Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH2:9][NH:8][CH2:7][CH2:6]2.[Br:15][CH2:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)=[O:18]>C(O)C.C(Cl)Cl>[BrH:15].[N+:25]([C:22]1[CH:21]=[CH:20][C:19]([C:17](=[O:18])[CH2:16][N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:9]2)=[CH:24][CH:23]=1)([O-:27])=[O:26]
Reactant: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Reactant: COc1cc2c(cc1OC)CNCC2
Solvent: CCO
Solvent: ClCCl
Product: Br
Product: COc1cc2c(cc1OC)CN(CC(=O)c1ccc([N+](=O)[O-])cc1)CC2
Temperature: 25 °C
Yield: 31.9 %

Procedure:
A solution of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (15.63 g) and 2-bromo-4'-nitroacetophenone (16.47 g) in a mixture of ethanol (150 ml) and methylene chloride (150 ml) was heated at 60° for 24 hours. After cooling to room temperature yellow crystals appeared. These were collected by filtration and dried in vacuo to give the title compound (9.4 g); MP: 216°. NMR(D6 -DMSO) includes signals at d 3.6(6H,s,2×OCH3); 4.2(2H,s,N--CH2 --Ph); 4.95(2H,s,CO--CH2 --N); 6.6(2H,aromatics isoquinoline); 8(4H,m,aromatics).
Reaction SMILES: O.[NH2:2][NH2:3].[OH-].[Na+].[CH3:6][CH2:7][O:8][C:9](C)=[O:10].[CH2:12]1[CH2:16][O:15][CH2:14][CH2:13]1>>[CH3:6][C:7]1([O:8][C:9](=[O:10])[NH:2][NH2:3])[CH2:13][CH2:14][O:15][CH2:16][CH2:12]1
Reactant: NN
Reactant: CCOC(C)=O
Reactant: C1CCOC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1(OC(=O)NN)CCOCC1
Reaction time: 3 h

Procedure:
In a round bottomed flask equipped with a magnetic stirrer, crude (4-methyltetrahydropyran-4-yl)-(4-nitrophenyl)-carbonate from previous step (ca. 3.8 g) was dissolved in THF (50 mL), then hydrazine hydrate (1.97 mL, 40.57 mmol) was added in one portion. A yellow color immediately appeared which deepened to red in 1 h. After 3 h, 1.25M NaOH solution (50 mL) and AcOEt (50 mL) were added and the mixture stirred for 20 min. The phases were separated and the aqueous one washed with more AcOEt (25 mL). The combined organic liquors were washed with 1.25M NaOH solution (30 mL) (until clear colorless), dried over Na2SO4 and concentrated to leave a colorless oil (0.540 g, 24% over two steps) which was used in the next step without further purification. 1H NMR (CDCl3) δ 1.58 (s, 3H), 1.73 (m, 2H), 2.15 (m, 2H), 3.73 (m, 6H), 6.0 (bs, 1H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22](OC)=[O:23])=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(OCC)(=O)C.O>CCOCC>[CH2:7]([O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][OH:23])=[CH:19][CH:20]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)Cc1ccc(OCc2ccccc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: O
Product: OCCc1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of lithium aluminum hydride (10.8 g, 285 mmoles) in Et2O (300 mL) was very carefully added a solution of methyl 4-(benzyloxy)phenylacetate (6, 72.8 g, 284 mmoles) in Et2O (200 mL) over 40 minutes. After an additional 30 minutes, ethyl acetate (200 mL) was added, followed by H2O (500 mL) and the mixture maintained at 0° C. The mixture was then allowed to separate into two phases. The aqueous phase was extracted with Et2O (2×500 mL). The combined extracts were dried over anhydrous Na2SO4 and evaporated to yield 1-benzyloxy-4-(2-hydroxyethyl)benzene as a white solid, (7, 64.5 g, mp=85° C.). NMR (CDCl3)δppm: 7.33(s, 4H); 6.97(q, 4H); 4.97(s, 2H); 3.67(t, 3H); 4.43(t, 3H); 4.27(s, 1H). (Scheme II, Step 2.)
