Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][C:4]([O:6]CC)=[O:5].O.[OH-].[Na+]>C(OC)(C)(C)C>[NH2:1][C@H:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)CC(N)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COC(C)(C)C
Product: N[C@@H](CC(=O)O)c1ccccc1

Procedure:
9.2 mmol of the racemic compound ethyl rac-3-amino-3-phenylpropionate (1.79 g) are taken up in 50 ml of a two-phase solvent mixture composed of 25 ml of water and 25 ml of methyl tert-butyl ether (MTBE) as the organic solvent component and set to a pH of 8.2 by automatic pH adjustment through adding 1 M sodium hydroxide solution (obtained through Merck). On reaching a reaction temperature of 20° C., 200 mg of lipase PS (Pseudomonas cepacia; obtained through Amano Enzymes, Inc.) are added to start the reaction. After a reaction time of 3, 5 and 24 hours, the conversion rate of the (S)-3-amino-3-phenylpropionic acid formed is determined. A conversion of 23.5% after 3 hours or a quantitative conversion of approximately 50% after 15 hours and an enantioselectivity of 89.0% ee (after 15 hours) are determined. The conversion and enantioselectivity are determined by means of HPLC.
Reaction SMILES: [ClH:1].C([O:5][C:6]1[CH:7]=[C:8]([C:16](=[O:42])[CH2:17][N:18]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:19][CH2:20][CH2:21][N:22]2[C:31]3[C:30](=[O:32])[N:28]([CH3:29])[C:27](=[O:33])[N:26]([CH3:34])[C:25]=3[N:24]=[CH:23]2)[CH:9]=[C:10]([O:12]C(=O)C)[CH:11]=1)(=O)C.Cl>CO>[ClH:1].[OH:5][C:6]1[CH:7]=[C:8]([C:16](=[O:42])[CH2:17][N:18]([CH2:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:19][CH2:20][CH2:21][N:22]2[C:31]3[C:30](=[O:32])[N:28]([CH3:29])[C:27](=[O:33])[N:26]([CH3:34])[C:25]=3[N:24]=[CH:23]2)[CH:9]=[C:10]([OH:12])[CH:11]=1
Reactant: CC(=O)Oc1cc(OC(C)=O)cc(C(=O)CN(CCCn2cnc3c2c(=O)n(C)c(=O)n3C)Cc2ccccc2)c1
Agent: Cl
Solvent: CO
Product: Cn1c(=O)c2c(ncn2CCCN(CC(=O)c2cc(O)cc(O)c2)Cc2ccccc2)n(C)c1=O
Reaction time: 1 h

Procedure:
The wet product of step (b) containing 12.8 kg of diacetyl compound was added to 25.6 liters of methanol and 12.8 liters of 10% hydrochloric acid. The mixture was boiled for one hour at reflux, treated with some activated carbon and kieselguhr, filtered and allowed to cool. On the next day it was centrifuged, washed with water and dried.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH2:18][CH3:19])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:5]2=[N:20][CH:21]=[C:22]([C:23]#[N:24])[N:4]2[N:3]=1.[NH2:25][C:26]1[C:27]([Cl:46])=[C:28]([N:34]2[CH2:39][CH2:38][C@@H:37]([NH:40][C:41](=[O:44])[O:42][CH3:43])[C@H:36]([OH:45])[CH2:35]2)[CH:29]=[C:30]([C:32]#[N:33])[CH:31]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CC([O-])=O.CC([O-])=O.[Pd+2].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>[Cl:46][C:27]1[C:26]([NH:25][C:2]2[N:7]=[C:6]([N:8]([CH2:18][CH3:19])[CH2:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=3)[C:5]3=[N:20][CH:21]=[C:22]([C:23]#[N:24])[N:4]3[N:3]=2)=[CH:31][C:30]([C:32]#[N:33])=[CH:29][C:28]=1[N:34]1[CH2:39][CH2:38][C@@H:37]([NH:40][C:41](=[O:44])[O:42][CH3:43])[C@H:36]([OH:45])[CH2:35]1
Reactant: CCN(Cc1ccc(OC)cc1)c1nc(Cl)nn2c(C#N)cnc12
Reactant: COC(=O)N[C@@H]1CCN(c2cc(C#N)cc(N)c2Cl)C[C@H]1O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Product: CCN(Cc1ccc(OC)cc1)c1nc(Nc2cc(C#N)cc(N3CC[C@@H](NC(=O)OC)[C@H](O)C3)c2Cl)nn2c(C#N)cnc12
Temperature: 90 °C
Reaction time: 16 h
Yield: 62.3 %

