Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:10][C:11]2[C:19]([N:20]=1)=[CH:18][C:17]1[C:16](=[O:21])[N:15]([CH:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)[C:14](=[O:29])[C:13]=1[CH:12]=2.[NH2:30][CH2:31][C@@H:32]([OH:43])[CH2:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][C:36]=1[CH3:42].CCN(CC)CC>CCO>[CH3:42][C:36]1[CH:37]=[C:38]([CH3:41])[CH:39]=[CH:40][C:35]=1[O:34][CH2:33][C@H:32]([OH:43])[CH2:31][NH:30][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:10][C:11]2[C:19]([N:20]=1)=[CH:18][C:17]1[C:16](=[O:21])[N:15]([CH:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)[C:14](=[O:29])[C:13]=1[CH:12]=2
Reactant: Cc1ccc(OC[C@H](O)CN)c(C)c1
Reactant: CN1CCC(N2C(=O)c3cc4nc(-c5c(Cl)cc[nH]c5=O)[nH]c4cc3C2=O)CC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1ccc(OC[C@H](O)CNc2cc[nH]c(=O)c2-c2nc3cc4c(cc3[nH]2)C(=O)N(C2CCN(C)CC2)C4=O)c(C)c1
Temperature: 100 °C
Yield: 64.6 %

Procedure:
To a solution of 2-(4-chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione (448.3 mg, 1.35 mmol) and (R)-1-amino-3-(2,4-dimethyl-phenoxy)-propan-2-ol (303.0 mg, 1.55 mmol) in EtOH (10 mL) was added Et3N (410 mg, 4.05 mmol). After it was heated at 100° C. for 14 h, the reaction mixture was concentrated under reduced pressure. The chromatography of the crude residue (150:10:1 CH2Cl2/MeOH/28% aqueous NH4OH) afforded the title compound (498 mg, 45%). 1H NMR (DMSO-d6) δ 1.60 (m, 2H), 1.95 (m, 2H), 2.18 (s, 3H, CH3), 2.18 (s, 3H, CH3), 2.21 (s, 3H, CH3), 2.39 (m, 2H), 2.90 (m, 2H), 3.57 (m, 1H), 3.71 (m, 1H), 3.90-4.08 (3H), 4.18 (m, 1H), 5.55 (d, J=6 Hz, 1H, NH), 6.22 (d, J=6 Hz, 1H), 6.83 (d, J=6 Hz, 1H), 6.92 (d, J=6 Hz, 1H), 6.97 (s, 1H), 7.39 (d, J=6 Hz, 1H), 7.64 (s, 1H), 8.09 (s, 1H), 10.96 (br s, 1H, NH), 11.31 (br s, 1H, NH); ESI-MS m/z 571.3 (MH+).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][C:9]=1[NH:17][S:18]([CH3:21])(=[O:20])=[O:19].[NH2:22][C:23](=[N:35]O)[C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]([Cl:34])[CH:25]=1.Cl.C(N=C=NCCCN(C)C)C.CCN(C(C)C)C(C)C>CC#N.C1COCC1>[Cl:34][C:26]1[CH:25]=[C:24]([C:23]2[N:22]=[C:12]([C:11]3[CH:15]=[CH:16][C:8]([N:3]4[CH2:4][CH2:5][CH2:6][CH2:7][CH:2]4[CH3:1])=[C:9]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH:10]=3)[O:14][N:35]=2)[CH:33]=[CH:32][C:27]=1[C:28]([O:30][CH3:31])=[O:29]
Reactant: CC1CCCCN1c1ccc(C(=O)O)cc1NS(C)(=O)=O
Reactant: COC(=O)c1ccc(C(N)=NO)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CC#N
Product: COC(=O)c1ccc(-c2noc(-c3ccc(N4CCCCC4C)c(NS(C)(=O)=O)c3)n2)cc1Cl
Temperature: 25 °C

