Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [B:1]([O:10][CH:11]([CH3:13])[CH3:12])([O:6][CH:7]([CH3:9])[CH3:8])OC(C)C.[Cl:14][CH2:15]I.C([Li])CCC.Cl.C(OCC)(=O)C.OC(C(O)(C)C)(C)C>CCCCCC.O1CCCC1>[Cl:14][CH2:15][B:1]1[O:6][C:7]([CH3:8])([CH3:9])[C:11]([CH3:12])([CH3:13])[O:10]1
Reactant: ClCI
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CC(C)(O)C(C)(C)O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC1(C)OB(CCl)OC1(C)C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 80 %

Procedure:
To the mixture of triisopropyl borate (15 ml, 65 mmol), chloroiodomethane (13 g, 72 mmol), and tetrahydrofuran (78 ml), n-butyllithium (a 1.6 M n-hexane solution, 41 ml, 65 mmol) was added dropwise at −78° C. (an outer temperature) for 20 min, and then the obtained mixture was stirred at room temperature for 2.5 hours. The reaction mixture was cooled to 0° C. (an outer temperature), and a 4 N hydrochloric acid-ethyl acetate solution was added dropwise thereto at the same temperature until the reaction mixture became neutral. At the same temperature, pinacol (7.7 g, 65 mmol) was added to the reaction mixture, and then the reaction mixture was stirred at room temperature for 40 min. The solvents were evaporated under reduced pressure, and then the obtained residue was distilled under reduced pressure (63-70° C., 11 mmHg), thereby obtaining the entitled compound (9.2 g, 52 mmol, 81%).
Reaction SMILES: C([N+](CCCC)(CCCC)CCCC)CCC.[P:18]([O:22][CH2:23][C@@H:24]1[C@@H:28]([O:29][P:30]([O:33][CH2:34][C@@H:35]2[C@@H:39]([OH:40])[C@@H:38]([OH:41])[C@H:37]([N:42]3[CH:50]=[N:49][C:48]4[C:43]3=[N:44][CH:45]=[N:46][C:47]=4[NH2:51])[O:36]2)([OH:32])=[O:31])[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25]1)([OH:21])([OH:20])=[O:19].[N:60]([CH2:63][CH2:64][CH2:65][CH2:66][C@H:67]([NH:74][C:75]([O:77][C:78]([CH3:81])([CH3:80])[CH3:79])=[O:76])[C:68](OCC#N)=[O:69])=[N+:61]=[N-:62]>O.O1CCCC1>[N:60]([CH2:63][CH2:64][CH2:65][CH2:66][C@@H:67]([NH:74][C:75]([O:77][C:78]([CH3:81])([CH3:80])[CH3:79])=[O:76])[C:68]([O:40][C@H:39]1[C@@H:38]([OH:41])[C@H:37]([N:42]2[CH:50]=[N:49][C:48]3[C:43]2=[N:44][CH:45]=[N:46][C:47]=3[NH2:51])[O:36][C@H:35]1[CH2:34][O:33][P:30]([O:29][C@H:28]1[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25][C@@H:24]1[CH2:23][O:22][P:18]([OH:21])([OH:20])=[O:19])([OH:32])=[O:31])=[O:69])=[N+:61]=[N-:62]
Reactant: Nc1ccn([C@H]2C[C@H](OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](COP(=O)(O)O)O2)c(=O)n1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCN=[N+]=[N-])C(=O)OCC#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CCCCN=[N+]=[N-])C(=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
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 27.8 %