Procedure:
(328F1): A 1 liter round bottom flask was loaded with 2-chloro-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (12.05 g, 35.2 mmol, Intermediate 10), methyl ((3R,4R)-1-(3-amino-2-chloro-5-cyanophenyl)-3-hydroxypiperidin-4-yl)carbamate (10.9 g, 28.5 mmol), Pd(OAc)2 (377 mg, 1.679 mmol), XANTPHOS (990 mg, 1.711 mmol) and Potassium phosphate (17.1 g, 81 mmol). The vial was evacuated and back-filled with nitrogen 4 times. Toluene (320 mL) was added and the flask was again evacuated and back-filled with nitrogen 4 times, then heated with stirring to 90° C. for 16 hours. LCMS shows product and both starting materials as separate peaks. (˜5:1:1 ratio by UV). The flask was opened under nitrogen, additional palladium(II) acetate (190 mg, 0.846 mmol), XANTPHOS (500 mg, 0.864 mmol) and potassium phosphate tribasic (7.5 g, 35.3 mmol) were added and the flask re-sealed, flushed with nitrogen again and heating continued for additional 6 hours. Celite was added to the reaction mixture. The suspension was stirred briefly, then filtered through a layer of Celite. Solids were washed with DCM. The filtrate was concentrated to a brown foam. (23.9 g). Purification by column chromatography on silica (1500 g) using a gradient from 100% CH2Cl2 to (50% EtOAc+50% CH2Cl2) gave methyl ((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)carbamate (11.2 g).
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][C:8]=1[CH2:28][CH3:29])C.[OH-].[Na+]>C(O)C>[CH2:28]([C:8]1[CH:9]=[C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[O:19][C:20]=2[CH3:21])[CH:11]=[CH:12][C:7]=1[O:6][CH2:5][C:4]([OH:30])=[O:3])[CH3:29]
Reactant: CCOC(=O)COc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1CC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1cc(OCCc2nc(-c3ccccc3)oc2C)ccc1OCC(=O)O
Temperature: 55 °C
Yield: 87.4 %

Procedure:
A solution of {2-ethyl-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}acetic acid ethyl ester (0.22 g, 0.54 mmol) in ethanol (10 mL) was treated with 2.5 N aqueous NaOH (0.4 mL), and heated at 55° C. for 2 h. The reaction was cooled to ambient temperature and concentrated down to near dryness. The residue was then diluted with EtOAc (40 mL) and water (20 mL) and acidified to pH=1 with 1N aqueous HCl. The organic layer was washed with brine (20 mL), dried (Na2SO4) and concentrated in vacuo to give a white solid (0.18 g, 87%). 1H NMR (400 MHz, CDCl3) δ 7.97 (dd, J=8.3, 2.9 Hz, 2H), 7.44-7.41 (m, 3H), 6.75 (d, J=2.9 Hz, 1H), 6.69-6.60 (m, 2H), 4.60 (s, 2H), 4.14 (t, J=6.6 Hz, 2H), 2.98 (t, J=6.60 Hz, 2H), 2.65 (q, J=7.5 Hz, 2H), 2.38 (s, 3H), 1.19 (t, J=7.6 Hz, 3H); MS (FIA) m/e 382 (M+1).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]([C:14]([NH:17][S:18]([CH2:21][C:22]([F:25])([F:24])[F:23])(=[O:20])=[O:19])([CH3:16])[CH3:15])[CH:11]=[CH:12][CH:13]=2)[N:5]([CH2:26][CH3:27])[N:4]=1.C([N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])C>CN(C)C=O.O>[CH2:26]([N:5]1[C:6]([C:8]2[CH:9]=[C:10]([C:14]([NH:17][S:18]([CH2:21][C:22]([F:23])([F:24])[F:25])(=[O:20])=[O:19])([CH3:16])[CH3:15])[CH:11]=[CH:12][CH:13]=2)=[CH:7][C:3]([CH2:2][N:30]2[CH2:31][CH:32]=[C:21]([C:22]([F:25])([F:24])[F:23])[CH2:34][CH2:33]2)=[N:4]1)[CH3:27]
Reactant: CCn1nc(CCl)cc1-c1cccc(C(C)(C)NS(=O)(=O)CC(F)(F)F)c1
Reactant: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCn1nc(CN2CC=C(C(F)(F)F)CC2)cc1-c1cccc(C(C)(C)NS(=O)(=O)CC(F)(F)F)c1
Temperature: 80 °C