Reaction SMILES: [Na].[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5](Cl)[N:4]=1.[CH2:14]([OH:17])[CH:15]=[CH2:16]>>[CH2:14]([O:17][C:5]1[N:4]=[C:3]([NH2:2])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1)[CH:15]=[CH2:16]
Reactant: Nc1nc(Cl)nc2ccccc12
Reactant: C=CCO
Agent: [Na]
Product: C=CCOc1nc(N)c2ccccc2n1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To the solution of sodium metal (0.7 g) in dried allylalcohol (90 ml) was added 4-amino-2-chloroquinazoline (3.5 g) and the mixture was stirred for 5 hours at 100° C. After the resultant mixture was concentrated under reduced pressure, to the residue was added a small volume of water. The aqueous mixture was extracted twice with ethyl acetate. The organic layer was washed with water and with aqueous solution saturated with sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a crystalline residue, which was recrystallized from a mixture of ethyl acetate and hexane to give crystalline 2-allyloxy-4-aminoquinazoline (2.8 g).
Reaction SMILES: N1C=CC=CC=1.[FH:7].C([O:11][C:12]1[CH:13]=[C:14]([CH:32]=[CH2:33])[C:15]2[O:19][C:18]([C:20]3[CH:25]=[CH:24][C:23]([O:26]C(=O)C)=[C:22]([F:30])[CH:21]=3)=[N:17][C:16]=2[CH:31]=1)(=O)C.[Br:34]N1C(C)(C)C(=O)N(Br)C1=O>S1(CCCC1)(=O)=O.Cl>[Br:34][CH2:33][CH:32]([C:14]1[C:15]2[O:19][C:18]([C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([F:30])[CH:21]=3)=[N:17][C:16]=2[CH:31]=[C:12]([OH:11])[CH:13]=1)[F:7]
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: F
Reactant: C=Cc1cc(OC(C)=O)cc2nc(-c3ccc(OC(C)=O)c(F)c3)oc12
Agent: Cl
Solvent: c1ccncc1
Solvent: O=S1(=O)CCCC1
Product: Oc1cc(C(F)CBr)c2oc(-c3ccc(O)c(F)c3)nc2c1
Reaction time: 0.08 h

Procedure:
Hydrogen fluoride pyridine (1.14 mL) was added dropwise into a cold (0° C.) solution of 2-[4-(acetyloxy)-3-fluorophenyl]-7-vinyl-1,3-benzoxazol-5-yl acetate (0.25 g, 0.7 mmol), in sulfolane (3 mL). The reaction mixture was stirred for 5 min and then 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (120 mg) was added in one portion. The mixture was stirred at room temperature for 24 h, diluted with HCl (1N) and extracted with EtOAc. The organic layer was dried over MgSO4. Evaporation and purification by flash chromatography (CH2Cl2/isopropyl alcohol 0.3%) gave 7-(2-bromo-1-fluoroethyl)-2-(3-fluoro-4-hydroxyphenyl)-1,3-benzoxazol-5-ol as a white solid (0.25 g, m.p. 185–186° C.). The product was taken in acetonitrile (2 mL) and 1,8-diazabicyclo[5.4.0]undec-7-ene (150 mg) was added. The reaction mixture was stirred for 24 h, poured into cold (0° C.) HCl (1N, 10 mL) and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography (20% EtOAc/hexanes) gave a white solid (160 mg, m.p. 213–214° C.); MS m/e 290 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[SH:16][CH2:17][C:18]([OH:20])=[O:19].CC(N(C)C)=O.[OH-].[Na+]>O>[C:18]([CH2:17][S:16][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1)([OH:20])=[O:19]
Reactant: O=C(O)CS
Reactant: O=C(c1ccccc1)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=C(O)CSc1ccc(C(=O)c2ccccc2)cc1
Temperature: 107.5 °C
Yield: 80 %

Procedure:
55 g 4-chloro benzophenone and 24 g mercaptoacetic acid are added into a 500 ml three-neck flask, and are dissolved with 350 ml DME (dimethyl acetamide) to obtain a solution, and then 23 g solid sodium hydroxide is added into the solution. Heating the solution to reflux (105-110° C.), and starting to cool the solution when the content of 4-chloro benzophenone detected by HPLC is less than 1%. The reaction solution is added into 500 ml water, and then water insoluble substances are extracted with 100 ml methylbenzene. Concentrated hydrochloric acid is used to regulate the pH value of the aqueous phase to 3-4, then some solid substances precipitate, filtering to obtain crude products, and the weight after drying is 60 g; the dried crude products are recrystallized in dichloroethane to obtain 55.3 g white crystal, and the yield was 80%.