Procedure:
A solution of ((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-(((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (hydroxy)phosphoryl)oxy)tetrahydrofuran-2-yl)methyl dihydrogenphosphate (Compound 1h) (78 mg, 0.122 mmol) in water (0.3 mL) and a solution of (S)-cyanomethyl 6-azido-2-((tert-butoxycarbonyl)amino)hexanoate (Compound tk49) (152 mg, 0.488 mmol) in tetrahydrofuran (0.3 mL) were added to buffer A (18 mL), and the mixture was stirred at room temperature for 0.75 hour. Following lyophilization, the resulting residue was purified by reverse-phase silica gel column chromatography (0.05% aqueous trifluoroacetic acid solution/0.05% trifluoroacetic acid-acetonitrile solution) to afford (2S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 6-azido-2-((tert-butoxycarbonyl)amino)hexanoate (Compound tk50) (30.2 mg, 28%).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=3)[CH:12]=2)([OH:10])[CH:7]([CH3:9])[CH3:8])[N:3]=[CH:2]1.[C:23]([O:26][CH2:27]Br)(=[O:25])[CH3:24].C(N(CC)CC)C>C1COCC1>[C:23]([O:26][CH2:27][N:1]1[CH:5]=[C:4]([C:6]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=3)[CH:12]=2)([OH:10])[CH:7]([CH3:9])[CH3:8])[N:3]=[CH:2]1)(=[O:25])[CH3:24]
Reactant: CC(=O)OCBr
Reactant: COc1ccc2cc(C(O)(c3c[nH]cn3)C(C)C)ccc2c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc2cc(C(O)(c3cn(COC(C)=O)cn3)C(C)C)ccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.1 %

Procedure:
1-(1H-Imidazol-4-yl)-1-(6-methoxynaphthalen-2-yl)-2-methyl-1-propanol (100 mg) was dissolved in THF (6 ml), and to the solution were added bromomethyl acetate (160 mg) and triethylamine (40 mg). The mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated, and the residue was purified by silica gel chromatography (eluent, dichloromethane-methanol=20:1) to give the titled compound (30 mg) as a colorless solid.
Reaction SMILES: [C:1](=[O:8])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[NH2:2].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.Br[C:58]1[CH:63]=[N:62][CH:61]=[C:60]2[N:64]([CH2:67][CH3:68])[N:65]=[CH:66][C:59]=12>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C.O1CCOCC1>[CH2:67]([N:64]1[C:60]2=[CH:61][N:62]=[CH:63][C:58]([NH:2][C:1](=[O:8])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[C:59]2[CH:66]=[N:65]1)[CH3:68]
Reactant: CC(C)(C)OC(N)=O
Reactant: CCn1ncc2c(Br)cncc21
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCn1ncc2c(NC(=O)OC(C)(C)C)cncc21
Yield: 84.7 %

Procedure:
tert-Butyl carbamate (90 mg), cesium carbonate (500 mg), Pd2(dba)3 (46 mg), and Xantphos (58 mg) were added to a dioxane solution (2 ml) containing 4-bromo-1-ethyl-1H-pyrazolo[3,4-c]pyridine (115 mg) obtained in the 1st step, followed by microwave irradiation (Initiator™, 130° C., 1 hour, 2.45 GHz, 0-240 W). Ethyl acetate was added to the reaction solution, insoluble matter was removed by filtration, and the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=1:0 to 3:1). A white solid of tert-butyl (1-ethyl-1H-pyrazolo[3,4-c]pyridin-4-yl)carbamate (113 mg) was thus obtained.
Reaction SMILES: CO[C:3](=O)[C:4]([S:9]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=1)(=[O:11])=[O:10])=[CH:5][O:6]CC.[N+:21]([C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=1)[NH2:27])([O-:23])=[O:22]>>[F:19][C:14]1[CH:13]=[C:12]([S:9]([C:4]2[CH:3]=[N:27][C:26]3[C:28]([C:5]=2[OH:6])=[CH:29][CH:30]=[C:24]([N+:21]([O-:23])=[O:22])[CH:25]=3)(=[O:10])=[O:11])[CH:17]=[CH:16][C:15]=1[F:18]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: CCOC=C(C(=O)OC)S(=O)(=O)c1ccc(F)c(F)c1
Product: O=[N+]([O-])c1ccc2c(O)c(S(=O)(=O)c3ccc(F)c(F)c3)cnc2c1