Procedure:
In a 2-5 microwave vial, placed in a dry-ice acetone bath, was added THF (2 mL) and CH3CN (2 mL) to a mixture of Intermediate 25 (156.19 mg; 0.50 mmol), Intermediate 34 (114.32 mg; 0.50 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (115.02 mg; 0.60 mmol). The reaction mixture was allowed to warm to RT for half a hour then DIEA (204.07 μL; 1.20 mmol) was added and the mixture was heated by microwave irradiation at 150° C. for 30 min. The reaction mixture was filtered through a SPE NH2 column (2 g) and rinsed with ACN. The filtrate was passed through a SPE SCX column (2 g) and rinsed with ACN. After evaporation of the solvents, the crude product was purified by flash chromatography (c-hex/EtOAc: 9.5/0.5), affording the title compound. LC/MS (Method B): 503.4 (M−H)−, 505.3 (M+H)+. HPLC (Method A) Rt 5.64 min (Purity: 100.0%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:13][CH2:12][CH2:11][CH2:10][N:9]([C:14](=[O:16])[CH3:15])[C:8]=2[CH:17]=1)([O-])=O>[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[O:13][CH2:12][CH2:11][CH2:10][N:9]([C:14](=[O:16])[CH3:15])[C:8]=2[CH:17]=1
Reactant: CC(=O)N1CCCOc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: CCO
Product: CC(=O)N1CCCOc2ccc(N)cc21
Yield: 99.2 %

Procedure:
1-(2-Nitro-7,8-dihydro-6H-5-oxa-9-aza-benzocyclohepten-9-yl)-ethanone (0.520 g, 2.20 mmol) and 10% Palladium on Carbon (50% Wet) (0.12 g) in Ethanol (40 mL) was shaken under an atmosphere of Hydrogen (30 psi) overnight. The mixture was filtered and washed with ethanol (100 mL). Conc. in vacuo afforded 1-(2-Amino-7,8-dihydro-6H-5-oxa-9-aza-benzocyclohepten-9-yl)-ethanone (450 mg, 99%). 1H-NMR (CDCl3): 6.94 (d, 1H, J=8.1 Hz), 6.32 (d, 1H, J=8.1 Hz), 6.56 (s, 1H), 4.78 (m, 1H), 4.36 (m, 1H), 3.58 (m, 1H), 2.69 (m, 1H), 2.22 (m, 1H), 1.93 (s, 3H), 1.73 (m, 1H).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][CH3:26])=[CH:21][CH:20]=3)[CH:12]=2)[C@@H:9]([O:27][C:28](=[O:30])[CH3:29])[C@H:8]([CH2:31][O:32][C:33](=[O:35])[CH3:34])[C@@H:7]([O:36][C:37](=[O:39])[CH3:38])[C@@H:6]1[O:40][C:41](=[O:43])[CH3:42])(=[O:3])[CH3:2].C(O)(=[O:46])C>O>[C:1]([O:4][C@H:5]1[C@H:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([C:25](=[O:46])[CH3:26])=[CH:23][CH:24]=3)[CH:12]=2)[C@@H:9]([O:27][C:28](=[O:30])[CH3:29])[C@H:8]([CH2:31][O:32][C:33](=[O:35])[CH3:34])[C@@H:7]([O:36][C:37](=[O:39])[CH3:38])[C@@H:6]1[O:40][C:41](=[O:43])[CH3:42])(=[O:3])[CH3:2]
Reactant: CC(=O)O
Reactant: CCc1ccc(Cc2cc([C@H]3[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](COC(C)=O)[C@@H]3OC(C)=O)ccc2Cl)cc1
Solvent: O
Product: CC(=O)OC[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](c2ccc(Cl)c(Cc3ccc(C(C)=O)cc3)c2)[C@H]1OC(C)=O
Temperature: 125 °C
Reaction time: 22 h