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH:14]([F:16])[F:15])=[CH:10][CH:9]=2)[C:3]1=[O:17].[F:18][C:19]1[CH:24]=[C:23]([C@@H:25]2[CH2:30][CH2:29][NH:28][CH2:27][C@H:26]2[F:31])[CH:22]=[CH:21][C:20]=1[OH:32].C(N(CC)CC)C>C(#N)C.O>[F:15][CH:14]([F:16])[C:11]1[CH:12]=[CH:13][C:8]([CH2:7][N:4]2[CH2:5][CH2:6][CH:2]([N:28]3[CH2:29][CH2:30][C@@H:25]([C:23]4[CH:22]=[CH:21][C:20]([OH:32])=[C:19]([F:18])[CH:24]=4)[C@H:26]([F:31])[CH2:27]3)[C:3]2=[O:17])=[CH:9][CH:10]=1
Reactant: O=C1C(Br)CCN1Cc1ccc(C(F)F)cc1
Reactant: Oc1ccc([C@@H]2CCNC[C@H]2F)cc1F
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: O=C1C(N2CC[C@@H](c3ccc(O)c(F)c3)[C@H](F)C2)CCN1Cc1ccc(C(F)F)cc1
Temperature: 120 °C
Reaction time: 0.42 h
Yield: 47.5 %

Procedure:
A stirred mixture of 3-bromo-1-(4-(difluoromethyl)benzyl)pyrrolidin-2-one (100 mg, 0.328 mmol, intermediate 2a), 2-fluoro-4-((3S,4S)-3-fluoropiperidin-4-yl)phenol (70 mg, 0.328 mmol, from example 114, step E), and triethylamine (0.137 mL, 0.985 mmol) in acetonitrile (2 mL) was heated at 120° C. in a CEM microwave for one hour. The reaction mixture was diluted with water and extracted with ethyl acetate (100 mL). The organic layer was washed with brine solution, dried over sodium sulfate, and evaporated under reduced pressure to give a crude residue. The crude residue was purified via preparative LC/MS (column: Waters Xbridge C18, 19×150 mm, 5 μm; guard column: Waters XBridge C18, 19×10 mm, 5 μm; mobile phase A: 5:95 methanol:water with 10 mM NH4OAc; mobile Phase B: 95:5 methanol:water with 10 mM NH4OAc; Gradient: 15-50% B over 25 min, followed by a 10 min hold at 50% B and 5 min hold at 100% B; flow: 15 ml/min) to afford 1-(4-(difluoromethyl)benzyl)-3-((3S,4S)-3-fluoro-4-(3-fluoro-4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one (68 mg, 46%). The diastereomeric mixture was separated by preparative chiral SFC (column=Chiralpak AD-H (250 mm×21 mm, 5 μm); isocratic solvent=40% methanol (w/0.25% DEA) in CO2, 100 bar; temp=25° C.; flow rate=75 g/min; injection volumn=1.1 mL (˜6 mg/mL in MeOH); λ=220 nM; Peak 1=3.2 min, Peak 2=5.0 min) to afford the titled compounds of example 117 (18 mg of peak-1, and 20 mg of peak-2). Data for example 117, P-1: LC-MS m/z 437 (M+H)+; 1H NMR (400 MHz, methanol-d4) δ ppm 7.55 (d, J=8.03 Hz, 2H) 7.42 (s, 2H) 6.97-7.04 (m, 1H) 6.62-6.95 (m, 3H) 4.48-4.68 (m, 3H) 3.76 (t, J=8.78 Hz, 1H) 3.50 (dt, J=3.31, 1.64 Hz, 0H) 3.25-3.31 (m, 0H) 3.11-3.18 (m, 0H) 2.99-3.05 (m, 0H) 2.41-2.71 (m, 3H) 2.16-2.26 (m, 1H) 2.08 (dq, J=12.91, 8.79 Hz, 1H) 1.78-1.91 (m, 2H). Data for example 117, P-2: LC-MS m/z 437 (M+H)+; 1H NMR (400 MHz, methanol-d4) δ ppm 7.55 (d, J=8.03 Hz, 2H) 7.41 (d, J=8.28 Hz, 2H) 7.00 (dd, J=12.39, 1.91 Hz, 1H) 6.62-6.93 (m, 3H) 4.47-4.70 (m, 3H) 3.69-3.77 (m, 1H) 3.38-3.55 (m, 1H) 3.24-3.30 (m, 1H) 3.15 (dt, J=3.31, 1.64 Hz, 1H) 2.74-2.83 (m, 2H) 2.52-2.72 (m, 2H) 2.44 (td, J=10.02, 4.80 Hz, 1H) 2.03-2.27 (m, 2H) 1.76-1.90 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:45])[NH:4][C@H:5]([C:10]([NH:12][N:13]([CH2:37][C:38]1[CH:43]=[CH:42][C:41](Br)=[CH:40][CH:39]=1)[CH2:14][C@:15]([OH:36])([C:23](=[O:35])[NH:24][C@H:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][C@H:26]1[OH:34])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:11])[C:6]([CH3:9])([CH3:8])[CH3:7].