Procedure:
The chloride from Step 1 (45 mg, 0.106 mmol) was dissolved in dimethylformamide (3 ml) and treated with triethylamine (0.03 ml, 0.212 mmol) and the appropriate amine (20 mg, 0.108 mmol). The reaction was then heated to 80° C. for 16 hours. The reaction was then diluted with water (20 ml) and the products extracted into ethyl acetate (2×20 ml). The combined organic phase was washed with brine, dried over MgSO4 and evaporated to dryness. The product was isolated using silica gel chromatography eluting with hexane-ethyl acetate mixtures to give 0.06 g. 1H NMR (CDCl3, 360 MHz) δ 7.57-7.54 (2H, m), 7.48 (1h, t, J=7.6 Hz), 7.35 (1H, d, J=7.5 Hz), 6.26 (1H, s), 6.29 (1H, m), 5.01 (1H, brs), 4.15-4.11 (2H, q, J=7.1, 14 Hz), 3.70 (2H, s), 3.49-3.43 (2H, q, J=8.7, 17.6 Hz), 3.20 (2H, m), 2.74 (2H, t, J=5.6 Hz), 2.32 (2H, m), 1.82 (6H, s) and 1.39 (3H, t, J=7.2 Hz). MS (ES+) 539 (M+H+, 100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]2[S:8][CH:9]=[CH:10][C:3]=12.C([O-])(=O)C.[Na+].[Br:16]Br>C(O)(=O)C>[Br:16][C:10]1[C:3]2[C:4](=[CH:5][N:6]=[CH:7][C:2]=2[F:1])[S:8][CH:9]=1
Reactant: BrBr
Reactant: Fc1cncc2sccc12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Fc1cncc2scc(Br)c12
Temperature: 90 °C
Yield: 50.8 %

Procedure:
To a solution of 4-fluorothieno[2,3-c]pyridine (100 mg, 0.653 mmol) and sodium acetate (109 mg, 1.30 mmol) in acetic acid (2.65 mL) was added bromine (101 uL, 1.96 mmol). The reaction was heated in a microwave at 90° C. for 90 min. The reaction was concentrated. Purification by ISCO chromatography (5 to 40% ethyl acetate:heptane) afforded 77 mg (51%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.96 (s, 1 H), 8.40 (d, J=2.3 Hz, 1 H), 7.67 (d, J=0.8 Hz, 1 H); MS (ESI): 231.99, 233.95 [M+H]+; HPLC tR=3.28 min (ZQ3, polar—4 min).
Reaction SMILES: [NH2:1][C:2]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[CH2:5][N:4]1[C:11](=[O:29])[C:12]([OH:28])=[C:13]([C:15]3[O:16][C:17]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)=[N:18][N:19]=3)[N:14]=[C:3]21.[CH3:30][N:31]([CH3:37])[C:32](=[O:36])[C:33](O)=[O:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CN(C1C=CN=CC=1)C>[F:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][C:17]2[O:16][C:15]([C:13]3[N:14]=[C:3]4[C:2]5([NH:1][C:33](=[O:34])[C:32]([N:31]([CH3:37])[CH3:30])=[O:36])[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]5)[CH2:5][N:4]4[C:11](=[O:29])[C:12]=3[OH:28])=[N:19][N:18]=2)=[CH:22][CH:23]=1
Reactant: NC12CCC(CC1)Cn1c2nc(-c2nnc(Cc3ccc(F)cc3)o2)c(O)c1=O
Reactant: CN(C)C(=O)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CN(C)C(=O)C(=O)NC12CCC(CC1)Cn1c2nc(-c2nnc(Cc3ccc(F)cc3)o2)c(O)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 22.64 %

