Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH2:5][C@@H:6]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]3[N:22]([N:24]=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=4)[N:26]=3)[CH:23]=2)=[CH:12][CH:11]=1)[C:7]#[C:8][CH3:9])[CH3:2].Br[CH2:36][CH2:37][O:38][CH3:39].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH2:1]([O:3][C:4](=[O:34])[CH2:5][C@@H:6]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]3[N:22]([N:24]=[C:25]([C:27]4[CH:28]=[CH:29][C:30]([O:33][CH2:36][CH2:37][O:38][CH3:39])=[CH:31][CH:32]=4)[N:26]=3)[CH:23]=2)=[CH:12][CH:11]=1)[C:7]#[C:8][CH3:9])[CH3:2]
Reactant: CC#C[C@@H](CC(=O)OCC)c1ccc(OCc2ccc3nc(-c4ccc(O)cc4)nn3c2)cc1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC#C[C@@H](CC(=O)OCC)c1ccc(OCc2ccc3nc(-c4ccc(OCCOC)cc4)nn3c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution (S)-3-{4-[2-(4-hydroxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-6-ylmethoxy]-phenyl}-hex-4-ynoic acid ethyl ester (0.250 g, 0.585 mmol) and 1-bromo-2-methoxy-ethane (0.22 mL, 2.34 mmol) in acetonitrile (10 mL) is added cesium carbonate (0.381 g, 1.17 mmol) at room temperature and the reaction mixture is stirred at room temperature overnight. The reaction mixture is filtered through diatomaceous earth and washed with EtOAc (20 mL), and the filtrate is concentrated to dryness. The residue is dissolved in EtOAc (30 mL), washed with water (2×30 mL), brine solution (30 mL), dried over sodium sulphate, and evaporated under reduced pressure. The crude compound is purified by silica gel (combiflash purifier) and is eluted with 17-19% EtOAc in hexane to give the title compound as a white semi solid (0.190 g, 64%). LCMS m/z 514 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:11][CH2:10][C:9](=[O:12])[C:8]2[CH:7]=[C:6]([C:13]([OH:15])=[O:14])[CH:5]=[CH:4][C:3]1=2.CN([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22]N=1)C.[C:26]([O:29][CH2:30][CH3:31])(=[O:28])[CH3:27]>CN(C)C=O>[CH2:30]([O:29][C:26](=[O:28])[C:27]1[CH:10]=[CH:11][C:2]([O:14][C:13]([C:6]2[CH:5]=[CH:4][C:3]3[C:2]([CH3:16])([CH3:1])[CH2:11][CH2:10][C:9](=[O:12])[C:8]=3[CH:7]=2)=[O:15])=[CH:3][CH:8]=1)[C:31]1[CH:20]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CN(C)c1ccccn1
Reactant: CC1(C)CCC(=O)c2cc(C(=O)O)ccc21
Reactant: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)CCC(=O)c2cc(C(=O)Oc3ccc(C(=O)OCc4ccccc4)cc3)ccc21
Reaction time: 0.17 h

Procedure:
To a solution of 5,5-dimethyl-5,6,7,8-tetrahydro-8-oxo-naphthalen-2-carboxylic acid (Compound E3, 386 mg, 1.77 mmol) in dimethylformamide (4 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarboimide hydrochlorde (440 mg, 2.3 mmol) followed by dimethylamino pyridine (DMAP) (280 mg, 2.3 mmol). The mixture was stirred for 10 minutes, and benzyl 4-hydroxy benzoate (426 mg, 1.9 mmol) was added and stirred at ambient temperature for 16 hours. The mixture was diluted with ethyl acetate (100 mL) and washed with water (10 mL), brine (10 mL), dried and solvent distilled off. The title compound was obtained as a pale yellow solid after chromatographic purification.
