Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:11]1[CH2:14][CH:13]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:25][C@@H:24]([CH2:26][N:27]=[N+]=[N-])[O:23][C:22]3=[O:30])=[CH:17][C:16]=2[F:31])[CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[C:1]([N:11]1[CH2:14][CH:13]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:25][C@H:24]([CH2:26][NH2:27])[O:23][C:22]3=[O:30])=[CH:17][C:16]=2[F:31])[CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: [N-]=[N+]=NC[C@@H]1CN(c2ccc(C3CN(C(=O)OCc4ccccc4)C3)c(F)c2)C(=O)O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NC[C@H]1CN(c2ccc(C3CN(C(=O)OCc4ccccc4)C3)c(F)c2)C(=O)O1
Reaction time: 3 h

Procedure:
To a stirred solution of (S)-(−)-N-carbobenzyloxy-3-[2-fluoro-4-[5-azidomethyl-2-oxo-3-oxazolidinyl]phenyl]azetidine (Example 81, Step 7, 1.63 g, 3.84 mmol) in dry THF (20 mL) was added triphenylphosphine (1.11 g, 4.23 mmol). After 3 hr, water (0.69 mL, 38.4 mmol) was added and the reaction stirred for 2 days at which time the solvents were evaporated. The residue was chromatographed over silica gel (150 g, 40-60 μm) eluting with 5-10% methanol-chloroform. The title compound was isolated as a viscous colorless oil. FAB-HRMS: theory 400.1672 (M+1); meas. 400.1676.
Reaction SMILES: C1(C[N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][NH:14][CH2:15][C:16]([F:19])([F:18])[F:17])[CH2:9]2)C=CC=CC=1.[H][H]>[Pd].CO>[F:19][C:16]([F:17])([F:18])[CH2:15][NH:14][CH2:13][CH:10]1[CH2:11][CH2:12][NH:8][CH2:9]1
Reactant: [H][H]
Reactant: FC(F)(F)CNCC1CCN(Cc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: FC(F)(F)CNCC1CCNC1
Yield: 53.2 %

Procedure:
A mixture of 7.15 g (26.3 mmole) 1-(phenylmethyl)-N-(2,2,2-trifluoroethyl)-3-pyrrolidinemethanamine 100 ml of methanol and 0.7 g of 20% palladium on carbon was shaken in an atmosphere of hydrogen at about 4.5×105Pa and at room temperature for 24 hours. The catalyst was filtered and the filtrate evaporated under reduced pressure. The residue was distilled under vacuum (63-65° C., 2.8 mm Hg) to give 2.55 g of N-(2,2,2-trifluoroethyl)-3-pyrrolidinemethanamine.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3](OCC)=O.[NH2:10][CH2:11][CH:12]([OH:15])[CH2:13][NH2:14]>CC1C=CC(C)=CC=1>[F:9][C:2]([F:1])([F:8])[C:3]1[NH:10][CH2:11][CH:12]([OH:15])[CH2:13][N:14]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: NCC(O)CN
Solvent: Cc1ccc(C)cc1
Product: OC1CN=C(C(F)(F)F)NC1
Temperature: 160 °C
Reaction time: 4 h
Yield: 97.5 %

Procedure:
To a solution of ethyl trifluoroacetate (5.80 g, 40.8 mmol) in p-Xylene (30 mL) was added 1,3-diamino-2-propanol (3.60 g, 40 mmol). The mixture was stirred at 160° C. for 4 h. Concentration in vacuo then afforded the title compound (6.55 g, 39.0 mmol, 97% yield).
Reaction SMILES: [CH:1]1([CH2:7][NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:10][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>[OH-].[Na+].C1C=CC=CC=1>[C:15]([O:14][C:12](=[O:13])[CH2:11][CH2:10][NH:8][CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)([CH3:18])([CH3:17])[CH3:16]
Reactant: NCC1CCCCC1
Reactant: CC(C)(C)OC(=O)CCCl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)CCNCC1CCCCC1
Reaction time: 1 h
Yield: 89.7 %

