])=[C:30]([O:33][CH3:34])[CH:29]=[C:28]([O:35][CH3:36])[C:27]=2[Cl:37])=[C:20]2[C:25]=1[N:24]=[CH:23][CH:22]=[CH:21]2)=[O:15])C1C=CC=CC=1>CO.[Pd]>[NH:8]1[CH:12]=[CH:11][N:10]=[C:9]1[NH:13][C:14]([C:16]1[CH:17]=[CH:18][C:19]([C:26]2[C:31]([Cl:32])=[C:30]([O:33][CH3:34])[CH:29]=[C:28]([O:35][CH3:36])[C:27]=2[Cl:37])=[C:20]2[C:25]=1[N:24]=[CH:23][CH:22]=[CH:21]2)=[O:15]
Reactant: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3nccn3Cc3ccccc3)c3ncccc23)c1Cl
Agent: [Pd]
Solvent: CO
Product: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ncc[nH]3)c3ncccc23)c1Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 2.9 %

Procedure:
A suspension of 5-(2,6-dichloro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylic acid (1-benzyl-1H-imidazol-2-yl)-amide (Example 160) (100 mg, 1.16 mmol) and palladium hydroxyde (75 mg) in MeOH (5 mL) was stirred for 72 h at rt, under a hydrogen atmosphere. The reaction mixture was filtered through a pad of celite and concentrated. The residue was purified by silica gel column chromatography (Hex/EtOAc, 1:4) followed by trituration in Et2O to provide 15 mg of the title compound as a yellow solid: ES-MS: 442.9 [M+H]+; tR=4.05 min (System 1); TLC: Rf=0.08 (Hex/EtOAc, 1:4).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)([CH2:16][CH2:17][CH2:18][OH:19])[CH2:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.CC(C)=[O:30].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:16][CH2:17][C:18]([OH:30])=[O:19])([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:12][C:11]2=[O:27])[CH3:9])=[CH:6][CH:7]=1
Reactant: CC(C)=O
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)CC1=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCC(=O)O)(c2ccc(F)cc2)CC1=O
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a solution of (S)-1-((S)-1-(4-bromophenyl)ethyl)-4-(4-fluorophenyl)-4-(3-hydroxypropyl)piperidin-2-one (30 mg, 0.069 mmol) in acetone (2 mL) was added Jones reagent (0.3 mL, 2.5 M) at 0° C. The mixture was stirred for 0.5 h, diluted with EtOAc, and washed with water. The organic phase was concentrated to give the crude 3-((S)-1-((S)-1-(4-bromophenyl)ethyl)-4-(4-fluorophenyl)-2-oxopiperidin-4-yl)propanoic acid (28 mg, 90%), which was used for the next step without further purification.
Reaction SMILES: [OH:1][C:2]([CH3:11])([C:6](=[CH2:10])[CH2:7][CH2:8][CH3:9])[CH2:3][C:4]#[CH:5].N1C=CN=C1.CN(C)C=O.Cl[Si:23]([CH3:26])([CH3:25])[CH3:24]>O>[CH3:11][C:2]([O:1][Si:23]([CH3:26])([CH3:25])[CH3:24])([C:6](=[CH2:10])[CH2:7][CH2:8][CH3:9])[CH2:3][C:4]#[CH:5]
Reactant: C[Si](C)(C)Cl
Reactant: C#CCC(C)(O)C(=C)CCC
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: C#CCC(C)(O[Si](C)(C)C)C(=C)CCC
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of 25.77 g. of 4-hydroxy-4-methyl-5-methylene-1-octyne and 28.6 g. of imidazole in 50 ml. of dimethylformamide is added 22.9 g. of chlorotrimethylsilane. The mixture is stirred at room temperature for 40 minutes, poured into cold water and extracted with petroleum ether. The extract is washed with water and saturated sodium bicarbonate solution, dried over magnesium sulfate and the solvent is removed. The residue is distilled and the desired product recovered at 85°-87° C. (0.45 mm.) as a colorless liquid.
Reaction SMILES: S(C1C=CC(C)=CC=1)(OC1CCCC=1)(=O)=O.N[C:18]1[N:26]=[C:25]2[C:21]([NH:22][CH:23]=[N:24]2)=[C:20](Cl)[N:19]=1.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>CS(C)=O>[N:19]1[CH:20]=[C:21]2[C:25]([N:24]=[CH:23][NH:22]2)=[N:26][CH:18]=1
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Agent: Cc1ccc(S(=O)(=O)OC2=CCCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: c1ncc2[nH]cnc2n1
Temperature: 25 °C
Reaction time: 42 h