Reaction SMILES: [CH:1]([Mg]Cl)=[CH:2][CH2:3][CH3:4].[Cl-].[NH4+].C([O:11][CH2:12][CH3:13])C>[Cu]Cl>[CH2:4]([C@@H:4]1[CH2:3][CH2:2][CH2:1][C@@:12]1([CH3:13])[OH:11])[CH2:3][CH:2]=[CH2:1]
Reactant: CCOCC
Reactant: CCC=C[Mg]Cl
Agent: Cl[Cu]
Agent: [Cl-]
Agent: [NH4+]
Product: C=CCC[C@@H]1CCC[C@@]1(C)O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a 0° C. solution of butenyl magnesium chloride (45.6 mL, 0.5 M) was added copper(I) chloride (0.113 g) followed by methylcyclopropane oxide (1.12 g) in diethyl ether (5 ml). The reaction mixture was warmed to room temperature and stirred for 20 hours. The mixture was cooled back to 0° C. before pouring into a saturated solution of ammonium chloride (at 0° C.). The mixture was extracted with ethyl acetate (3×). The combined organic fractions were dried over magnesium sulfate, filtered and concentrated carefully. The residue was purified by flash chromatography (ISCO, 0 to 30% ethyl acetate in hexanes) to give the desired product (1.3 g). 1H NMR (400 MHz, CDCl3): δ (ppm) 5.86-5.79 (m, 1H), 5.05-4.99 (m, 1H), 4.97-4.93 (m, 1H), 2.20-2.09 (m, 1H), 2.02-1.92 (m, 2H), 1.73-1.50 (m, 7H), 1.31-1.10 (m, 5H).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:71]=[CH:70][C:67]([C:68]#[N:69])=[CH:66][C:65]=1[O:72][CH3:73]>ClCCCl>[C:68]([C:67]1[CH:70]=[CH:71][C:64]([NH:63][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:35])([CH3:36])[CH3:37])[C:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])=[C:65]([O:72][CH3:73])[CH:66]=1)#[N:69]
Reactant: COc1cc(C#N)ccc1N
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C#N)ccc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3cc(Cl)ccc32)C1c1cccc(Cl)c1F

Procedure:
In a manner similar to the method described in Example 27, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.95 g, 1.64 mmol), was reacted with diisopropylethylamine (1.7 g, 13.1 mmol), diphenylphosphinic chloride (1.55 g, 6.6 mmol), then reacted with 4-amino-3-methoxy-benzonitrile (0.49 g, 3.28 mmol) in 1,2-dichloroethane at 70° C. to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-cyano-2-methoxy-phenyl)-amide as a off white foam (Yield, 0.34 g, 35%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[NH2:10].[C:11]([NH:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1)(=[O:13])[CH3:12].CO[CH:25](OC)[N:26]([CH3:28])[CH3:27]>C(O)C.CCCCCC>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]=[CH:19][C:18]2[CH:21]=[CH:22][C:15]([NH:14][C:11](=[O:13])[CH3:12])=[CH:16][CH:17]=2)[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]=[CH:25][N:26]([CH3:28])[CH3:27]
Reactant: CC(=O)Nc1ccc(C=O)cc1
Reactant: Nc1cc(Cl)c(N)c(Cl)c1
Reactant: COC(OC)N(C)C
Solvent: CCO
Solvent: CCCCCC
Product: CC(=O)Nc1ccc(C=Nc2cc(Cl)c(N=CN(C)C)c(Cl)c2)cc1
Reaction time: 16 h

Procedure:
A mixture of 3.5 g. of 2,6-dichloro-1,4-phenylenediamine and 3.3 g. of p-acetamidobenzaldehyde in 50 ml. of ethanol is refluxed for 21/2 hours. The reaction mixture is allowed to stand at room temperature for 16 hours, then evaporated in vacuo to give a solid. The solid in 25 ml. of N,N-dimethylformamide dimethylacetal is refluxed for 18 hours. The solvent is evaporated to provide a syrup which is dissolved in ethanol and n-hexane. The addition of more ethanol provides crystals. The crude product is collected, dissolved in 50 ml. of hot ethanol and filtered through diatomaceous earth. The filter is washed with ethanol and n-hexane is added to the filtrate until turbid. The clear liquid is decanted and evaporated in vacuo to give hard, yellow-orange crystals. The material is recrystallized from ethyl acetate/hexane to give 830 mg. of the product of the Example as bright yellow crystals, m.p. 171°-173° C.