[S:46]1[C:50](B(O)O)=[CH:49][C:48]2[CH:54]=[CH:55][CH:56]=[CH:57][C:47]1=2.C([O-])([O-])=O.[Na+].[Na+].CCO>COCCOC>[CH3:1][O:2][C:3](=[O:45])[NH:4][C@H:5]([C:10]([NH:12][N:13]([CH2:14][C@:15]([OH:36])([C:23](=[O:35])[NH:24][C@H:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][C@H:26]1[OH:34])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:37][C:38]1[CH:43]=[CH:42][C:41]([C:50]2[S:46][C:47]3[CH:57]=[CH:56][CH:55]=[CH:54][C:48]=3[CH:49]=2)=[CH:40][CH:39]=1)=[O:11])[C:6]([CH3:9])([CH3:8])[CH3:7]
Reactant: COC(=O)N[C@H](C(=O)NN(Cc1ccc(Br)cc1)C[C@@](O)(Cc1ccccc1)C(=O)N[C@H]1c2ccccc2C[C@H]1O)C(C)(C)C
Reactant: OB(O)c1cc2ccccc2s1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: COC(=O)N[C@H](C(=O)NN(Cc1ccc(-c2cc3ccccc3s2)cc1)C[C@@](O)(Cc1ccccc1)C(=O)N[C@H]1c2ccccc2C[C@H]1O)C(C)(C)C

Procedure:
The title compound was prepared according to Method B, using 19 (83.4 mg, 0.123 mmol), benzo[b]thiophene-2-boronic acid (109 mg, 0.613 mmol), Pd(PPh)3Cl2 (4.32 mg, 0.00615 mmol), 2 M Na2CO3 (aq., 0.185 mL, 0.369 mmol), EtOH (0.4 mL) and DME (1.6 mL). Purification by RP-LC-MS (35 min gradient of 20-100% CH3CN in 0.05% aqueous formic acid) afforded the product (56.4 mg, 62%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH:9][C:10](=[O:29])[C@H:11]([CH2:23][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:12][N:13]([O:16]C2CCCCO2)[CH:14]=[O:15])[C:5]([F:30])=[C:4]([N:31]2[CH2:35][CH:34]([N:36]([CH3:38])[CH3:37])[C:33]([CH3:40])([CH3:39])[CH2:32]2)[N:3]=1>CC(O)=O.O>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH:9][C:10](=[O:29])[C@H:11]([CH2:23][CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28]2)[CH2:12][N:13]([OH:16])[CH:14]=[O:15])[C:5]([F:30])=[C:4]([N:31]2[CH2:35][CH:34]([N:36]([CH3:38])[CH3:37])[C:33]([CH3:40])([CH3:39])[CH2:32]2)[N:3]=1
Reactant: CN(C)C1CN(c2nc(Cl)nc(NNC(=O)[C@H](CC3CCCC3)CN(C=O)OC3CCCCO3)c2F)CC1(C)C
Solvent: CC(=O)O
Solvent: O
Product: CN(C)C1CN(c2nc(Cl)nc(NNC(=O)[C@H](CC3CCCC3)CN(O)C=O)c2F)CC1(C)C
Yield: 51.3 %

Procedure:
A solution of [(2R)-3-(2-{2-chloro-6-[4-(dimethylamino)-3,3-dimethyl-1-pyrrolidinyl]-5-fluoro-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide (0.0681 g, 0.117 mmol) in 4:1 HOAc-water (5 mL) was stirred for 56 h and then concentrated in vacuo. A solution of the residue in DCM (100 mL) was washed with sat. aq. NaHCO3 (30 mL), and the organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by Gilson RPLC and crystallized from EtOAc-hexanes to provide [(2R)-3-(2-{2-chloro-6-[4-(dimethylamino)-3,3-dimethyl-1-pyrrolidinyl]-5-fluoro-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl]hydroxyformamide (0.0300 g, 51% yield, mixture of diastereomers) as a white solid. LCMS: (M+H)+: 500.3.