Procedure:
To a vigorously stirred solution of (1S,2R,3R,4S,5R,6R)-4-(acetoxymethyl)-6-(4-chloro-3-(4-ethylbenzyl)phenyl)cyclohexane-1,2,3,5-tetrayl tetraacetate (19) (300 mg, 48.7 μmol) in acetic acid (5 mL) was added K2Cr2O7 (172 mg, 0.58 mmol) and the mixture was stirred for 22 hours at 125° C. The mixture was cooled to room temperature, diluted with water (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organic extracts were washed with saturated NaHCO3 (3×10 mL) and then with brine (20 mL), dried (Na2SO4), filtered and concentrated. Preparative TLC (2:1 hexane:ethyl acetate) afforded 100 mg of the desired compound. MS (ESI+): 631 [M+H]+, 648 [M+H2O]+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]([CH2:13][NH:14][CH:15]([CH3:17])[CH3:16])[C@@H:10]([CH2:18][N:19]([CH:36]([CH3:38])[CH3:37])[C:20](=[O:35])[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH2:30][CH2:31][CH2:32][O:33][CH3:34])[CH:22]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:46]1([CH2:52][C:53](Cl)=[O:54])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.[OH-].[Na+]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:15]([CH3:17])[CH3:16])[C:53](=[O:54])[CH2:52][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C@@H:10]([CH2:18][N:19]([CH:36]([CH3:38])[CH3:37])[C:20](=[O:35])[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH2:30][CH2:31][CH2:32][O:33][CH3:34])[CH:22]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCCOc1cc(C(=O)N(C[C@H]2CN(Cc3ccccc3)C[C@H]2CNC(C)C)C(C)C)ccc1OC
Reactant: O=C(Cl)Cc1ccccc1
Agent: CN(C)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCCOc1cc(C(=O)N(C[C@H]2CN(Cc3ccccc3)C[C@H]2CN(C(=O)Cc2ccccc2)C(C)C)C(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-[(3R*,4R*)-1-benzyl-4-(isopropylamino-methyl)-pyrrolidin-3-ylmethyl]-N-isopropyl-4-methoxy-3-(3-methoxy-propoxy)-benzamide (0.19 g, 0.36 mmol), triethyl-amine (0.15 mL, 1.09 mmol), and DMAP (0.013 g, 0.11 mmol) in CH2Cl2, is added dropwise phenyl-acetyl chloride (0.058 mL, 0.44 mmol) at 0° C. under a nitrogen atmosphere. The solution is stirred overnight at room temperature. The mixture is added an aqueous solution of NaOH 0.1N (50 mL) and CH2Cl2 (50 mL). The organic layer is separated and the aqueous phase extracted twice with CH2Cl2, dried over MgSO4, filtered, and concentrated in vacuo. The crude product is purified by flash chromatography on silica gel (eluent: CH2Cl2/MeOH 90:10) to give the title product. TLC, Rf (CH2Cl2/MeOH 9:1)=0.23. MS (LC-MS): [M+H]+; 644.4 tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/2.5 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 mL/min): 5.95 min.
Reaction SMILES: [CH2:1]1[S:5][C@@H:4]([CH2:6][CH2:7][CH2:8][CH2:9][C:10](NCCCCCC(ON2C(=O)C(S([O-])(=O)=O)CC2=O)=O)=[O:11])[C@H:3]2[NH:32][C:33]([NH:35][C@@H:2]12)=[O:34].[Na+].[OH:37]P([O-])(O)=O.OP([O-])([O-])=O.[Na+].[Na+].[Na+].[Cl-].[Cl-].[K+].[K+].OP([O-])(O)=O.[K+].OP([O-])([O-])=O.[K+].[K+].[Na+].[Cl-].Cl.CN1C(=O)C=CS1.[Cl-].[Cl-].[Ca+2]>>[OH:37][C:10]([CH2:9][CH2:8][CH2:7][CH2:6][C@H:4]1[C@@H:3]2[C@@H:2]([NH:35][C:33]([NH:32]2)=[O:34])[CH2:1][S:5]1)=[O:11]
Reactant: O=P([O-])(O)O
Reactant: O=C(CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21)NCCCCCC(=O)ON1C(=O)CC(S(=O)(=O)[O-])C1=O
Agent: Cl
Agent: Cn1sccc1=O
Agent: O=P([O-])([O-])O
Product: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Temperature: 0 °C