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][CH:6]([O:9][C:10]2[C:21]3[C:20]4[C@@H:19]([CH2:22][CH2:23][OH:24])[CH2:18][CH2:17][C:16]=4[S:15][C:14]=3[N:13]=[CH:12][N:11]=2)[CH2:5][CH2:4]1.Cl[CH2:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1)=[O:28].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(Cl)Cl>[OH:24][CH2:23][CH2:22][C@H:19]1[CH2:18][CH2:17][C:16]2[S:15][C:14]3[N:13]=[CH:12][N:11]=[C:10]([O:9][CH:6]4[CH2:5][CH2:4][CH:3]([N:2]([CH3:1])[CH2:26][C:27]([N:29]5[CH2:33][CH2:32][CH2:31][CH2:30]5)=[O:28])[CH2:8][CH2:7]4)[C:21]=3[C:20]1=2
Reactant: O=C(CCl)N1CCCC1
Reactant: CNC1CCC(Oc2ncnc3sc4c(c23)[C@@H](CCO)CC4)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(CC(=O)N1CCCC1)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CCO)CC4)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a solution of 2-[(3R)-12-[[4-(methylamino)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]ethan-1-ol (120 mg, 0.35 mmol, 1.00 equiv) in distilled DMF (5 mL) was added 2-chloro-1-(pyrrolidin-1-yl)ethan-1-one (75 mg, 0.51 mmol, 1.50 equiv) and potassium carbonate (26 mg, 0.19 mmol, 2.00 equiv) at room temperature. The resulting solution was stirred overnight at room temperature. The reaction mixture was diluted with DCM (100 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with methanol/DCM (1:10) to afford the desired 2-[(4-[[(3R)-3-(2-hydroxyethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)(methyl)amino]-1-(pyrrolidin-1-yl)ethan-1-one (130 mg, 82%) as a white solid. MS (ES): m/z 459 [M+H]+. 1H NMR (400 MHz, CD3OD): δ 8.47 (1H, s), 5.32-5.20 (1H, m), 3.66 (2H, t), 3.58 (2H, t), 3.50-3.41 (3H, m), 3.37 (2H, s), 3.15-3.05 (1H, m), 3.00-2.92 (1H, m), 2.75-2.60 (2H, m), 2.37 (3H, s), 2.33-2.15 (4H, m), 2.03-1.88 (6H, m), 1.71-1.54 (4H, m).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.F[C:7]1[CH:8]=[C:9]2[C:15]([C:16]3[N:17]=[N:18][C:19]([C:23]([CH3:29])([CH3:28])[C:24]([O:26]C)=O)=[C:20](O)[N:21]=3)=[N:14][N:13]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[F:37])[C:10]2=[N:11][CH:12]=1.[NH3:38].[Cl-].[Na+]>C(#N)C>[F:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[CH2:30][N:13]1[C:10]2=[N:11][CH:12]=[CH:7][CH:8]=[C:9]2[C:15]([C:16]2[N:17]=[N:18][C:19]3[C:23]([CH3:28])([CH3:29])[C:24](=[O:26])[NH:38][C:20]=3[N:21]=2)=[N:14]1
Reactant: N
Reactant: COC(=O)C(C)(C)c1nnc(-c2nn(Cc3ccccc3F)c3ncc(F)cc23)nc1O
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
50 ml of phosphoryl chloride were added to 9.700 g (22.025 mmol) of the compound from Example 61A, and the mixture was stirred at RT overnight. The reaction mixture was dissolved in 150 ml of acetonitrile and, with ice cooling, stirred into a mixture of 1337 ml of concentrated aqueous ammonia solution (35% strength) and 1300 ml of acetonitrile. The mixture was stirred at room temperature for 2 days. 300 g of sodium chloride were then added. Two phases formed. The organic phase was separated off and concentrated to dryness. The residue was taken up in ethyl acetate (150 ml). A precipitate formed and was filtered off with suction through a frit. The filter cake was washed three times with water and then three times with ethyl acetate (5 ml). The residue was dried under high vacuum. This gave 4.58 g (51% of theory) of the title compound.
