Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:18][C:19]1[N:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:22]=[C:21]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:20]=1.C(N(CC)C(C)C)(C)C.CCCP(=O)=O>CC1CCCO1>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([NH:18][C:19]1[N:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:22]=[C:21]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:20]=1)=[O:6]
Reactant: O=C(O)c1cc(-c2ccccn2)c(F)cc1Cl
Reactant: CCOC(=O)c1cc(N)n(-c2ccccc2)n1
Agent: CCCP(=O)=O
Solvent: CC1CCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc(NC(=O)c2cc(-c3ccccn3)c(F)cc2Cl)n(-c2ccccc2)n1
Temperature: 25 °C
Yield: 299.7 %

Procedure:
To a refluxing mixture of 2-chloro-4-fluoro-5-(pyridin-2-yl)benzoic acid (Preparation 22A, 9.2 g, 36.6 mmol), ethyl 5-amino-1-phenyl-1H-pyrazole-3-carboxylate (8.45 g, 36.6 mmol), N,N-diisopropylethylamine (19.2 mL, 110 mmol) and 2-methyltetrahydrofuran (320 mL), was added propylphosphonic anhydride solution (255 mL, 429 mmol, >50% by weight in EtOAc) dropwise under argon, and the reaction maintained at reflux for 5 hours. After cooling to room temperature, the reaction was filtered and the filtrate concentrated in vacuo. The residue was dissolved in ethyl acetate (350 mL) and washed with saturated aqueous sodium hydrogen carbonate solution (300 mL). The organic layer was filtered under vacuum and the solids washed with EtOAc (20 mL) and TBME (200 mL) to give the title compound (51 g, 78%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:32]1[C:36](=[O:37])[C:35]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:34]2[C:33]1=[O:42].N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][O:10][N:32]1[C:36](=[O:37])[C:35]2[C:34](=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:33]1=[O:42])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC(C)(C)OC(=O)NCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 85.2 %

Procedure:
tert-Butyl(2-hydroxyethyl)carbamate (1.61 g, 10.0 mmol) was stirred under an argon atmosphere at room temperature with dehydrated tetrahydrofuran (50 mL). Then, triphenylphosphine (2.75 g) and N-hydroxyphthalimide (Pht-OH, 1.71 g) were added. After the reaction mixture was under ice cooling, diethyl azodicarboxylate (DEAD, 1.82 g) was added dropwise gradually, followed by stirring at room temperature for 24 hours. After completion of the reaction, the residue resulting from distilling off the solvent under reduced pressure was subjected to silica gel column chromatography (hexane/ethyl acetate=4/1→1/1) to afford 2.61 g of the title compound (yield 85.2%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[C:9]([CH3:16])[CH:8]=1)(=O)=O.[N+:19]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)([O-:21])=[O:20].C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>C1(C)C=CC=CC=1>[CH3:16][C:9]1[CH:8]=[C:7]([C:25]2[CH:26]=[CH:27][C:22]([N+:19]([O-:21])=[O:20])=[CH:23][CH:24]=2)[CH:12]=[CH:11][C:10]=1[C:13](=[O:15])[CH3:14]
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Reactant: CC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)cc1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1C
Temperature: 85 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
A mixture of 4-acetyl-3-methylphenyl trifluoromethanesulfonate (6.90 g, 24.0 mmol), 4-nitrophenylboronic acid (3.80 g, 24 mmol), 2 N aqueous sodium carbonate (88.0 mL), dioxane (88.0 mL), and toluene (296 mL) was purged with argon for 30 minutes before [1,1′-bis(diphenyl-phosphino)-ferrocene]dichloro palladium(II) (1:1 complex with dichloromethane, 1.90 g, 2.30 mmol) was added. The reaction mixture was heated at 85° C. and stirred overnight. The layers were separated and the organic layer was washed with water (2×50 mL), dried over magnesium sulfate, and concentrated under reduced pressure to give a dark brown oil. This material was purified by flash chromatography (7 to 20% ethyl acetate/hexane) to give 1-(3-methyl-4′-nitro-1,1′-biphenyl-4-yl)ethanone as a light yellow solid (6.12 g, 99% yield). GC-MS m/z 255 (M+), ret. time 9.89 min; 1H NMR (CDCl3) δ: 2.61 (s, 3H), 2.62 (s, 3H), 7.49-55 (m, 2H), 7.78 (d, 2H), 7.81 (d, 1H), 8.32 (d, 2H).
Reaction SMILES: C(O[C:4]1[C:5](=[O:16])[C:6](=[O:15])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)C.[Cl:17][C:18]1[CH:33]=[CH:32][C:21]([O:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][NH2:31])=[CH:25][CH:24]=2)=[CH:20][CH:19]=1>CCO>[Cl:17][C:18]1[CH:33]=[CH:32][C:21]([O:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][NH:31][C:4]3[C:5](=[O:16])[C:6](=[O:15])[C:7]=3[NH:8][C:9]3[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=3)=[CH:25][CH:24]=2)=[CH:20][CH:19]=1
Reactant: NCCc1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: CCOc1c(Nc2ccncc2)c(=O)c1=O
Solvent: CCO
Product: O=c1c(NCCc2ccc(Oc3ccc(Cl)cc3)cc2)c(Nc2ccncc2)c1=O
Temperature: 150 °C