Procedure:
An EZ-Link® Sulfo-NHS-LC Biotin stock (Cat: 23224, Thermo Fisher Scientific, Rockford, Ill.) was freshly prepared by adding 300 μL of ice-cold water in a single polypropylene microcentrifuge tube containing 1.0 mg of EZ-LINK® Sulfo-NHS-LC Biotin resulting in a concentration of 5.99 nMole/μL. To a 0.25 mL solution of ANTI-FLAG® M1 antibody (4.041 mg/mL) in a microcentrifuge tube, 11 μL of the freshly prepared EZ-LINK® Sulfo-NHS-LC Biotin water solution was added. This solution was incubated and mixed continuously for 1 hour at room temperature. After the incubation, the antibody was buffer exchanged to a phosphate buffered saline (PBS) containing 37.5 mM KH2PO4, 112.5 mM K2HPO4, 150.6 mM NaCl, 0.10% 2-Methyl-4-isothiazolin-3-one Hydrochloride (MIT), and 7 mM CaCl2. The post modification concentration was 0.975 mg/mL in approximately 1.0 mL.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10](=O)[CH2:11][C:12]1[N:13]=[C:14]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)[S:15][C:16]=1[CH3:17])C>C1COCC1>[OH:9][CH2:10][CH2:11][C:12]1[N:13]=[C:14]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)[S:15][C:16]=1[CH3:17]
Reactant: CCOC(=O)Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1sc(-c2ccc(C(F)(F)F)cc2)nc1CCO
Temperature: 5 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
Cool (0° C.) a solution of lithium aluminum hydride (5.3 mL, 1M in THF) and add a solution of [5-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-acetic acid ethyl ester (Example 1, 1.4g, 4.25 mmol) in THF (15 mL). On complete addition, remove the cold bath and stir for 2 hrs. Cool this solution to 5° C., and then add water (0.2 mL), dropwise, followed by NaOH solution (0.2 mL, 5M in water) and water (0.2 mL). Dilute the resulting mixture with ethyl acetate and then filter through a pad of celite. Wash the solids with dichloromethane and then concentrate the combined filtrates under reduced pressure. Purify the residue by flash chromatography (elute with 30% ethyl acetate 40% dichloromethane in heptane) to give the title compound as a yellow solid (0.879 g) Use the compound of Example 1 as the starting material to obtain the title compound.
Reaction SMILES: [C:1]([NH2:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:7](Cl)([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:8]>O1CCCC1>[C:7]([NH:6][C:1](=[O:5])[C:2]([CH3:4])=[CH2:3])([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:8]
Reactant: CCOC(=O)C(=O)Cl
Reactant: C=C(C)C(N)=O
Solvent: C1CCOC1
Product: C=C(C)C(=O)NC(=O)C(=O)OCC
Reaction time: 4 h
Yield: 70.2 %

Procedure:
Into the same reaction vessel as used in Example 1, tetrahydrofuran (50 ml), methacrylamide (4.26 g; 50 mmol) and ethoxalyl chloride (6.83 g; 50 mmol) were charged, and refluxing was continued for 4 hours. Removal of the organic solvent by distillation under reduced pressure gave N-ethoxalylmethacrylamide (6.5 g). Yield, 70.6%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:22]=[C:21]3[C:16]([CH:17]=[CH:18][CH:19]=[N:20]3)=[C:15](OS(C(F)(F)F)(=O)=O)[N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[NH2:31][CH2:32][C@@H:33]1[O:37][C:36](=[O:38])[NH:35][CH2:34]1.C(N(C(C)C)CC)(C)C>CC(N(C)C)=O.ClCCl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:22]=[C:21]3[C:16]([CH:17]=[CH:18][CH:19]=[N:20]3)=[C:15]([NH:31][CH2:32][C@@H:33]3[O:37][C:36](=[O:38])[NH:35][CH2:34]3)[N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: NC[C@H]1CNC(=O)O1
Reactant: COc1cc(-c2cc3ncccc3c(OS(=O)(=O)C(F)(F)F)n2)cc(OC)c1OC
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(-c2cc3ncccc3c(NC[C@H]3CNC(=O)O3)n2)cc(OC)c1OC
Temperature: 70 °C