Reaction SMILES: [CH2:1]([C:5]12[CH2:17][CH2:16][C:15](=[O:18])[C:14]([C:19]3[CH:24]=[CH:23][C:22](OS(C(F)(F)F)(=O)=O)=[CH:21][CH:20]=3)=[C:13]1[C:12]1[C:7](=[CH:8][C:9]([O:33][CH3:34])=[CH:10][CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4].C([Sn](CCCC)(CCCC)/[CH:40]=[CH:41]/[C:42]([O:44][CH3:45])=[O:43])CCC.[Cl-].[Li+]>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([C:5]12[CH2:17][CH2:16][C:15](=[O:18])[C:14]([C:19]3[CH:20]=[CH:21][C:22](/[CH:40]=[CH:41]/[C:42]([O:44][CH3:45])=[O:43])=[CH:23][CH:24]=3)=[C:13]1[C:12]1[C:7](=[CH:8][C:9]([O:33][CH3:34])=[CH:10][CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[Sn](/C=C/C(=O)OC)(CCCC)CCCC
Reactant: CCCCC12CCC(=O)C(c3ccc(OS(=O)(=O)C(F)(F)F)cc3)=C1c1ccc(OC)cc1C2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCCCC12CCC(=O)C(c3ccc(/C=C/C(=O)OC)cc3)=C1c1ccc(OC)cc1C2
Temperature: 90 °C
Yield: 96.4 %

Procedure:
A mixture of 9a-butyl-7-methoxy-4-[4-(trifluoromethane-sulfonyloxy)-phenyl]-1,2,9,9a-tetrahydro-3H-fluoren-3-one (98.9 mg, 0.2 mmol), methyl (E)-3-tributylstannyl-acrylate (112.5 mg, 0.3 mmol) and lithium chloride (25.4 mg, 0.6 mmol) in anhydrous dimethylformamide (1.0 mL) was purged with nitrogen and treated with bis(triphenylphosphine)palladium(II) chloride (7.0 mg, 0.01 mmol). The resulting mixture was purged with nitrogen then stirred under a nitrogen atmosphere with heating in an oil bath at 90° C. for 60 minutes. After cooling, the solvent was evaporated under vacuum. The residue in EtOAc (10 mL) was washed with water (2×5 mL) and brine (5 ml), dried over MgSO4, filtered, and evaporated under vacuum to a gum (194 mg). The crude product was purified by preparative layer chromatography (PLC) on two 0.1×20×20 cm silica gel GF plates, developing with 4:1-hexanes-EtOAc. The major UV visible band at Rf 0.15-0.25 was eluted with EtOAc and the solvent evaporated under vacuum to afford methyl (2E)-3-[4-(9a-butyl-7-methoxy-3-oxo-2,3,9,9a-tetrahydro-1H-fluoren-4-yl)phenyl]-2-propenoate (83 mg) as a pale yellow solid. NMR showed approximately 7-8% of a Bu3SnX impurity.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[C:14]([NH2:16])[N:13]=[C:12]([N:17]3[C@H:22]([CH3:23])[CH2:21][CH2:20][C@H:19]([C:24]([OH:26])=O)[CH2:18]3)[CH:11]=2)=[CH:6][C:5]=1[F:27])(=[O:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:61]([NH2:68])[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1>CN(C=O)C.CCOC(C)=O>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[C:14]([NH2:16])[N:13]=[C:12]([N:17]3[C@H:22]([CH3:23])[CH2:21][CH2:20][C@H:19]([C:24]([NH:68][CH2:61][C:62]4[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=4)=[O:26])[CH2:18]3)[CH:11]=2)=[CH:6][C:5]=1[F:27])(=[O:3])[CH3:2]