Procedure:
The title compound was prepared applying the procedure described in Example 4 from 2-(3,4-difluoro-benzenesulfonyl)-3-ethoxy-acrylic acid methyl ester (3.49 g, 11.4 mmol) and 3-nitroaniline (1.57 g, 11.4 mmol). The yield was 1.6 g (38.3%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:11](=[O:26])[C@:10]([CH2:28][C:29](O)=[O:30])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.Cl.[NH2:50][NH:51][C:52]([NH2:54])=[O:53]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:11](=[O:26])[C@:10]([CH2:28][C:29]([NH:50][NH:51][C:52]([NH2:54])=[O:53])=[O:30])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: NNC(N)=O
Reactant: CCC(CC)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC(CC)N1C(=O)[C@@](C)(CC(=O)NNC(N)=O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of 320 mg (0.69 mmol) of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)acetic acid (Example 71, Step F) and 921 mg (2.42 mmol) of HOBt in DMF (13 mL) was added 0.58 mL (4.15 mmol) of triethylamine. After stirring at room temperature for 40 min, added 270 mg (2.42 mmol) of semicarbazide hydrochloride. The resulting dark red solution was stirred at room temperature for 2.5 h, and then was concentrated under reduced pressure. Purification of the residue by reversed phase prep. HPLC (Sunfire™ Prep C18 OBD 10 μm column (Waters, Milford, Mass.), gradient elution of 40% MeCN in water to 90% MeCN in water over a 30 min period, where both solvents contain 0.1% TFA) provided the title compound as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:5]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:8][C:6]=2[N:7]=1.[N+:24]([C:27]1[CH:28]=[C:29]([CH:35]=[CH:36][CH:37]=1)[O:30][CH2:31][C:32](O)=[O:33])([O-:26])=[O:25].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[NH2:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][N:21]([C:32](=[O:33])[CH2:31][O:30][C:29]3[CH:35]=[CH:36][CH:37]=[C:27]([N+:24]([O-:26])=[O:25])[CH:28]=3)[CH2:20][CH2:19]2)[C:5]2[N:10]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[O:8][C:6]=2[N:7]=1
Reactant: O=C(O)COc1cccc([N+](=O)[O-])c1
Reactant: Nc1nc(N2CCNCC2)c2nc(-c3ccc(F)cc3)oc2n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(N2CCN(C(=O)COc3cccc([N+](=O)[O-])c3)CC2)c2nc(-c3ccc(F)cc3)oc2n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 5-amino-2-(4-fluorophenyl)-7-piperazin-1-yl-oxazolo[5,4-d]pyrimidine (50 mg, 0.15 mmol) and 2-(3-nitrophenoxy)acetic acid (0.22 mmol) in DMF (2 ml) was added TBTU (0.22 mmol) followed by diisopropylethylamine (0.22 mmol, 36 μL). The reaction was stirred at room temperature for 24 hours after which the solvent was removed in vacuo. The resulting residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 100% CH2Cl2 to 1% CH3OH in CH2Cl2), yielding the pure title compound which was characterized by its mass spectrum: MS m/z (%): 522 ([M+H]+, 100).
Reaction SMILES: [CH3:1][C:2]([NH2:7])([CH2:5][CH3:6])[CH2:3][CH3:4].Cl[CH2:9][CH2:10][O:11][CH:12]([OH:14])[CH3:13].[OH-].[K+]>COCCO>[CH3:1][C:2]([NH:7][CH2:9][CH2:10][O:11][CH:12]([OH:14])[CH3:13])([CH2:5][CH3:6])[CH2:3][CH3:4]
Reactant: CCC(C)(N)CC
Reactant: CC(O)OCCCl
Agent: [K+]
Agent: [OH-]
Solvent: COCCO
Product: CCC(C)(CC)NCCOC(C)O