Procedure:
A mixture of the cyclopentenyl tosylate 2 (0.25 g, 0.58 mmol), 2-amino-6-chloropurine (0.212 g, 1.25 mmol, 2.2 eq), and K2CO3 (~1 g) was suspended in 2 mL of DMSO and stirred at room temperature for 42 h. The suspension was then poured into CH2Cl2 and washed with dilute NaCl. Evaporation of the CH2Cl2 gave an oil which was further dried under high vacuum to remove residual DMSO. Purification by preparative TLC (silica, 3:2 EtOAc:Hexane) gave two major purine containing products of which the faster moving and predominant was the desired N-9 alkylated purine 18 (0.117 g, 47%), mp 137°-140°; 1H-NMR (CDCl3) δ 1.35 (s, 3H, CH3), 1.46 (s, 3H, CH3), 4.27 (s, 2H, H-6'a,b), 4.61 and 4.62 (2H, PhCH2), 4.67 (d, J=5.3 Hz, 1H, H-2'), 5.10 (br s, 2H, NH2, exchangeable), 5.36 (d, J=5.3 Hz, 1H, H-3'), 5.43 (br s, 1H, H-1'), 5.78 (br s, 1H, H-5'), 7.34 (m, 5H, Ph), 7.65 (s, 1H, H-8); 13C-NMR (CDCl3) δ 25.8 (CH3), 27.2 (CH3), 64.3 (C-1'), 66.2 (C-6'), 72.8 (PhCH2), 83.7 (C-2'), 83.9 (C-3'), 112.4 (methylethylidene C), 122.7 (C-5'), 125.2 (d, J=12.6 Hz, C-5), 127.3 (Ph), 127.5 (Ph), 128.1 (Ph), 128.2 (Ph), 137.6 (Ph), 140.1 (dd, J=210 Hz, J'=4.4 Hz, C-8), 149.2 (C-4'), 151.0 (s, C-6), 153.2 (dd, J=4.7 Hz, J'=3.1 Hz, C-4), 159.1 (s, C-2).
Reaction SMILES: [C:1]([C:5]1[CH:40]=[CH:39][C:8]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2/[CH:17]=[CH:18]/[CH:19]([CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[CH:33][CH:32]=2)[CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C[Si]([N:45]=[N+:46]=[N-:47])(C)C.C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:40]=[CH:39][C:8]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2/[CH:17]=[CH:18]/[CH:19]([CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]3[NH:47][N:46]=[N:45][N:38]=3)=[CH:33][CH:32]=2)[CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)CCCCC(/C=C/c1ccccc1OCc1ccc(C(C)(C)C)cc1)CCc1ccc(C#N)cc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCCC(/C=C/c1ccccc1OCc1ccc(C(C)(C)C)cc1)CCc1ccc(-c2nnn[nH]2)cc1
Temperature: 80 °C

Procedure:
A solution of 1 g (1.86 mmol) of ethyl (7E)-8-{2-[(4-tert-butylbenzyl)oxy]phenyl}-6-[2-(4-cyanophenyl)ethyl]-oct-7-enoate in 70 ml of toluene is mixed with 3.7 ml (27.9 mmol) of trimethylsilyl azide and 694 mg (2.79 mmol) of di-n-butyltin oxide and heated at 80° C. for 12 hours. After cooling to room temperature, the mixture is washed with saturated sodium bicarbonate solution. The organic phase is separated off, washed with saturated sodium chloride solution and dried over sodium sulfate. After filtration, the filtrate is concentrated to dryness. The resulting crude product is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 4:1→1:1). 622 mg (1.1 mmol, 34% of theory) of a white foam are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.O.[C:12]1(=[O:17])[CH2:16][CH2:15][CH:14]=[CH:13]1.CCN(CC)CC>O1CCOCC1.[B-](F)(F)(F)F.C1C2C=CC1C=C2.C1C2C=CC1C=C2.[Rh]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:14]2[CH2:15][CH2:16][C:12](=[O:17])[CH2:13]2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(Br)cc1
Reactant: O=C1C=CCC1
Agent: [Rh]
Agent: C1=CC2C=CC1C2
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: O
Product: O=C1CC[C@H](c2ccc(Br)cc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.6 %