Procedure:
To a solution of 10-amino-2-(5-(4-fluorobenzyl)-1,3,4-oxadiazol-2-yl)-3-hydroxy-7,8,9,10-tetrahydro-7,10-ethanopyrimido[1,2-a]azepin-4(6H)-one, Intermediate 12 (20 mg, 0.042 mmol) in DMF (1.5 mL) was added 2-(dimethylamino)-2-oxoacetic acid (9.79 mg, 0.084 mmol), N,N-dissopropylethylamine (0.044 mL, 0.251 mmol), HATU (31.8 mg, 0.084 mmol) and DMAP (5.11 mg, 0.042 mmol) and the resulting mixture stirred at room temp for 3 h and then purified by preparative HPLC to afford the title compound (5 mg, 9.47 μmol, 22.64% yield) as a purple solid. 1H NMR (500 MHz, CDCl3) δ ppm 11.10 (1H, br. s.), 9.60 (1H, s), 7.54 (2H, dd, J=8.39, 5.34 Hz), 7.10 (2H, t, J=8.55 Hz), 4.35 (2H, s), 4.24 (2H, br. s.), 3.44 (3H, s), 3.13 (3H, s), 2.99-3.08 (3H, m), 2.54 (1H, br. s.), 2.03-2.13 (2H, m), 1.85-1.94 (2H, m), 1.72-1.81 (2H, m). LCMS (M+H)+=497.18.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH2:12][CH2:13][C:14](=O)[CH3:15])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH:18]1([NH2:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH:18]1([N:24]2[C:11]([C:8]3[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=3)=[CH:12][CH:13]=[C:14]2[CH3:15])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: NC1CCCCC1
Reactant: CC(=O)CCC(=O)c1ccc(S(C)(=O)=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccc(S(C)(=O)=O)cc2)n1C1CCCCC1
Yield: 34.1 %

Procedure:
A mixture of 1-(4-methylsulfonylphenyl)-1,4-pentanedione (Example 1, Step 2) (820 mg, 3.23 mmol), cyclohexylamine (410>1, 3.55 mmol) and p-toluenesulfonic acid (50 mg) in toluene (75 ml) was heated to reflux for 24 hours. The reaction mixture was cooled, filtered and concentrated. The crude solid (1.14 g) was purified by chromatography (silica gel, hexane/ethyl acetate, 1/1) to give 1-cyclohexyl-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrole (350 mg, p6%) as a white solid: mp (DSC) 141 ° C. Anal Calc'd. for C18H23NSO2 : C, 68.10; H, 7.30; N, 4.41; S, 10.10. Found: C, 68.22; H, 7.25; N, 4.30; S, 10.16.
Reaction SMILES: [ClH:1].[CH:2]1([NH:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13](=[O:26])[C:14]([C:24]#[N:25])=[CH:15][N:16]3[CH:19]3[CH2:23][CH2:22][NH:21][CH2:20]3)=[CH:11][C:10]=2[F:27])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.Cl.[H][H]>[Pt]=O.C(O)C>[ClH:1].[NH2:25][CH2:24][C:14]1[C:13](=[O:26])[C:12]2[C:17](=[CH:18][C:9]([NH:8][CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]3)=[C:10]([F:27])[CH:11]=2)[N:16]([CH:19]2[CH2:23][CH2:22][NH:21][CH2:20]2)[CH:15]=1
Reactant: [H][H]
Reactant: N#Cc1cn(C2CCNC2)c2cc(NC3CCCCC3)c(F)cc2c1=O
Agent: O=[Pt]
Agent: Cl
Solvent: CCO
Product: NCc1cn(C2CCNC2)c2cc(NC3CCCCC3)c(F)cc2c1=O
Reaction time: 8 h
Yield: 81.7 %