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13]1[CH:18]2[CH2:19][C:20](=O)[CH2:21][CH:14]1[CH2:15][O:16][CH2:17]2)(=[O:12])=[O:11])([O-:3])=[O:2].C(OC([N:32]([CH3:34])C)N(C)C)(C)(C)C.[NH2:35]N.O>O1CCOCC1>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13]1[CH:18]2[CH2:17][O:16][CH2:15][CH:14]1[C:21]1[CH:34]=[N:32][NH:35][C:20]=1[CH2:19]2)(=[O:11])=[O:12])([O-:3])=[O:2]
Reactant: O=C1CC2COCC(C1)N2S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: NN
Solvent: O
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)N1C2COCC1c1cn[nH]c1C2
Temperature: 60 °C
Reaction time: 16 h
Yield: 29.8 %

Procedure:
A mixture of compound 107b (4.9 g, 15 mmol, 1.0 eq) and tert-butoxy-N,N,N′,N′-tetra-methyl-methanediamine (3.92 g, 22.5 mmol, 1.5 eq) in dioxane (50 mL) was stirred at 60° C. for 16 h, then the solvent was removed in vacuo, the residue was dissolved in EtOH (50 mL), NH2NH2.H2O (3.5 mg, 75 mmol, 5.0 eq) was added and then stirred at 60° C. for 2 h. The reaction mixture was concentrated and then purified by silica gel (EA/PE=1:2) to give 12-(2-Nitro-benzenesulfonyl)-10-oxa-4,5,12-triaza-tricyclo[6.3.1.0*2,6*]dodeca-2(6),3-diene 107c as a slight yellow oil, 1.57 g, yield: 29.8%. MS: calc'd (MH+) 351, measured (MH+) 351.
Reaction SMILES: [C@@H:1]1([N:9]2[CH:13]=[C:12](I)[CH:11]=[C:10]2[N+:15]([O-:17])=[O:16])[O:6][C@H:5]([CH2:7][OH:8])[C@@H:3]([OH:4])[CH2:2]1.C(N(CC)CC)C.[CH2:25]([NH:28][C:29](=[O:33])[CH:30]([Cl:32])[Cl:31])[C:26]#[CH:27]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[C@@H:1]1([N:9]2[CH:13]=[C:12]([C:27]#[C:26][CH2:25][NH:28][C:29](=[O:33])[CH:30]([Cl:32])[Cl:31])[CH:11]=[C:10]2[N+:15]([O-:17])=[O:16])[O:6][C@H:5]([CH2:7][OH:8])[C@@H:3]([OH:4])[CH2:2]1
Reactant: O=[N+]([O-])c1cc(I)cn1[C@H]1C[C@H](O)[C@@H](CO)O1
Reactant: C#CCNC(=O)C(Cl)Cl
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NCC#Cc1cc([N+](=O)[O-])n([C@H]2C[C@H](O)[C@@H](CO)O2)c1)C(Cl)Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 80.8 %

Procedure:
1-(2-Deoxy-β-D-ribofuranosyl)-4-iodo-2-nitropyrrole (Compound 1) (354 mg, 1.0 mmol), Pd(PPh3)4 (58 mg, 0.05 mmol), CuI (30 mg, 0.16 mmol) and triethylamine (209 μl, 1.5 mmol) were dissolved in DMF (3.5 ml), followed by addition of a 1 M DMF solution of N-(2-propynyl)-dichloroacetamide (1.5 ml, 1.5 mmol). After stirring at room temperature for 12 hours, the reaction mixture was partitioned between ethyl acetate and water, and the organic layer was washed three times with water. After drying over anhydrous sodium sulfate, the organic layer was concentrated and purified on a silica gel column (CH2Cl2:MeOH, 20:1, v/v) and by HPLC (34%-35% CH3CN, 12 minutes) to give Compound 3 (317 mg, 81%).