Procedure:
A solution of 4-bromophenylboronic acid (20 g, 100 mmol) in 1,4-dioxane (120 mL) in a 500 ml flask was purged with nitrogen for 5 mins. S-BINAP (0.992 g, 1.593 mmol) and bis(norbornadiene)rhodium (I) tetrafluoroborate (0.559 g, 1.494 mmol) were added sequentially to the solution under a positive pressure of nitrogen. After 2 hours of agitation at room temperature, water (20 mL) was added followed by cyclopent-2-enone (8.06 mL, 100 mmol) and Et3N (13.88 mL, 100 mmol). The mixture was allowed to stir at room temperature for 16 hours. The resulting dark solids were removed by filtration and the filtrate was poured into 250 ml of ethyl acetate. The solution was washed with water twice and the organic layer was concentrated. The residue was purified by flash column chromatography (split into two batches, each run on a 330 g silica column 0%-25% ethyl acetate in hexane) to afford 12.1 grams of (5)-3-(4-bromophenyl)cyclopentanone. HPLC purity was >98% and Chiral HPLC analysis indicated approximately 90% ee. The material was further purified under the Chiral SFC conditions described below. Experimental Details: Instrument: Berger SFC MGIII; Preparative Conditions: Column: CHIRALPAK® AD-H 25×5 cm, 5 μm; Column Temperature: 40° C.; Flow rate: 200 mL/min; Mobile Phase: CO2/MeOH=80/20; Detector Wavelength: 225 nm; Injection Vol.: 1.0 mL; Sample Preparation: 12.1 g in; 210 mL MeOH (Conc. 60 mg/ml); Analytical Conditions: Column: CHIRALPAK® AD 25×0.46 cm, 10 μm; Column Temperature: 40° C.; Flow rate: 2.0 min; Mobile Phase: CO2/MeOH=70/30; Detector Wavelength: 220 nm; Injection Vol.: 5 μL.
Reaction SMILES: [C:1]([Cl:4])(=O)C.Br.[NH2:6][CH:7]([CH2:11][CH2:12][Br:13])[C:8]([OH:10])=[O:9]>CO>[ClH:4].[Br:13][CH2:12][CH2:11][CH:7]([NH2:6])[C:8]([O:10][CH3:1])=[O:9]
Reactant: CC(=O)Cl
Reactant: NC(CCBr)C(=O)O
Agent: Br
Solvent: CO
Product: COC(=O)C(N)CCBr
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.5 %

Procedure:
Acetyl chloride (61 mL, 860 mmol) was added dropwise to 200 mL of MeOH at 0° C. The mixture was stirred at room temperature for 30 min, and 22.5 g (124 mmol) of 2-amino-4-bromo-butyric acid hydrobromide was added. The mixture was stirred overnight and concentrated. The residue was washed with Et2O to provide 23.5 g (82%) of methyl 4-bromo-2-amino-butyrate hydrochloride. A solution of 27.7 g (330 mmol) of NaHCO3 in 100 mL of water was slowly added to 19.2 g (82.5 mmol) of this material along with 21.6 g (99.0 mmol) of Boc2O in 140 mL of 1,4-dioxane at 0° C., The mixture was warmed to room temperature and stirred overnight. N,N-dimethylpropane-1,3-diamine (5 mL) was added to the mixture, and stirring was continued for 20 min. The mixture was diluted with water then extracted twice with EtOAc. The extracts were washed with water, 1M NaHSO4, and brine, and then combined, dried with Na2SO4, filtered, and concentrated to provide 21.5 g (88%) of 4-bromo-2-tert-butoxycarbonylamino-butyric acid methyl ester as a white solid.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([F:25])[CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)=[C:20]([F:25])[CH:19]=1
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Reactant: Nc1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(Oc2ccnc3[nH]c(=O)c4ccccc4c23)c(F)c1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 89.9 %