Procedure:
A solution of 124.7 g of 1-methyl-1-ethylpropylamine and 76.9 g of 2-chloroethoxyethanol in 300 ml of ethylene glycol monomethylether was refluxed overnight. The reaction mixture was treated with a stoichiometric excess of KOH and refluxed for one hour, filtered, and distilled. The product had a b.p. of 153° C. (2 mm). Analysis calculated for C10H23NO2 :% N, 7.4, found %N, 7.15.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][N:6]=1)=[O:4].[H-].[Na+].FC(F)(F)S(O[CH2:20][C:21]([F:24])([F:23])[F:22])(=O)=O>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[C:10]([O:11][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:9][CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1ncccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ncccc1OCC(F)(F)F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 3-hydroxy-pyridine-2-carboxylic acid methyl ester (200 mg, 1.3 mmol) in N,N-dimethylformamide (2.0 ml) was added at 22° C. sodium hydride (55% in oil, 64 mg) and stirring was continued until gas evolution ceased. The suspension was cooled to 0° C. and treated with trifluoroethyl trifluoromethanesulfonate (728 mg) and stirring was continued at 22° C. for 2 hours. The mixture was partitioned between saturated sodium hydrogen-carbonate solution and ethyl acetate, and the organic layer was dried and evaporated. The residue was purified by chromatography on silica using n-heptane and ethyl acetate (3:1) as the eluent to give 3-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid methyl ester as a pale green oil. Mass (calculated) C9H8F3NO3 [235.16]; (found) [M+H]+=236. b) A solution of 3-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid methyl ester (216 mg, 0.9 mmol) in methanol (1 ml) was treated with a solution of lithium hydroxide (78 mg, 3.3 mmol) in water (0.1 ml) and stirring was continued at 22° C. for 2 hours. The solution was evaporated and the residue triturated with 1N aqueous hydrochloric acid. The suspension was filtered, the residue washed with water and dried to give 3-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid as a colorless solid. Mass (calculated) C8H6F3NO3 [221.14]; (found) [M−H]−=220.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Al+3].[Cl-].[Cl-].[Cl-].O=[C:12]1[C:15]2([CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH:14]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)[N:13]1[CH:35]([CH3:37])[CH3:36]>C1COCC1>[Cl:34][C:31]1[CH:30]=[CH:29][C:28]([CH:14]2[C:15]3([CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:19][CH2:20]3)[CH2:12][N:13]2[CH:35]([CH3:37])[CH3:36])=[CH:33][CH:32]=1
Reactant: CC(C)N1C(=O)C2(CCN(C(=O)OC(C)(C)C)CC2)C1c1ccc(Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: CC(C)N1CC2(CCN(C(=O)OC(C)(C)C)CC2)C1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Under a nitrogen atmosphere, in a dry 500 mL 3-necked flask, add LiAlH4 (0.87 g) and THF (dried over Mol sieves) (96 mL) and cool to 10 C (ice bath). Add AlCl3 (3.33 g) portionwise keeping the temperature at ˜10 C. Heat to 50-60 C for 30 min., then cool to −40 to −50 C, Add 1,1-dimethylethyl 1-oxo-3-(4-chlorophenyl)-2-isopropyl-2,7-diazaspiro[3.5]nonane-7-carboxylate (5.75 g in dry THF (150 mL). Warm the reaction mixture to −20 C and monitor at 15 min intervals until starting material is gone (˜60 min.). At −30 C, quench the reaction mixture at ˜−30 C with 10% NaOH, then warm to room temperature. Extract with diethyl ether (2×300 mL). Extract the diethyl ether with brine, Concentrate the dried (MgSO4) Et2O in vacuo to give the title compound as a viscous oil (9.79 g). Add EtOAc (5 mL) and hexane (25 ml) and let stand at RT to give the title compound as a white solid (0.031 g). Filtrate (4.47 g) in EtOAc (30 mL) and hexane (30 mL) gave additional compound (3.56 g) which was placed on an Analogix system: Column of silica gel (115 g) and eluted with hexane/EtOAc, 20 mL fractions collected. Concentration of fraction 54-145 gave the title compound (2.94 g) as a white solid.
Reaction SMILES: CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[K+].[K+].[CH:41]1([B-](F)(F)F)[CH2:43][CH2:42]1.[K+].Cl[C:50]1[CH:51]=[C:52]([CH:62]=[O:63])[CH:53]=[C:54]2[C:59]=1[O:58][CH2:57][CH2:56][C:55]2([CH3:61])[CH3:60]>C1(OC)CC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:41]1([C:50]2[CH:51]=[C:52]([CH:62]=[O:63])[CH:53]=[C:54]3[C:59]=2[O:58][CH2:57][CH2:56][C:55]3([CH3:60])[CH3:61])[CH2:43][CH2:42]1
Reactant: CC1(C)CCOc2c(Cl)cc(C=O)cc21
Reactant: F[B-](F)(F)C1CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Product: CC1(C)CCOc2c(C3CC3)cc(C=O)cc21
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A vial was charged with Pd(OAc)2 (2.40 mg, 10.7 μmol), XPhos (10.2 mg, 0.02 mmol), potassium carbonate (148 mg, 1.07 mmol), potassium cyclopropyltrifluoroborate (58.0 mg, 0.39 mmol) and 8-chloro-4,4-dimethyl-3,4-dihydro-2H-chromene-6-carbaldehyde (80.0 mg, 0.36 mmol). The mixture was dissolved in cyclopropylmethyl ether (2.00 mL) and water (0.20 mL) and purged with Ar. The reaction mixture was then stirred at 100° C. overnight, cooled to room temperature, and filtered through a pad of celite. The filtrate was concentrated under vacuum, and the crude residue was purified by silica gel chromatography eluting with 0-15% EtOAc/hexanes to afford the desired product as a yellow oil.
Reaction SMILES: O=C1CCC(=O)N1O[C:9](=[O:27])[C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17](=[O:26])[N:18]([CH3:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][CH:11]=1.[C:28]1([NH:34][CH2:35][CH2:36][NH2:37])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[C:28]1([NH:34][CH2:35][CH2:36][NH:37][C:9]([C:10]2[CH:11]=[CH:12][C:13]([O:16][C:17](=[O:26])[N:18]([CH3:25])[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:14][CH:15]=2)=[O:27])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: NCCNc1ccccc1
Reactant: CN(C(=O)Oc1ccc(C(=O)ON2C(=O)CCC2=O)cc1)c1ccccc1
Product: CN(C(=O)Oc1ccc(C(=O)NCCNc2ccccc2)cc1)c1ccccc1