Procedure:
To 0.31 g of 7-(cyclohexylamino)-6-fluoro-4-oxo-1-pyrrolidin-3-yl-1,4-dihydroquinoline-3-carbonitrile hydrochloride were added 5 ml of ethanol, 0.2 ml of concentrated hydrochloric acid and 0.10 g of platinum oxide, followed by overnight stirring in an atmosphere of hydrogen. After adding water, celite filtration was carried out and the solvent was evaporated under a reduced pressure. By purifying the resulting residue by an ODS column chromatography, 256 mg of 3-(aminomethyl)-7-(cyclohexylamino)-6-fluoro-1-pyrrolidin-3-ylquinolin-4(1H)-one hydrochloride was obtained.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:9][N:10]=2)[NH:5][C:4](=[O:19])[C:3]=1[C:20](OCC)=[O:21].[CH:25]1([NH2:32])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH:25]1([NH:32][C:20]([C:3]2[C:4](=[O:19])[NH:5][C:6]3[C:11]([C:2]=2[OH:1])=[N:10][CH:9]=[C:8]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=3)=[O:21])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccccc3)cc2[nH]c1=O
Reactant: NC1CCCCCC1
Product: O=C(NC1CCCCCC1)c1c(O)c2ncc(Cc3ccccc3)cc2[nH]c1=O

Procedure:
This compound was prepared from ethyl 4-hydroxy-2-oxo-7-(phenylmethyl)-1,2-dihydro-1,5-naphthyridine-3-carboxylate and cycloheptylamine employing methods similar to those described in Example 2 and was obtained as a white solid; 1H NMR (d6-DMSO) δ 10.75 (1H, br), 8.23 (1H, s), 7.38 (1H, s), 7.35-7.20 (5H, m), 4.04 (2H, s), 4.00 (1H, m), 1.88-1.34 (12H, m); HRMS calcd for C23H25N3O3+H+: 392.1974. Found: 392.1956.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20](Cl)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:35][C:36]1[CH:46]=[CH:45][C:39](/[CH:40]=[CH:41]/B(O)O)=[CH:38][CH:37]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20]([CH2:41][CH2:40][C:39]2[CH:45]=[CH:46][C:36]([Cl:35])=[CH:37][CH:38]=2)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: OB(O)/C=C/c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(CCc2ccc(Cl)cc2)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Temperature: 85 °C

Procedure:
In a 30 mL sealed cap glass vial, tert-butyl 6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (150 mg, 0.301 mmol), (E)-4-chlorostyrylboronic acid (54.8 mg, 0.301 mmol) and PdCl2(PPh3)2 (42.2 mg, 0.060 mmol) were dissolved in dioxane (5 mL). To the reaction mixture was added 2N aqueous sodium carbonate solution (2.0 mL). The cap was sealed and the reaction mixture was heated at 85° C. for 3 hours. The reaction mixture was subsequently diluted with water (5 mL) and extracted with EtOAc (2×30 mL). The combined organic phase was dried over sodium sulfate and evaporated to give the intermediate, tert-butyl 6-(((1R,2S)-2-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-4-(4-chlorophenethyl)-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate, which was treated with TFA (4 mL) at room temperature for 1 hour to remove the protecting groups. TFA was subsequently evaporated from the reaction. The residual material was dissolved in DMSO (8 mL) and purified by preparative HPLC, eluting with a gradient of 10-30% ACN (0.035% TFA) and water (0.05% TFA). The pure product fractions were combined, evaporated to a minimal volume, and lyophilized to give a TFA salt of the title compound as a pale yellow solid (31 mg, 26%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.48 (d, J=6.82 Hz, 2H), 1.62 (d, J=7.58 Hz, 1H), 1.66-1.80 (m, 3H), 1.80-2.02 (m, 2H), 3.74 (br s, 1H), 4.41 (d, J=2.27 Hz, 1H), 4.50 (br s, 1H), 6.86 (d, J=5.56 Hz, 1H), 7.50 (d, J=8.59 Hz, 1H), 7.56-7.68 (m, 2H), 7.69 (s, 1H), 7.76 (br s, 3H), 8.21 (d, J=15.92 Hz, 1H), 8.51 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C21H22ClFN4O, 401. found, 401.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[C:20]1(=[O:26])[NH:24][C:23](=[O:25])[CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>[I-].[K+].O>[CH2:2]([N:24]1[C:20](=[O:26])[CH2:21][CH2:22][C:23]1=[O:25])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: O=C1CCC(=O)N1
Reactant: CCCCCCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCN1C(=O)CCC1=O
Temperature: 100 °C
Yield: 88.3 %