Reaction SMILES: [C:1]([C:3]1[C:4](=[C:11]([C:14]#[N:15])[C:12]#[N:13])[O:5][C:6]([CH3:10])([CH3:9])[C:7]=1[CH3:8])#[N:2].[C:16]([SiH2:20][O:21][C:22]([CH3:49])([CH3:48])[CH:23]1[CH2:28][O:27][C:26]2=[C:29]([CH:34]=[CH:35][C:36]3[CH:41]=[CH:40][C:39]([N:42]([CH2:46][CH3:47])[CH2:43][CH2:44][OH:45])=[CH:38][CH:37]=3)[S:30][C:31]([CH:32]=O)=[C:25]2[O:24]1)([CH3:19])([CH3:18])[CH3:17].O>N1CCCCC1.C(Cl)(Cl)Cl>[C:16]([SiH2:20][O:21][C:22]([CH3:48])([CH3:49])[CH:23]1[CH2:28][O:27][C:26]2=[C:29]([CH:34]=[CH:35][C:36]3[CH:37]=[CH:38][C:39]([N:42]([CH2:46][CH3:47])[CH2:43][CH2:44][OH:45])=[CH:40][CH:41]=3)[S:30][C:31]([CH:32]=[CH:8][C:7]3[C:6]([CH3:9])([CH3:10])[O:5][C:4](=[C:11]([C:12]#[N:13])[C:14]#[N:15])[C:3]=3[C:1]#[N:2])=[C:25]2[O:24]1)([CH3:17])([CH3:19])[CH3:18]
Reactant: CCN(CCO)c1ccc(C=Cc2sc(C=O)c3c2OCC(C(C)(C)O[SiH2]C(C)(C)C)O3)cc1
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(C)C
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: C1CCNCC1
Product: CCN(CCO)c1ccc(C=Cc2sc(C=CC3=C(C#N)C(=C(C#N)C#N)OC3(C)C)c3c2OCC(C(C)(C)O[SiH2]C(C)(C)C)O3)cc1
Reaction time: 2 h
Yield: 31.3 %

Procedure:
15 mL of anyhdrous chloroform was added to 1.99 g (0.010 mol) of 2-(3-cyano-4,5,5-trimethyl-5H-furan-2-ylidene)-malononitrile, and 2.91 g of 4 (0.007 mol). Once in solution, 5 drops of piperidine were added and the reaction mixture was stirred at reflux. The reaction went to completion in 2 h. The crude reaction mixture was poured into water, and an equal amount of chloroform was added. The organic layered was washed three times with water, dried over MgSO4, and filtered. The solvent was removed under reduced pressure. The compound was purified on a silica column with a hexane/ethyl acetate mobile phase to yield 1.5 g of 5 (37.5% yield).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([NH:9][C@@H:10]([CH3:14])[CH2:11][O:12][CH3:13])[N:3]=1.[IH:15].[I-:16].[Na+].C(Cl)Cl>CCOC(C)=O>[I:15][C:2]1[CH:7]=[C:6]([I:16])[N:5]=[C:4]([NH:9][C@@H:10]([CH3:14])[CH2:11][O:12][CH3:13])[N:3]=1
Reactant: COC[C@H](C)Nc1nc(Cl)cc(Cl)n1
Reactant: I
Reactant: [I-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC[C@H](C)Nc1nc(I)cc(I)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (S)-4,6-dichloro-N-(1-methoxypropan-2-yl)pyrimidin-2-amine (260 mg, 0.11 mmol, Example 122(a)), hydriodic acid (57 wt. % in water, 40.4 μl, 0.165 mmol, Aldrich), sodium iodide (248 mg, 0.165 mmol) and DCM (5 mL) was stirred at room temperature for 2 h. The reaction mixture was diluted with EtOAc (50 mL), washed with 1N NaOH (2×25 mL) and brine (60 mL), dried over Na2SO4 and filtered. The filtrate was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (7% EtOAc/hexane) to give the title compound. MS (ESI, pos. ion) m/z: 420 (M+1).