Procedure:
3-Ethoxy-4-(pyridine-4-yl-amino)-3-cyclobutene-1,2-dione (70 mg, 0.32 mmol) and 2-[4-(4-chlorophenoxy)-phenyl]-ethylamine (105 mg, 0.45 mmol) in EtOH (1.5 mL) were stirred and heated to 150° C. in a sealed vessel in a microwave synthesizer for 30 s. After cooling to r.t. the precipitate was filtered off, washed with EtOH (3×3 mL) and dried in vacuo.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][N:5]=[C:4]2[NH:14][CH:15]=[CH:16][C:3]=12.[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.C(Cl)Cl>[Br:17][C:16]1[C:3]2[C:4](=[N:5][CH:6]=[C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:2]=2[Cl:1])[NH:14][CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Clc1c(-c2ccccc2)cnc2[nH]ccc12
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Clc1c(-c2ccccc2)cnc2[nH]cc(Br)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.6 %

Procedure:
4-Chloro-5-phenyl-1H-pyrrolo[2,3-b]pyridine (0.912 g, 3.99 mmol) was placed in CHCl3 (5 mL) at room temperature. N-Bromosuccinimide (0.710 g, 3.99 mmol) was then added, and the reaction was stirred at room temperature for 1 hour. The reaction was diluted with DCM and washed with saturated NaHCO3. The organic fraction was dried, filtered, and concentrated to give the crude product 3-bromo-4-chloro-5-phenyl-1H-pyrrolo[2,3-b]pyridine (1.1 g, 89.7% yield).
Reaction SMILES: Cl.[C:2]([C:4]1[CH:30]=[CH:29][C:7]([CH2:8][N:9]2[C:13]([CH2:14][CH2:15][NH:16][C:17]([C@@H:19]3[CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21][NH:20]3)=[O:18])=[CH:12][N:11]=[CH:10]2)=[CH:6][CH:5]=1)#[N:3].ON1C2C=CC=CC=2N=N1.C(Cl)CCl.[CH3:45][C:46]1[C:54]([CH3:55])=[CH:53][CH:52]=[CH:51][C:47]=1[C:48](O)=[O:49].CN1CCOCC1>CN(C=O)C>[C:2]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]2[C:13]([CH2:14][CH2:15][NH:16][C:17]([C@@H:19]3[CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21][N:20]3[C:48](=[O:49])[C:47]3[CH:51]=[CH:52][CH:53]=[C:54]([CH3:55])[C:46]=3[CH3:45])=[O:18])=[CH:12][N:11]=[CH:10]2)=[CH:29][CH:30]=1)#[N:3]
Reactant: N#Cc1ccc(Cn2cncc2CCNC(=O)[C@@H]2Cc3ccccc3CN2)cc1
Reactant: Cc1cccc(C(=O)O)c1C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1cccc(C(=O)N2Cc3ccccc3C[C@H]2C(=O)NCCc2cncn2Cc2ccc(C#N)cc2)c1C
Reaction time: 18 h