Procedure:
100 mg 6.1 and 70 mg of (S)-5-(aminomethyl)oxazolidine-2-one (2.19) (50%) were dissolved in dimethylacetamide. 0.175 mL (1.01 mmol) of diisopropylethylamine was added and the mixture was heated at 70° C. for 30 minutes and overnight at ambient temperature. The mixture was diluted with 20 mL dichloromethane and 20 mL water. The phases were separated and the water phase extracted with additional 10 mL dichloromethane. The combined organic phases were concentrated and the product purified via chromatography (SiO2:dichloromethane→dichloromethane/methanol 90:10). The product was recrystallized from ethyl acetate and methyl-tert-butylether.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[F:27])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:22])[CH:10]=[N+:11]([O-])[C:12]=2[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:7]1=[O:23]>C(OC(=O)C)(=O)C>[C:16]([O:18][C:10]1[N:11]=[C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:13]2[CH2:14][CH2:15][N:6]([CH2:5][C:4]3[CH:24]=[CH:25][C:26]([F:27])=[C:2]([Cl:1])[CH:3]=3)[C:7](=[O:23])[C:8]=2[C:9]=1[O:22][C:9](=[O:22])[CH3:8])(=[O:17])[CH3:12]
Reactant: CCOC(=O)c1c2c(c(O)c[n+]1[O-])C(=O)N(Cc1ccc(F)c(Cl)c1)CC2
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1nc(OC(C)=O)c(OC(C)=O)c2c1CCN(Cc1ccc(F)c(Cl)c1)C2=O

Procedure:
A solution of ethyl 6-(3-chloro-4-fluorobenzyl)-4-hydroxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate 2-oxide (23 g, 58 mol) in acetic anhydride (400 mL) was heated under nitrogen at 100° C. for one hour. The product mixture was concentrated under vacuum to the title bisacetate and was used in the following step without further purification.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH2:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:14](=[O:17])[CH:15]=[CH2:16])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[CH3:25][O:26][CH2:27][CH2:28][O:29][CH2:30][C:31]1[S:35][C:34]([CH:36]=[O:37])=[N:33][CH:32]=1.C(N(CC)CC)C.O1CCCC1>[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(O)C>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([CH2:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:14](=[O:17])[CH2:15][CH2:16][C:36]([C:34]3[S:35][C:31]([CH2:30][O:29][CH2:28][CH2:27][O:26][CH3:25])=[CH:32][N:33]=3)=[O:37])=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: COCCOCc1cnc(C=O)s1
Reactant: C=CC(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCCOCc1cnc(C(=O)CCC(=O)C(CC2CCOCC2)c2ccc(S(=O)(=O)C3CC3)cc2)s1
Yield: 76.7 %

Procedure:
A mixture of 4-[4-(cyclopropylsulfonyl)phenyl]-5-(tetrahydro-2H-pyran-4-yl)pent-1-en-3-one (0.43 g), 5-[(2-methoxyethoxy)methyl]-1,3-thiazole-2-carbaldehyde (0.26 g), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (32 mg), triethylamine (0.07 mL), tetrahydrofuran (4 mL) and ethanol (4 mL) was stirred with heating under reflux for 2 hr. The reaction mixture was concentrated, and the residue was subjected to basic silica gel column chromatography, and the title compound (0.52 g, yield 79%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (4:1, volume ratio). MS: 550 (MH+).
Reaction SMILES: [CH:1](=O)[CH3:2].[ClH:4].Cl.Cl.[CH3:7][O:8][C:9]1[CH:33]=[CH:32][C:12]([CH2:13][NH:14][C:15]([NH:17][C:18]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[NH:19])=[NH:16])=[CH:11][CH:10]=1>C(O)C>[ClH:4].[CH2:21]([NH:20][CH:18]1[N:19]=[C:1]([CH3:2])[N:16]=[C:15]([NH:14][CH2:13][C:12]2[CH:11]=[CH:10][C:9]([O:8][CH3:7])=[CH:33][CH:32]=2)[NH:17]1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CC=O
Reactant: CCCCCCCCCCCNC(=N)NC(=N)NCc1ccc(OC)cc1
Agent: Cl
Solvent: CCO
Product: CCCCCCCCCCCNC1N=C(C)N=C(NCc2ccc(OC)cc2)N1