Procedure:
In a 500 ml flask equipped with a stirrer and a condenser were charged 30.6 g of 1-bromoctadecane, 10.0 g of succinimide, 13.9 g of potassium carbonate, 0.5 g of potassium iodide and 60 ml of DMF, and the mixture was stirred on an oil bath at 100° C. After cooling the reaction mixture to room temperature, it was poured into a large amount of distilled water, and the precipitated crystals were collected by filtration under reduced pressure and washed with distilled water. The residue was recrystallized from IPA to obtain 28.5 g of the title compound. Melting point: 76° C.
Reaction SMILES: [O:1]=[S:2]1(=[O:34])[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][N:9]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH:17]=2)[C:12]([OH:27])=[C:11]([C:28](OCC)=[O:29])[C:10]1=[O:33].[CH2:35]([CH2:37][NH2:38])[OH:36]>>[O:34]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][N:9]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH:17]=2)[C:12]([OH:27])=[C:11]([C:28]([NH:38][CH2:37][CH2:35][OH:36])=[O:29])[C:10]1=[O:33]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCS2(=O)=O)c1=O
Reactant: NCCO
Product: O=C(NCCO)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCS2(=O)=O)c1=O

Procedure:
This compound was prepared from ethyl 1-[2-(1,1-dioxido-2-isothiazolidinyl)ethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and ethanolamine employing methods similar to those described in Example 202 and was obtained as an white solid. 1H NMR (400 MHz, CDCl3) δ 10.37 (t, J=5.3 Hz, 1 H), 8.59 (s, 1 H), 7.87 (s, 1 H), 7.24 (m, 2 H), 7.02 (t, J=8.6 Hz, 2 H), 4.42 (t, J=7.0 Hz, 2 H), 4.13 (s, 2 H), 3.87 (t, J=5.2 Hz, 2 H), 3.65 (m, 2 H), 3.36 (t, J=7.0 Hz, 2 H), 3.26 (t, J=6.5 Hz, 2 H), 3.08 (t, J=7.5 Hz, 2 H), 2.25 (m, 2 H); HRMS C23H25FN4O6S (M+H)+ calcd 505.1479, found 505.1558.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:7][C@H:6]([SH:8])[CH2:5][N:4]1[C:9]([O:11][CH2:12][CH:13]=[CH2:14])=[O:10].C(N(CC)CC)C.C[Si](C)(C)Cl.[S:27](Cl)(=[O:30])(=[O:29])[NH2:28]>ClCCl>[CH2:12]([O:11][C:9]([N:4]1[CH2:5][C@@H:6]([SH:8])[CH2:7][C@H:3]1[CH2:2][NH:1][S:27](=[O:30])(=[O:29])[NH2:28])=[O:10])[CH:13]=[CH2:14]
Reactant: NS(=O)(=O)Cl
Reactant: C=CCOC(=O)N1C[C@@H](S)C[C@H]1CN
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCOC(=O)N1C[C@@H](S)C[C@H]1CNS(N)(=O)=O
Reaction time: 0.33 h
Yield: 68 %