Procedure:
To a solution of 1,2,3,4-Tetrahydro-isoquinoline-3(S)-carboxylic acid {2-[3-(4-cyanobenzyl)-3H-imidazol-4-yl]-ethyl}-amide hydrochloride (Example 1, Step C) (0.23 g, 0.52 mmol) in DMF (5 mL) was added l-hydroxybenzotriazole (0.079 g, 0.52 mmol), EDC (0.099 g, 0.52 mmol), 2,3-dimethylbenzoic acid (0.077 g, 0.52 mmol) and N-methylmorpholine (0.23 mL, 2.08 mmol). After stiffing for 18 hr. the mixture was evaporated in vacuo and the residue was partitioned betweem EtOAc (50 mL) and saturated NaHCO3 solution (30 mL). The organic layer was washed with saturated NaCl solution (30 mL) and dried (MgSO4). Filtration and concentration gave the title compound after purification by preparative HPLC on a Delta-pak C-18 column eluting with 0.1%TFA/H2O: 0.1%TFA/CH4CN, 95:5 to 5:95.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([F:14])[CH:3]=1.C([Li])CCC.CN([CH:23]=[O:24])C>O1CCCC1>[F:14][C:4]1[CH:3]=[C:2]([CH:23]=[O:24])[CH:7]=[CH:6][C:5]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CN(C)C=O
Reactant: Fc1cc(Br)ccc1-c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ccc(-c2ccccc2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.4 %

Procedure:
4-Bromo-2-fluoro-biphenyl (2 gm, 8 mmole) was dissolved in 20 ml of anhydrous tetrahydrofuran, THF, cooled to −78° C. under argon (Ar), n-Butyl lithium 2.5 M (3.5 ml, 8.8 mmole) was added drop wise over 10 min, and was stirred for additional 1 hr, DMF anhydrous (0.68 ml, 8.8 mmole) was then added, stirred for additional 1 hr, then warmed to room temperature over 4 hr, It was then quenched with water, extracted with ether, ether was dried, evaporated, the produced compound was purified using 9:1 hexane/ethyl acetate, to produce white solid (1 gm, 62.5%); H1-NMR INOVA-500 (CDCl3) δ 7.416-7.495 (m, 3H), 7.581-7.661 (m, 4H), 7.723 (d, J=8.0 Hz, 1H), 9.991 (s, 1H).
Reaction SMILES: C([O:5][C:6](=[O:46])[CH2:7][N:8]1[CH:12]=[C:11]([C:13](=[O:23])[N:14]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH2:17][CH3:18])[N:10]=[C:9]1[C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][C:25]=1[C:34]([N:36]1[CH2:45][CH2:44][C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:37]1)=[O:35])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:19]([N:14]([CH2:15][CH2:16][CH2:17][CH3:18])[C:13]([C:11]1[N:10]=[C:9]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][C:25]=2[C:34]([N:36]2[CH2:45][CH2:44][C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH2:37]2)=[O:35])[N:8]([CH2:7][C:6]([OH:46])=[O:5])[CH:12]=1)=[O:23])[CH2:20][CH2:21][CH3:22]
Reactant: CCCCN(CCCC)C(=O)c1cn(CC(=O)OC(C)(C)C)c(-c2ccc(C(=O)OC)cc2C(=O)N2CCc3ccccc3C2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCN(CCCC)C(=O)c1cn(CC(=O)O)c(-c2ccc(C(=O)OC)cc2C(=O)N2CCc3ccccc3C2)n1
Reaction time: 1 h
Yield: 79.1 %