Reaction SMILES: [CH2:1]([C@@:4]1(C)[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:28][CH3:29])[CH:25]([OH:27])[CH3:26])[C:5]1=[O:30])C=C.CC[O:34][C:35]([CH3:37])=[O:36]>CC#N.O.C(Cl)Cl.O.[Ru](Cl)(Cl)Cl>[Cl:16][C:12]1[CH:11]=[C:10]([C@@H:8]2[C@@H:7]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[N:6]([C@@H:24]([CH2:28][CH3:29])[C:25](=[O:27])[CH3:26])[C:5](=[O:30])[C@:4]([CH2:37][C:35]([OH:34])=[O:36])([CH3:1])[CH2:9]2)[CH:15]=[CH:14][CH:13]=1
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)C(C)O)C1=O
Reactant: CCOC(C)=O
Agent: Cl[Ru](Cl)Cl
Solvent: O
Solvent: ClCCl
Solvent: CC#N
Product: CC[C@@H](C(C)=O)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
Ruthenium(III) chloride hydrate (1.404 g, 6.23 mmol) was added to a solution of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-2-hydroxypentan-3-yl)-3-methylpiperidin-2-one (Example 151, Step C) (130.30 g, 283 mmol) and NaIO4 (61.5 g) in EtOAc (630 mL), CH3CN (630 mL) and water (935 mL) at 18° C. The remaining NaIO4 (307.5 g) was added in five portions over 2.5 hours while maintaining the temperature below 26° C. 15 minutes after the final addition of NaIO4 the cooling bath was removed and the reaction mixture was stirred at ambient temperature for 50 minutes. The tan reaction mixture was filtered using a Büchner funnel and washed with EtOAc (500 mL) and CH3CN (500 mL). The layers were separated and the aqueous layer was extracted with EtOAc twice. The organics were pooled, washed with 10% aq. NaHSO3 (3×1 L), brine (1 L), dried (Na2SO4), decanted and concentrated in vacuo to provide a green oil. The material was dissolved in a minimum amount of DCM and purified using two 1.5 kg Biotage® Snap™ columns (Biotage, LLC, Charlotte, N.C.) and eluting with 10-50% (15% MeOH/acetone)/hexanes to provide a light pink foam (109.67 g).
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[Mg].C(Br)C.[Cl:9][C:10]1[CH:24]=[CH:23][C:13]([C:14]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[O:15])=[CH:12][CH:11]=1.[Cl-].[NH4+]>CCOCC>[Cl:9][C:10]1[CH:24]=[CH:23][C:13]([C:14]([CH2:1][CH3:2])([OH:15])[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1
Reactant: O=C(c1ccc(O)cc1)c1ccc(Cl)cc1
Reactant: CC[Mg]Br
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCBr
Product: CCC(O)(c1ccc(O)cc1)c1ccc(Cl)cc1
Temperature: -10 °C

Procedure:
To a solution of ethyl magnesium bromide prepared from 3.9 g. of magnesium turnings and 17.4 g. of ethyl bromide in 50 ml. of dry ether a solution of 9.3 g. of 4-chloro-4'-hydroxy-benzophenone in 40 ml. of dry ether is added dropwise, with stirring at -10° C., in nitrogen atmosphere. The reaction mixture is allowed to warm up to room temperature, stirred at this temperature for an additional half an hour, and is then poured onto a solution of ammonium chloride in ice water under cooling. The aqueous phase is extracted with ether, the ethereal phases are combined, washed to neutral with water, and dried over anhydrous magnesium sulfate. After filtering the solvent is distilled off in vacuo, the residue is decolored with charcoal in methanol, the solution is filtered, and the solvent is evaporated under reduced pressure. The crude mixture is crystallized from a mixture of benzene and ethyl acetate to yield 5.5 g. of the named compound, melting at 148° to 149° C.