Reactant: NCc1ccccc1
Reactant: CC(=O)c1ccc(-c2cc(N3C[C@@H](C(=O)O)CC[C@H]3C)nc(N)n2)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1ccc(-c2cc(N3C[C@@H](C(=O)NCc4ccccc4)CC[C@H]3C)nc(N)n2)cc1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88.8 %

Procedure:
To a solution of (3S,6R)-1-[6-(4-acetyl-3-fluorophenyl)-2-amino-4-pyrimidinyl]-6-methyl-3-piperidinecarboxylic acid (308 mg, 0.827 mmol) and HATU (377 mg, 0.992 mmol) in DMF (3 mL) was added Hunig's base (0.289 ml, 1.654 mmol), and the mixture was stirred at room temperature for 15 minutes. Then benzylamine (0.11 mL, 0.99 mmol) was added, and the reaction mixture was stirred at room temperature for 0.5 hours. LCMS showed reaction was completed. The reaction was poured onto water, and EtOAc was added to extract the product. The product stayed in the EtOAc layer. The organic solution was concentrated to dryness to give the title compound (339 mg) as a yellow solid. LC-MS (ES) m/z=462 [M+H]+.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.Cl.[CH3:17][NH:18][C:19]([C:21]1[CH:22]=[C:23]([NH:27][CH:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:29]([OH:31])=[O:30])[CH:24]=[CH:25][CH:26]=1)=[O:20].C1C=CC2N(O)N=NC=2C=1.[N:48]12[CH2:55][CH2:54][CH:51]([CH2:52][CH2:53]1)[C@@H:50](O)[CH2:49]2>C1COCC1>[CH3:17][NH:18][C:19]([C:21]1[CH:22]=[C:23]([NH:27][CH:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:29]([O:31][C@@H:50]2[CH:51]3[CH2:54][CH2:55][N:48]([CH2:53][CH2:52]3)[CH2:49]2)=[O:30])[CH:24]=[CH:25][CH:26]=1)=[O:20]
Reactant: O[C@H]1CN2CCC1CC2
Reactant: CNC(=O)c1cccc(NC(C(=O)O)c2ccccc2)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CNC(=O)c1cccc(NC(C(=O)O[C@H]2CN3CCC2CC3)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
PS-DCC (798 mg, 0.998 mmol, loading: 1.25 mmol/g) was suspended in dry THF (10 ml). 2-(3-(Methylcarbamoyl)phenylamino)-2-phenylacetic acid hydrochloride (I9) (160 mg, 0.50 mmol), HOBT (153 mg, 0.10 mmol), and (R)-quinuclidin-3-ol (190 mg, 1.50 mmol) were added, and the mixture was shaken at room temperature for 16 hours (UPLC-MS: complete conversion). PS-DCC was removed by filtration and washed with THF and EtOAc. The filtrate was evaporated and the resulting residue was dissolved in EtOAc and washed with NaHCO3, water and brine. The organic layer was separated, dried over Na2SO4, filtered and evaporated. The resulting oil (196 mg, quantitative yield, mixture of diastereomers) was used for the next step without any further purification.