Procedure:
To a solution of methyl 4-(1-(2-tert-butoxy-2-oxoethyl)-4-(dibutylcarbamoyl)-1H-imidazol-2-yl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate (300 mg, 0.44 mmol) in DCM (3.0 mL) was added trifluoroacetic acid (3.0 mL) at 0° C. The reaction mixture was allowed to room temperature and stirring was continued for 1 h. The reaction mixture was concentrated in vacuo and the resulting residue was dissolved in DCM and washed with sat. NaHCO3 solution. The organic layer was dried over Na2SO4 and concentrated to give the title compound (200 mg, 80%). MS(ESI) m/z 575.4 (M+H)+.
Reaction SMILES: C(OC([NH:8][C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=O)=O)(C)(C)C.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH3:46][N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.Cl>C1COCC1.CCOC(C)=O>[NH2:8][C:9]([CH3:13])([CH3:14])[C:10]([N:50]1[CH2:51][CH2:52][N:47]([CH3:46])[CH2:48][CH2:49]1)=[O:12]
Reactant: CN1CCNCC1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN1CCN(C(=O)C(C)(C)N)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-((tert-Butoxycarbonyl)amino)-2-methylpropanoic acid (Boc-Aib-OH, 54, 10.0 g, 49.2 mol), EDC.HCl (11.3 g, 59.0 mmol), HOBt (9.97 g, 73.8 mmol) and DIPEA (25.6 mL, 148 mmol) were stirred in 250 mL of THF until all solids dissolved. N-methyl-piperazine was added (10.9 mL, 98.4 mmol) and the reaction was stirred at room temperature for 18 hrs. The mixture was diluted with 300 mL of EtOAc and washed twice with saturated aqueous NaHCO3. The organic layer was then washed with brine, dried over MgSO4, filtered, and the solvent was removed in vacuo. This crude material was dissolved in 300 mL of CH3CN. HCl (4N in dioxane, 49 mL, 196 mmol) was added over 10 minutes. The reaction was stirred for 8 hrs, during which time the product forms a white precipitate. The product was filtered, washed with CH2Cl2, and dried under high vacuum over night to provide the product 55 as the bis-hydrochloride salt (10.4 g, 82% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.30 (br. s., 3 H), 4.35 (d, J=13.6 Hz, 2 H), 3.52 (br. s., 2 H), 3.41 (d, J=11.1 Hz, 2 H), 3.01 (q, J=11.1 Hz, 2 H), 2.77 (d, J=3.5 Hz, 3 H), 1.56 (s, 6 H). MS (ES+) [M+H]+=186.
Reaction SMILES: NC1N=C(N)C2C(=NC=C(CN(C3C=CC=CC=3)C3C=CC=CC=3)N=2)N=1.[CH:27]1[C:37]2[C:31](=[N:32][C:33]3[CH:41]=[CH:40][CH2:39][CH2:38][C:34]=3[CH2:35][CH:36]=2)[CH:30]=[CH:29][CH:28]=1.[H-].[Na+].Br.[NH2:45][C:46]1[N:47]=[C:48]([NH2:58])[C:49]2[N:55]=[C:54]([CH2:56]Br)[CH:53]=[CH:52][C:50]=2[N:51]=1>>[NH2:45][C:46]1[N:47]=[C:48]([NH2:58])[C:49]2[N:55]=[C:54]([CH2:56][CH:38]3[C:34]4[CH2:35][CH:36]=[C:37]5[CH:27]=[CH:28][CH:29]=[CH:30][C:31]5=[N:32][C:33]=4[CH:41]=[CH:40][CH2:39]3)[CH:53]=[CH:52][C:50]=2[N:51]=1
Reactant: C1=CC2=C(CC=c3ccccc3=N2)CC1
Reactant: Nc1nc(N)c2nc(CBr)ccc2n1
Agent: Br
Agent: Nc1nc(N)c2nc(CN(c3ccccc3)c3ccccc3)cnc2n1
Agent: [H-]
Product: Nc1nc(N)c2nc(CC3CC=CC4=C3CC=c3ccccc3=N4)ccc2n1

Procedure:
9-[(2,4-Diaminopyrido[3,2-d]pyrimidin-6-yl)methyl]-9,10-dihydrodibenz-[b,f]azepine (Formula I: Ar=2,4-diaminopyrido[3,2-d]pyrimidin-6-yl; W=CH2; X=N; Z=CH2CH2; m=n=0) is prepared similarly to N-[(2,4-diaminopteridin-6-yl)methyl]-N,N-diphenylamine as disclosed above by using 9,10-dihydrodibenz[b,f]azepine (158 mg, 0.8 mmol), NaH (50 mg, 2.1 mmol), and 2,4-diamino-6-bromomethylpyrido[3,2-d]pyrimidine hydrobromide (100 mg, 0.3 mmol). The product can be purified by chromatography.
Reaction SMILES: [OH:1][P:2]([CH2:20][CH:21]([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:22]([NH:24][C@H:25]([C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:23])([CH:4]([NH:12]C(OC(C)(C)C)=O)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[F:50][C:51]([F:56])([F:55])[C:52]([OH:54])=[O:53].ClCCl>>[F:50][C:51]([F:56])([F:55])[C:52]([OH:54])=[O:53].[NH2:12][CH:4]([P:2]([CH2:20][CH:21]([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:22]([NH:24][C@H:25]([C:33]([O:35][CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)=[O:34])[CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:23])([OH:3])=[O:1])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)P(=O)(O)CC(Cc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(Cc1ccccc1)P(=O)(O)CC(Cc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Yield: 98 %

Procedure:
Phenylmethyl N- [2 -[[hydroxy [2 -phenyl-1-[[(tert-butoxy) carbonyl]amino]ethyl]phosphinyl]methyl]-1-oxo-3-phenylpropyl]-L-phenylalaninate is treated with a trifluoroacetic acid/dichloromethane mixture for one hour at room temperature. The mixture is evaporated to dryness. The product obtained is precipitated from ether. The product is recovered in a yield of 98%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]([NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])=[CH:5][C:6]1[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:7]=1[F:13]>C(O)C>[CH3:1][O:2][C:3](=[O:25])[C@@H:4]([NH:14][C:15]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16])[CH2:5][C:6]1[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:7]=1[F:13]
Reactant: COC(=O)C(=Cc1c(F)cccc1F)NC(=O)OCc1ccccc1
Solvent: CCO
Product: COC(=O)[C@H](Cc1c(F)cccc1F)NC(=O)OCc1ccccc1
Reaction time: 48 h