Procedure:
The title product was prepared from 4-(methyl-phenyl-carbamoyloxy)-benzoic acid 2,5-dioxo-pyrrolidin-1-yl ester and N-phenylethylenediamine. The crude product was used without further purification (80%, off-white foam). HPLC-MS: m/z=390.2 (M+1); Rt: 3.51 min.
Reaction SMILES: C(N(CC)CC)C.[CH:8]1([S:14](Cl)(=[O:16])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[NH2:18][C:19]1[N:24]=[C:23]([C:25]2[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([F:33])[CH:26]=2)[CH:22]=[C:21]([N:34]2[C@H:39]([CH3:40])[CH2:38][O:37][C@H:36]([CH2:41][NH2:42])[CH2:35]2)[N:20]=1>C1COCC1>[NH2:18][C:19]1[N:20]=[C:21]([N:34]2[C@H:39]([CH3:40])[CH2:38][O:37][C@H:36]([CH2:41][NH:42][S:14]([CH:8]3[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)(=[O:16])=[O:15])[CH2:35]2)[CH:22]=[C:23]([C:25]2[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([F:33])[CH:26]=2)[N:24]=1
Reactant: O=S(=O)(Cl)C1CCCCC1
Reactant: C[C@@H]1CO[C@H](CN)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@@H]1CO[C@H](CNS(=O)(=O)C2CCCCC2)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Temperature: 25 °C
Reaction time: 22 h
Yield: 147.4 %

Procedure:
Triethylamine (41 μL, 0.30 mmol) and cylcohexanesulfonyl chloride (44 μL, 0.27 mmol) were added to a solution of 4-{2-amino-6-[(2R,5R)-2-(aminomethyl)-5-methyl-4-morpholinyl]-4-pyrimidinyl}-2-fluorobenzonitrile (85 mg, 0.25 mmol) in THF (3 mL), and the mixture was stirred at room temperature under nitrogen for 22 hours. LC-MS indicated only about 25% conversion, so more triethylamine (0.15 mL, 1.08 mmol) and cyclohexanesulfonyl chloride (0.15 mL, 1.03 mmol) were added, and stirring continued at room temperature for another 26 hours. The mixture was then quenched with saturated aqueous NaHCO3 (25 mL) and extracted with EtOAc (3×15 mL). The extracts were washed with brine (15 mL), dried (Na2SO4), filtered, and concentrated in vacuo to give the crude title compound (180 mg, about 45% pure according to LC-MS) as a yellow foam. LC-MS (ES) m/z=489 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH3:12])=[C:10]([CH2:13]O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[CH3:27][N:28]([C@@H:36]([CH3:60])[C:37]([NH:39][C@H:40]1[C@H:46]([CH3:47])[N:45]([C:48](=[O:54])[CH2:49][S:50]([CH3:53])(=[O:52])=[O:51])[C:44]2[CH:55]=[CH:56][CH:57]=[CH:58][C:43]=2[NH:42][C:41]1=[O:59])=[O:38])[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[Na+]>C(Cl)Cl.CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:11]([CH3:12])=[C:10]([CH2:13][N:42]2[C:41](=[O:59])[C@@H:40]([NH:39][C:37](=[O:38])[C@@H:36]([N:28]([CH3:27])[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:32])[CH3:33])[CH3:60])[C@H:46]([CH3:47])[N:45]([C:48](=[O:54])[CH2:49][S:50]([CH3:53])(=[O:52])=[O:51])[C:44]3[CH:55]=[CH:56][CH:57]=[CH:58][C:43]2=3)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: C[C@@H](C(=O)N[C@@H]1C(=O)Nc2ccccc2N(C(=O)CS(C)(=O)=O)[C@H]1C)N(C)C(=O)OC(C)(C)C
Reactant: Cc1c(Cl)nc2ccccc2c1CO
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1c(Cl)nc2ccccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@H](C)N(C(=O)CS(C)(=O)=O)c2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 45.4 %