Reaction SMILES: C(OC([N:8]([CH2:21][CH:22]1[CH2:24][CH2:23]1)[CH2:9][C@H:10]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:11]([OH:13])=[O:12])=O)(C)(C)C.Cl>C(Cl)Cl>[ClH:20].[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([C@@H:10]([CH2:9][NH:8][CH2:21][CH:22]2[CH2:24][CH2:23]2)[C:11]([OH:13])=[O:12])=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N(CC1CC1)C[C@@H](C(=O)O)c1ccc(Cl)cc1
Agent: Cl
Solvent: ClCCl
Product: O=C(O)[C@H](CNCC1CC1)c1ccc(Cl)cc1
Reaction time: 8 h
Yield: 190.9 %

Procedure:
Crude (S)-3-(tert-butoxycarbonyl(cyclopropylmethyl)amino)-2-(4-chlorophenyl)propanoic acid (4.6 g, 13 mmol) was dissolved into DCM (130 mL) and excess 4N HCl was added. The reaction was allowed to stir overnight, after which it was concentrated. The resulting white solid was taken up into EtOAC and filtered. The resulting solid washed with EtOAc (4×) to give pure (S)-2-(4-chlorophenyl)-3-(cyclopropylmethylamino)propanoic acid hydrochloride (3.60 g, 95%). This (S)-2-(4-chlorophenyl)-3-(cyclopropylmethylamino)propanoic acid (0.57 g, 2.24 mmol) was dissolved into 10:1 CH3CN:H2O (50 mL) and tetramethylammonium hydroxide pentahydrate (1.00 g) was added followed by Boc2O (0.73 g, 3.36 mmol). The reaction mixture was allowed to stir at room temperature overnight, and the reaction was quenched by the addition of 1N HCl. The reaction was concentrated, and the residue was diluted with EtOAc. The organics were separated, and the aqueous portion was extracted with EtOAc. The combined organics were dried with MgSO4, filtered and concentrated. The crude residue was purified by silica plug eluting Hex to 1:1 Hex/EtOAc to give (S)-3-( tert-butoxycarbonyl(cyclopropylmethyl)amino)-2-(4-chlorophenyl)propanoic acid (0.58 g, 73%) as a clear oil. (LCMS (APCI+) [M-Boc+H]+ 254.0)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2.[CH2:21]([OH:24])[C:22]#[CH:23]>O1CCCC1.CCOCC.Cl.[Cu]I.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>[CH3:9][S:8][C:5]1[CH:6]=[CH:7][C:2]([C:23]#[C:22][CH2:21][OH:24])=[CH:3][CH:4]=1
Reactant: C#CCO
Reactant: CSc1ccc(Br)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOCC
Product: CSc1ccc(C#CCO)cc1
Temperature: 50 °C
Reaction time: 20 h

Procedure:
To a degassed solution of 4-bromothioanisole (10.15 g, 50.0 mmol) in tetrahydrofuran (50 mL) were in the following order added: copper(I) iodide (286 mg, 1.5 mmol), tetrakis(triphenylphosphine)palladium (1.73 g, 1.5 mmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (9.05 mL, 60.0 mmol). The resulting mixture was degassed one more time and a solution of propargyl alcohol (3.5 mL, 60.0 mmol) in tetrahydrofuran (5 mL) was added over period of 10 min. The reaction mixture was slowly heated up to 50° C. and then stirred at this temperature over night (˜20 h). The mixture was diluted with ether (350 mL) and 5% hydrochloric acid (100 mL) was added. The mixture was filtered and the phases were separated. The aqueous phase was extracted with ether (2×60 mL) and collected ethereal solutions were washed with 1M hydrochloric acid (30 mL) and saturated aqueous solution of sodium hydrogen carbonate (2×50 mL), dried with anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography (silica gel Fluka 60, chloroform) affording 3-(4-methylsulfanylphenyl)prop-2-yn-1-ol.