Procedure:
A mixture of 2-benzyloxycarbonylamino-3-(2,6-difluorophenyl)acrylic acid methyl ester (14.4 mmol), and catalyst, (+)-1,2-bis-[(2S,5S)2,5-diethylphopholano]benzene (cyclooctadiene)rhodium (1) trifluoromethanesulfonate (Strem. Chemical No. 45-0151; 104 mg, 0.14 mmol) was dissolved in ethanol (150 mL). Hydrogenation was performed at 50 psi H2 at room temperature over 2 days. The solvent was then removed by rotary evaporation to give 2(S)-benzyloxycarbonylamino-3-(2,6-difluorophenyl)propionic acid methyl ester.
Reaction SMILES: [C:1]1([C:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[S:8][CH2:9][CH2:10][C:11](ON2C(=O)CCC2=O)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:33][C:34]1[C:43]2[N:44]=[C:45]([CH2:56][O:57][CH2:58][CH3:59])[N:46]([CH2:47][C:48]([NH:51][S:52]([CH3:55])(=[O:54])=[O:53])([CH3:50])[CH3:49])[C:42]=2[C:41]2[CH:40]=[CH:39][C:38]([OH:60])=[CH:37][C:36]=2[N:35]=1>CN(C=O)C.C(OCC)(=O)C>[NH2:33][C:34]1[C:43]2[N:44]=[C:45]([CH2:56][O:57][CH2:58][CH3:59])[N:46]([CH2:47][C:48]([CH3:50])([NH:51][S:52]([CH3:55])(=[O:54])=[O:53])[CH3:49])[C:42]=2[C:41]2[CH:40]=[CH:39][C:38]([O:60][CH2:37][CH2:36][CH2:41][CH2:42][CH2:43][CH2:34][NH:33][C:11](=[O:12])[CH2:10][CH2:9][S:8][C:7]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:37][C:36]=2[N:35]=1
Reactant: CCOCc1nc2c(N)nc3cc(O)ccc3c2n1CC(C)(C)NS(C)(=O)=O
Reactant: O=C(CCSC(c1ccccc1)(c1ccccc1)c1ccccc1)ON1C(=O)CCC1=O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOCc1nc2c(N)nc3cc(OCCCCCCNC(=O)CCSC(c4ccccc4)(c4ccccc4)c4ccccc4)ccc3c2n1CC(C)(C)NS(C)(=O)=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
Succinimido 3-(triphenylmethylthio)propanoate (246 mg, 0.553 mmol) was added to a 0° C. solution of N-{2-[4-amino-2-(ethoxymethyl)-7-hydroxy-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}methanesulfonamide (280 mg, 0.553 mmol) in DMF (5 mL). The solution was stirred at 0° C. for 3 hours, then was diluted with ethyl acetate (100 mL) and washed with water (3×20 mL) and brine (40 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by HPFC on silica gel (gradient elution with 2-50% CMA in chloroform) to provide 0.22 g of N-{6-[(4-amino-2-(ethoxymethyl)-1-{2-methyl-2-[(methylsulfonyl)amino]propyl}-1H-imidazo[4,5-c]quinolin-7-yl)oxy]hexyl}-3-(tritylthio)propanamide as a white solid.
Reaction SMILES: [Na].[C:2]([NH:5][CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:4])[CH3:3].[C:17]1([CH2:27]Cl)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1.OS([O-])(=O)=O.[K+]>C(O)C.CCCCCC>[C:17]1([CH2:27][C:6]([NH:5][C:2](=[O:4])[CH3:3])([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: ClCc1cccc2ccccc12
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Na]
Solvent: CCCCCC
Solvent: CCO
Product: CCOC(=O)C(Cc1cccc2ccccc12)(NC(C)=O)C(=O)OCC
Temperature: 25 °C