Procedure:
Under ice-cooling, 100 ml of ethanol, 5 ml (89.2 mmol) of acetaldehyde and 0.4 ml of concentrated hydrochloric acid were added to 4.0 g (8.9 mmol) of N1-(4-methoxybenzyl)-N5-undecyl-biguanide dihydrochloride, and the mixture was refluxed for 24 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution with a mixture of chloroform and methanol (9:1.5)), and dissolved in 70% aqueous acetonitrile. The solvent was distilled off under reduced pressure, followed by sufficient drying under reduced pressure to obtain 1.4 g of a colorless resinous solid.
Reaction SMILES: C[CH:2]([CH:6]1[C:10]2=[C:11]([S:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[C:12]3[C:13](Br)=[CH:14][C:15]([F:18])=[CH:16][C:17]=3[N:9]2[CH2:8][CH2:7]1)[C:3]([O-:5])=[O:4].[N:28]1[C:37]2[C:32](=[CH:33][C:34](B(O)O)=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1>>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([S:20][C:11]2[C:12]3[C:13]([C:34]4[CH:33]=[C:32]5[C:37](=[CH:36][CH:35]=4)[N:28]=[CH:29][CH:30]=[CH:31]5)=[CH:14][C:15]([F:18])=[CH:16][C:17]=3[N:9]3[CH2:8][CH2:7][CH:6]([CH2:2][C:3]([OH:5])=[O:4])[C:10]=23)=[CH:22][CH:23]=1
Reactant: CC(C(=O)[O-])C1CCn2c1c(Sc1ccc(Cl)cc1)c1c(Br)cc(F)cc12
Reactant: OB(O)c1ccc2ncccc2c1
Product: O=C(O)CC1CCn2c1c(Sc1ccc(Cl)cc1)c1c(-c3ccc4ncccc4c3)cc(F)cc12

Procedure:
Starting from (+/−)-methyl[8-bromo-9-[(4-chlorophenyl)sulfanyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate (Example 7, Step 9) and quinolin-6-ylboronic acid, the title compound was synthesized following the procedures described in Example 108.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[NH:10][C:9]2=[O:17])[CH2:4][CH2:3]1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C.ClCCCl>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([C@@H:2]2[CH2:7][CH2:6][C@H:5]([N:8]3[C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=4[NH:10][C:9]3=[O:17])[CH2:4][CH2:3]2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C1CCC(n2c(=O)[nH]c3ccccc32)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCN([C@H]2CC[C@@H](n3c(=O)[nH]c4ccccc43)CC2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 24.3 %