Reaction SMILES: FC(F)(F)C(O)=O.[Si]([O:15][CH2:16][C:17]([O:19][C@H:20]1[C@@H:24]([OH:25])[C@H:23]([N:26]2[CH:34]=[N:33][C:32]3[C:27]2=[N:28][CH:29]=[N:30][C:31]=3[NH2:35])[O:22][C@@H:21]1[CH2:36][O:37][P:38]([O:41][C@H:42]1[CH2:46][C@H:45]([N:47]2[CH:52]=[CH:51][C:50]([NH2:53])=[N:49][C:48]2=[O:54])[O:44][C@@H:43]1[CH2:55][O:56][P:57]([OH:60])([OH:59])=[O:58])([OH:40])=[O:39])=[O:18])(C(C)(C)C)(C)C>ClCCl>[OH:15][CH2:16][C:17]([O:19][C@H:20]1[C@@H:24]([OH:25])[C@H:23]([N:26]2[CH:34]=[N:33][C:32]3[C:27]2=[N:28][CH:29]=[N:30][C:31]=3[NH2:35])[O:22][C@@H:21]1[CH2:36][O:37][P:38]([O:41][C@H:42]1[CH2:46][C@H:45]([N:47]2[CH:52]=[CH:51][C:50]([NH2:53])=[N:49][C:48]2=[O:54])[O:44][C@@H:43]1[CH2:55][O:56][P:57]([OH:59])([OH:60])=[O:58])([OH:40])=[O:39])=[O:18]
Reactant: CC(C)(C)[Si](C)(C)OCC(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccn([C@H]2C[C@H](OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3OC(=O)CO)[C@@H](COP(=O)(O)O)O2)c(=O)n1
Reaction time: 0.5 h
Yield: 23.2 %

Procedure:
Trifluoroacetic acid (2 ml) was added to a solution of (2R,3S,4R,5R)-2-((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-(phosphonooxymethyl)tetrahydrofuran-3-yloxy)(hydroxy)phosphoryloxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 2-(tert-butyldimethylsilyloxy)acetate (Compound 22) (70.0 mg, 87 μmol) in dichloromethane (2 ml) at room temperature, and the mixture was stirred at the same temperature for 30 minutes. Following concentration under reduced pressure, the resulting residue was purified by reverse-phase silica gel column chromatography (0.1% aqueous formic acid solution/0.1% formic acid-acetonitrile solution) to afford (2R,3S,4R,5R)-2-((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-(phosphonooxymethyl)tetrahydrofuran-3-yloxy)(hydroxy)phosphoryloxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 2-hydroxyacetate (HOGly-pdCpA) (Compound 20) (14.0 mg, 23%).
Reaction SMILES: CC1C=C(N2CCN(CCOC3C=CC=CC=3)C2=O)SC=1C(O)=O.[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41](O)=[O:42])=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:28][CH:27]=1.[CH3:48][C:49]1[CH:53]=[CH:52][S:51][C:50]=1[CH2:54][NH2:55]>>[F:25][C:26]1[CH:27]=[CH:28][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41]([NH:55][CH2:54][C:50]4[S:51][CH:52]=[CH:53][C:49]=4[CH3:48])=[O:42])=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:46][CH:47]=1
Reactant: Cc1ccsc1CN
Reactant: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: Cc1cc(N2CCN(CCOc3ccccc3)C2=O)sc1C(=O)O
Product: Cc1ccsc1CNC(=O)c1sc(N2CCN(Cc3ccc(F)cc3)C2=O)cc1C
Yield: 73 %

Procedure:
Following the procedures as described in Example 55, making variations as required to replace 3-methyl-5-(2-oxo-3-(2-phenoxyethyl)imidazolidin-1-yl)thiophene-2-carboxylic acid with 5-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-3-methylthiophene-2-carboxylic acid to react with (3-methylthiophen-2-yl)methanamine, the title compound was obtained as a colorless solid in 73% yield: 1H NMR (300 MHz, CDCl3) δ 7.30-7.23 (m, 2H), 7.13 (d, J=5.0 Hz, 1H), 7.08-6.99 (m, 2H), 6.82 (d, J=5.0 Hz, 1H), 6.08 (s, 1H), 5.83 (br s, 1H), 4.65 (d, J=5.0 Hz, 2H), 4.42 (s, 2H), 3.83-3.74 (m, 2H), 3.47-3.39 (m, 2H), 2.49 (5, 3H), 2.24 (s, 3H): MS (ES+) m/z 444.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:12])=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[OH-].[Na+].[CH3:20]O>O>[NH2:1][C:2]1[C:3]([Cl:12])=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5]([O:7][CH3:20])=[O:6]
Reactant: Nc1cc(Cl)cc(C(=O)O)c1Cl
Reactant: CO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)c1cc(Cl)cc(N)c1Cl
Reaction time: 3 h
Yield: 79 %

Procedure:
3-amino-2,5-dichlorobenzoic acid (5.00 g, 24.27 mmol) was stirred in methanol (30 ml) at room temperature. Sulfuric Acid (5 ml) was added dropwise. Reaction stirred for 3 hours and was then diluted with water (30 ml) and basified using sodium hydroxide. Mixture was extracted with ethyl acetate×3. Solvent was removed to afford methyl 3-amino-2,5-dichlorobenzoate (4.20 g, 79%) as a solid.