Procedure:
To a solution of (2S,4S)-2-aminomethyl-1-allyloxycarbonyl-4-mercaptopyrrolidine (2.80 g: ca. 13.14 mmole) in dichloromethane (66 ml) at -50° C., triethylamine (4.02 ml: 28.91 mmole) and trimethylchlorosilane (3.76 ml: 28.91 mmole) are added dropwise over 15 minutes. The mixture is stirred at the same temperature for 20 minutes. To the reaction mixture triethylamine (0.92 ml: 6.57 mmole) and a solution of sulfamoyl chloride (19.37 mmole) in dichloromethane (6.8 ml) are added dropwise over 20 minutes at -70° C., and the mixture is stirred for 30 minutes. To the reaction mixture triethylamine (3.84 ml: 27.59 mmole) is again added over 1 hour at -50° C. The reaction mixture is kept at the same temperature overnight and concentrated in vacuo. The residual oil is purified by silica gel chromatography (ethyl acetate) to give (2S,4S)-1-allyloxycarbonyl-2-(sulfamoylamino)methyl-4-mercaptopyrrolidine (2.64 g). Yield: 68%. White powder. NMR δ(CDCl3) ppm: 1.4 to 1.6(m, 1H), 1.83(d, J=6.2 Hz, 1H), 2.5 to 2.7(m, 1H), 3.11(dd, J=8.2 Hz, J=11.6 Hz, 1H), 3.3 to 3.4(m, 1H), 3.71(dd, J=2.9 Hz, J=15.2 Hz, 1H), 4.13(dd, J=7.3 Hz, J=11.7 Hz, 1H), 4.16(dd, J=10.3, 14.9 Hz, 1H), 4.3 to 4.6 (m, 3H), 4.7(m, 2H), 5.2 to 5.4(m, 4H), 5.8 to 6.0(m, 2H), 6.0(m, 2H). IR ν (CHCl3) cm-1 : 1684, 1158.
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][Si:4]([Cl:8])(Cl)[CH2:3][CH2:2]1.NC(N)=O.[C:13]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:16])[CH2:14][OH:15]>C1COCC1>[Cl:8][Si:4]1([O:15][CH2:14][C:13]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:3][CH2:2][CH2:1][CH2:6][CH2:5]1
Reactant: O=C(CO)OCc1ccccc1
Reactant: Cl[Si]1(Cl)CCCCC1
Agent: NC(N)=O
Solvent: C1CCOC1
Product: O=C(CO[Si]1(Cl)CCCCC1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To a solution of cyclopentamethylenedichlorosilane (0.5 mL; 3.42 mmol) in dry THF (10 mL) was added urea (0.246 g; 4.10 mmol). The mixture was then cooled to 0° C. and benzyl glycolate (0.48 mL; 3.42 mmol) was added dropwise over a 15 minute span. The mixture was then taken off the ice bath and allowed to stir at room temperature for 40 minutes. The mixture was then concentrated under high vacuum and diluted with chloroform. The aqueous layer was soaked up with excess Na2SO4 and the mixture was filtered. The filtrate was concentrated to a light yellow crude liquid which was used without further purification.
Reaction SMILES: C(O)(=O)C.[CH3:5][O:6][C:7]1[C:8]([CH3:27])=[C:9]([C:16]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=2)=[O:17])[N:10]2[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]2.O>[Fe].C(O)C>[NH2:24][C:21]1[CH:22]=[CH:23][C:18]([C:16]([C:9]2[N:10]3[C:15]([CH:14]=[CH:13][CH:12]=[CH:11]3)=[C:7]([O:6][CH3:5])[C:8]=2[CH3:27])=[O:17])=[CH:19][CH:20]=1
Reactant: COc1c(C)c(C(=O)c2ccc([N+](=O)[O-])cc2)n2ccccc12
Agent: [Fe]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: COc1c(C)c(C(=O)c2ccc(N)cc2)n2ccccc12
Temperature: 80 °C
Yield: 96.2 %

Procedure:
1.93 g (34.46 mmol) of iron and 8.21 ml (143.57 mmol) of glacial acetic acid are added to 2.97 g (9.57 mmol) of (1-methoxy-2-methylindolizin-3-yl)(4-nitrophenyl)methanone in 120 ml of a 2/1 mixture of water and ethanol. The reaction medium is heated at 80° C. for 3 hours. The reaction medium is extracted with ethyl acetate. The organic phase is washed with a saturated aqueous solution of sodium hydrogen carbonate and then with a saturated aqueous solution of sodium chloride, dried over sodium sulphate, and then concentrated under reduced pressure. The residue obtained is purified by silica gel column chromatography, elution being carried out with a dichloromethane/methanol (90/10) mixture. 2.58 g of a yellow solid are obtained.