Procedure:
Compound 83 (250 mg, 1.08 mmol), 4-amino-2-fluoro-phenol (276 mg, 2.17 mmol), and cesium carbonate (1.41 g, 4.34 mmol) were suspended in DMF (5 mL), and stirred for 30 minutes at 120° C. in microwave. The reaction mixture was diluted with H2O. The resulting precipitate was filtered. The precipitate was tritturated with MeOH, filtered, washed with MeOH, and dried under vacuum to provide 182 (312 mg, 90% yield) as a solid. LC-MS (M+H=322, obsd.=322).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:24])([C@H:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[C:25]1([N:31]=[C:32]=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(#N)C.C(OCC)(=O)C>[NH:31]([C:32]([N:21]1[CH2:20][CH2:19][N:18]([C@H:16]([CH3:17])[C@:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])([OH:24])[CH2:10][N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)[CH2:23][CH2:22]1)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: C[C@@H](N1CCNCC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: O=C=Nc1ccccc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: C[C@@H](N1CCN(C(=O)Nc2ccccc2)CC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 84.6 %

Procedure:
To a ice cooled solution of (2R,3R)-2-(2,4-diflurophenyl)-3-(piperazin-1-yl)-1-(1H-1,2,4-triazole-1-yl)butan-2-ol 2 (150 mg, 0.44 mmol) in acetonitrile (10 ml) was added phenylisocyanate (60 mg, 0.5 mmol) in acetonitrile (4 ml). The reaction mixture was stirred at 0° C. for 2 h, diluted with 20 ml of ethyl acetate and successively washed with water, brine and dried over sodium sulphate. This organic extract was concentrated and the residue was purified by passing through a column of silica gel (hexane/EtOAc) to give the title compound as a colorless solid (170 mg, 84%).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]2[N:19]=[C:18]([C:20](OCC)=[O:21])[C:17]([N+:25]([O-])=O)=[C:16]([NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[O:35][CH3:36])[N:15]=2)[CH2:9]1)=O)(C)(C)C.ClC1N=C([C:44](OCC)=[O:45])C([N+]([O-])=O)=C(NC2C=CC=CC=2OC)N=1.C([N:68]1CCC(N)C1)(OC(C)(C)C)=O.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:36][O:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[N:28]1[C:44](=[O:45])[NH:25][C:17]2[C:16]1=[N:15][C:14]([NH:13][C@@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)=[N:19][C:18]=2[C:20]([NH2:68])=[O:21]
Reactant: CCOC(=O)c1nc(Cl)nc(Nc2ccccc2OC)c1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(N)C1
Reactant: CCOC(=O)c1nc(N[C@@H]2CCN(C(=O)OC(C)(C)C)C2)nc(Nc2ccccc2OC)c1[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-n1c(=O)[nH]c2c(C(N)=O)nc(N[C@@H]3CCNC3)nc21
Yield: 94 %

Procedure:
(R)-Ethyl 2-(1-(tert-butoxycarbonyl)pyrrolidin-3-ylamino)-6-(2-methoxyphenylamino)-5-nitropyrimidine-4-carboxylate. Ethyl 2-chloro-6-(2-methoxyphenylamino)-5-nitro-pyrimidine-4-carboxylate (See Example 30.A) (0.300 g, 0.852 mmol), (R) 1-boc-3-aminopyrrolidine (0.190 g, 1.022 mmol) and diisopropylethylamine (0.164 g, 1.27 mmol) were reacted according to General Procedure C, except at room temperature and in dimethylformamide (5 ml). The crude reaction mixture was condensed and purified using Biotage chromatography (0-100% ethyl acetate in hexanes) to afford the title compound (0.403 g, 94%). MS (ESI) m/z 503 [M+1]+.