Procedure:
A mixture of 1.5 g of 1,3-dihydro-1-(4-oxocyclohexyl)-2H-benzimidazol-2-one, 1.21 g of tert-butyl-1-piperazinecarboxylate, 20 mL of 1,2-dichloroethane, 0.4 mL of acetic acid and 1.8 g of sodium triacetoxyborohydride was stirred at room temperature for 48 h. The reaction mixture was poured into 500 mL chloroform and 500 mL saturated aqueous Na2CO3 and the layers separated. The aqueous layer was extracted with 2×250 mL of chloroform and the combined organic layers dried over MgSO4 and concentrated under reduced pressure. Chromatography of the crude product on silica gel, eluting with 90:10 CHCl3 : MeOH gave 0.631 g of cis-1,3-dihydro-1-{4-[4-(tert-butyloxycarbonyl)piperazin-1-yl]-1-cyclohexyl}-2H-benzimidazol-2-one as white solid: mp=228°-30° C.; 1H NMR (400 MHz, CDCl3) 7.45 (m, 1H), 7.14 (m, 1H), 7.05 (m, 2H), 3.55 (br s, 4H), 2.49 (br s, 6H), 2.27 (s, 1H), 2.15 (br d, J=15.1, 2H), 1.58 (br d, J=10.6, 4H), 1.49 (s, 9H); followed by 0.52 g of trans-1,3-dihydro-1-{4-[4-(tert-butyloxycarbonyl)piperazin-1-yl]-1-cyclohexyl}-2H-benzimidazol-2-one as white solid: mp=195°-6° C.; 1H NMR (400 MHz, CDCl3) 7.14 (m, 2H), 7.12-7.04 (m, 2H), 4.28 (m, 1H), 3.46 (br s, 4H), 2.56 (br s, 5H), 2.49 (m, 1H), 2.29 (q, 2H), 2.06 (d, J=6.4, 2H), 2.0 (d, J=9, 2H), 1.52 (m, 1H), 1.47 (s, 9H).
Reaction SMILES: C([O:4][C@H:5]([CH3:29])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17]([CH3:21])[CH:16]=[N:15][C:14]=2[N:13]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]#[N:28])[C:11]1=[O:12])(=O)C.Cl.O1CCOCC1>CO>[C:27]([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][N:13]1[C:14]2[N:15]=[CH:16][N:17]([CH3:21])[C:18]=2[C:19](=[O:20])[N:10]([CH2:9][CH2:8][CH2:7][CH2:6][C@H:5]([OH:4])[CH3:29])[C:11]1=[O:12])#[N:28]
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(ncn2C)n(CCCCCC#N)c1=O
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: C[C@@H](O)CCCCn1c(=O)c2c(ncn2C)n(CCCCCC#N)c1=O
Temperature: 80 °C
Yield: 45.1 %

Procedure:
To a stirring solution of 0.37 g (R)-1-(5-acetoxyhexyl)-3-(5-cyanopentyl)-7-methylxanthine (0.92 mmol) in 20 ml methanol was added a solution of 4M hydrogen chloride in 70 ml 1,4-dioxane (2.77 mmol). The reaction was heated at reflux (80° C.) for five hours and then cooled to room temperature. The solvent was removed under reduced pressure and the resulting oil was treated with 25 ml saturated aqueous sodium bicarbonate solution and extracted three times with 25 ml dichloromethane. The combined extracts were washed 2× with 25 ml saturated aqueous sodium chloride solution dried over sodium sulfate, and concentrated under vacuum. The resulting residue was purified by flash chromatography eluting with 10% methanol-ethyl acetate to give 0.15 g (R)-3-(5-cyanopentyl)-1-(5-hydroxyhexyl)-7-methylxanthine (47% yield) as a viscous oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[F:22])[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[F:24][C:25]([F:42])([F:41])[C:26]1[C:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:34][C:33]2[CH2:32][CH2:31][NH:30][CH2:29][C:28]=2[N:27]=1.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>C(Cl)CCl>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[F:22])[CH2:10][C:11]([N:30]1[CH2:29][C:28]2[N:27]=[C:26]([C:25]([F:42])([F:41])[F:24])[C:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:34][C:33]=2[CH2:32][CH2:31]1)=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)c1cc2c(nc1C(F)(F)F)CNCC2
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)ccc1F
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc2c(nc1C(F)(F)F)CN(C(=O)C[C@@H](Cc1cc(F)ccc1F)NC(=O)OC(C)(C)C)CC2

Procedure:
(3R)-3-[(tert-Butoxycarbonyl)amino]-4-(2,5-difluorophenyl)butanoic acid (intermediate 1) and ethyl 2-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carboxylate hydrochloride (intermediate 27) were treated with EDC, HOBt and N,N-diisopropylethylamine according to the procedure described for Example 1, Step A to afford the title compound as a white foam.