Procedure:
To a rt suspension of (2-chloro-3-methylquinolin-4-yl)methanol (61 mg, 294 μmol) in CH2Cl2 (2.94 ml) was added triethylamine (81.9 μl, 588 μmol), followed by methanesulfonyl chloride (27.3 μl, 353 μmol), dropwise. The reaction was stirred at rt for 1.5 h, then diluted with CH2Cl2, washed with H2O and sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated. This material was mixed with tert-butyl methyl((S)-1-((2S,3S)-2-methyl-1-(2-(methylsulfonyl)acetyl)-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl)carbamate (100 mg, 201 μmol), cesium carbonate (85.3 mg, 262 μmol), and sodium iodide (39.2 mg, 262 μmol) in DMF (503 μl). The reaction was stirred at rt for 16 h, then diluted with EtOAc, washed with H2O and sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash chromatography to provide tert-butyl(S)-1-((3S,4S)-1-((2-chloro-3-methylquinolin-4-yl)methyl)-4-methyl-5-(2-(methylsulfonyl)acetyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (62.6 mg, 45%) as a white solid. MS m/z 708 (MNa)+.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:19]=[CH:18][C:17]2[NH:16][C:15](=[O:20])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[CH:7]=1)=[O:4].Cl.[C:22]([O:26][C:27](=[O:36])[NH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][NH2:35])([CH3:25])([CH3:24])[CH3:23].C(N(CC)CC)C>CN(C)C=O.ClCCl>[C:22]([O:26][C:27](=[O:36])[NH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][NH:35][CH2:2][C:3](=[O:4])[NH:5][C:6]1[CH:19]=[CH:18][C:17]2[NH:16][C:15](=[O:20])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[CH:7]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)NCCCCCCN
Reactant: O=C(CCl)Nc1ccc2[nH]c(=O)c3ccccc3c2c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCCCCNCC(=O)Nc1ccc2[nH]c(=O)c3ccccc3c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.6 %

Procedure:
To a stirred suspension of 65 mg of 2-chloro-N-(6-oxo-5,6-dihydro-phenanthridin-2-yl)-acetamide (XV) (0.23 mmol) in N,N-dimethylformamide (2 mL), 175 mg of (6-amino-hexyl)-carbamic acid tert-butyl ester hydrochloride (0.69 mmol) and 0.097 mL of triethylamine (0.69 mmol) were added. The reaction mixture was stirred at room temperature overnight, diluted with dichloromethane, and the resulting solution was washed first with water then with brine, dried over sodium sulfate and evaporated to dryness. The crude was purified by preparative HPLC on Waters X Terra RP 18 (19×250 mm, 5 m) column. Mobile phase A was 0.05% ammonia/acetonitrile:95/5 and mobile phase B was acetonitrile/water:95/5. Gradient from 10 to 75% B in 15 min. Fractions containing the desired compound were dried, affording 50 mg (47% yield) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][C:10]([O:12]C)=[O:11])[N:6]=1.[ClH:14]>>[ClH:14].[NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])[N:6]=1
Reactant: COC(=O)CCCc1csc(N)n1
Agent: Cl
Product: Nc1nc(CCCC(=O)O)cs1
Reaction time: 8 h

Procedure:
Ester 1-3 (1.3 g, 6.5 mmol) was dissolved in 32 mL 6 N HCl. After stirring overnight, the resulting suspension was concentrated, providing acid 1-4 as a white solid.