Procedure:
Sodium (28 mmol; 0.64 g) is introduced into 50 cm3 of absolute ethanol, under inert atmosphere. At 0° C., diethyl 2-acetamidomalonate (28 mmol; 6.08 g) dissolved in 35 cm3 of absolute ethanol is added, followed by dropwise addition, with a syringe, of (1-naphthyl)methyl chloride (28 mmol; 4.1 cm3). The mixture is maintained at reflux until the starting material has disappeared (6 h, then overnight at room temperature and then 2 h at reflux). The reaction medium is poured onto a KHSO4 (0.05M; 240 cm3)/hexane (120 cm3) mixture and stirred vigorously. A white precipitate, which is the expected malonic derivative, is recovered.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([OH:11])[CH2:5]2.C1N=CN([C:17](N2C=NC=C2)=[S:18])C=1>C(Cl)Cl>[N:1]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([OH:11])[CH2:5]2)=[C:17]=[S:18]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc2c(c1)CC(O)C2
Solvent: ClCCl
Product: OC1Cc2ccc(N=C=S)cc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
5-Amino-indan-2-ol (149 mg, 1 mmol) was dissolved in CH2Cl2 (10 mL) and TCDI (thiocarbodiimidazole, 178 mg, 1 mmol) was added to the solution. The reaction mixture was stirred at room temperature for 30 min. Silica gel was added to the reaction mixture and dried. Purification of silica gel coated crude product by column chromatography (EtOAc:Hexane=3:7) afforded the title product as a white solid (132 mg).
Reaction SMILES: CS(OS(C)(=O)=O)(=O)=O.[N:10]1([C:16]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH:28]=[C:27]([C:29]4[C:37]5[C:32](=[CH:33][CH:34]=[C:35]([CH2:38][OH:39])[CH:36]=5)[N:31](C5CCCCO5)[N:30]=4)[N:26]=[N:25]3)=[CH:20][CH:19]=2)=[O:17])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.CCN(C(C)C)C(C)C.O[C@@H:56]1[CH2:61][O:60][C:58](=[O:59])[CH2:57]1>C(Cl)Cl>[N:10]1([C:16]([C:18]2[CH:19]=[CH:20][C:21]([N:24]3[CH:28]=[C:27]([C:29]4[C:37]5[C:32](=[CH:33][CH:34]=[C:35]([CH2:38][O:39][C@@H:56]6[CH2:61][O:60][C:58](=[O:59])[CH2:57]6)[CH:36]=5)[NH:31][N:30]=4)[N:26]=[N:25]3)=[CH:22][CH:23]=2)=[O:17])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: O=C(c1ccc(-n2cc(-c3nn(C4CCCCO4)c4ccc(CO)cc34)nn2)cc1)N1CCOCC1
Reactant: O=C1C[C@H](O)CO1
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1C[C@H](OCc2ccc3[nH]nc(-c4cn(-c5ccc(C(=O)N6CCOCC6)cc5)nn4)c3c2)CO1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 7.2 %

Procedure:
A solution of methanesulfonic anhydride (113 mg; 0.65 mmol; 1.6 eq.) in DCM (3.0 mL) was added dropwise over 1 min to a solution of [3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl]methanol (194 mg; 0.40 mmol; 1.0 eq.) in DIEA (1.0 mL; 5.9 mmol; 15 eq.) and DCM (3.0 mL) containing activated molecular sieves. After 10 min, a solution of (S)-3-hydroxy-g-butyrolactone (160 mg; 1.57 mmol; 4 eq.) in DCM (1.0 mL) was added dropwise over 2 min. The reaction mixture was then stirred for 16 h at RT. It was filtered through a celite pad and the filtrate was concentrated under reduced pressure. The residue was redissolved in MeOH (2 mL) and hydrogen chloride (8 mL of a 4N solution in dioxane) was added. The reaction mixture was stirred at RT for 3 h and then concentrated under reduced pressure. Purification by preparative HPLC gave the title compound as a white solid (14 mg, 7%). 1H NMR (300 MHz, DMSO-d6) δ 13.41 (s, 1H), 9.38 (s, 1H), 8.33 (s, 1H), 8.15 (d, J=8.5 Hz, 2H), 7.69 (d, J=8.5 Hz, 2H), 7.61 (d, J=8.6 Hz, 1H), 7.49-7.37 (m, 1H), 4.69 (s, 2H), 4.47-4.34 (m, 3H), 3.82-3.40 (m, 8H), 2.88 (dd, J=17.8, 5.7 Hz, 1H), 2.56 (d, J=17.8 Hz, 1H). HPLC (max plot) 96.5%; Rt %2.59 min. UPLC/MS: (MS+) 489.5, (MS−) 487.6.