Procedure:
To 33.76 g of cyclohexylmethylamine was added with stirring 15.96 g of tert-butyl β -chloropropionate over a period of 30 minutes, while maintaining the temperature at 30°-70° C. The reaction mixture was held at 70° C. for an additional one hour. At the end of this period, the reaction mixture was taken up in 40 ml of 2N NaOH solution and 50 ml of benzene, transferred into a separatory funnel and well shaken. The benzene solution was separated, washed with water, dried over anhydrous sodium sulfate and filtered. After evaporation of benzene, the residue was distilled under reduced pressure to give 21.0 g (89 percent) of N-cyclohexylmethyl- β -alanine tert-butyl ester, B.P. 156° C./15 mmHg.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O.[Cl:12][C:13]1[CH:14]=[C:15](I)[C:16]([NH2:19])=[N:17][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[Cl:12][C:13]1[CH:14]=[C:15]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[S:2][CH3:1])[C:16]([NH2:19])=[N:17][CH:18]=1
Reactant: CSc1ccccc1B(O)O
Reactant: Nc1ncc(Cl)cc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CSc1ccccc1-c1cc(Cl)cnc1N
Temperature: 25 °C
Yield: 46.8 %

Procedure:
Mixture of 2-(methylthio)phenylboronic acid (5.0 g, 29.8 mmol), 5-chloro-3-iodopyridin-2-amine (7.56 g, 29.8 mmol), sodium carbonate (9.0 g, in 50 mL of water), Pd(PPh3)4 (621 mg) and 100 mL of toluene was refluxed overnight under N2. reaction mixture was cooled down to room temperature, organic layer was separated and concentrated in vacuum. The residue was subjected to column chromatography on silica gel with hexane/ethyl acetate gradient mixture as eluent, providing 3.5 g of 5-chloro-3-(2-(methylthio)phenyl)pyridin-2-amine.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].N1C=CC=CC=1.C(Cl)Cl.[CH2:23]([N:30]1[CH2:34][CH2:33][C@@H:32]([NH2:35])[CH2:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl>[N+:11]([C:8]1[CH:9]=[CH:10][C:5]([O:4][C:2](=[O:3])[NH:35][C@@H:32]2[CH2:33][CH2:34][N:30]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:31]2)=[CH:6][CH:7]=1)([O-:13])=[O:12]
Reactant: N[C@@H]1CCN(Cc2ccccc2)C1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(N[C@@H]1CCN(Cc2ccccc2)C1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Nitro-phenyl chloroformate (1 eq.) is added dropwise to a solution of pyridine/DCM (1:5) at 0° C. The reaction mixture is kept at 0° C. and a solution of (R)-1-benzyl-pyrrolidin-3-ylamine (1 eq.) in DCM is added dropwise. The reaction mixture is stirred at room temperature overnight. The reaction mixture is partitioned between (0.2 M) HCl(aq) and DCM. The organics are washed with water, saturated sodium hydrogen carbonate solution and brine. The combined organics are dried (MgSO4), filtered and reduced in vacuo to yield the title compound. MS (ES+) m/e 342.10 (MH+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.[CH3:10][CH:11]([OH:13])C.C(OC(=O)C)C>C(OC(=O)C)(=O)C>[C:11]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1)(=[O:13])[CH3:10]
Reactant: O=C(O)C1CCNCC1
Reactant: CC(C)O
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N1CCC(C(=O)O)CC1

Procedure:
Piperidine-4-carboxylic acid (208 g, 1.63 moles) was dissolved in acetic anhydride and the resulting solution heated at reflux under a nitrogen atmosphere for 48 hours. The flask contents were allowed to cool then concentrated under reduced pressure to give a pale yellow oil which solidified on standing. Recrystallisation from propan-2-ol then afforded the title compound as an off white solid (160 g, 0.94 moles, 58%), mp 164-166° C. (IPA-ethylacetate), δH (300 MHz;CDCl3) 1.7 (2H, m), 2.0 (2H, m), 2.2 (3H, s), 2.6 (1H, m), 2.85 (1H, m), 3.2 (1H, m), 3.8 (1H, m), and 4.4 (1H, m).
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([Cl:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:14][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[Cl:15])[C:11]([CH:12]=[O:13])=[CH:10]2
Reactant: OB(O)c1ccccc1Cl
Reactant: O=Cc1cc2cccc(Cl)c2nc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=Cc1cc2cccc(Cl)c2nc1-c1ccccc1Cl

Procedure:
Prepared according to Procedure A using 2,8-dichloroquinoline 3-carbaldehyde (1.70 g, 7.5 mmol), 2-chlorophenyl boronic acid (1.29 g, 8.25 mmol, 1.1 eq), tetrakis(triphenylphosphine)palladium (0.430 g, 0.375 mmol, 0.05 eq), and sodium carbonate (3.97 g, 37.5 mmol, 5 eq) in acetonitrile (57 mL) and water (19 mL). After purification, 8-chloro-2-(2-chlorophenyl)quinoline-3-carbaldehyde was obtained as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.25 (1 H, s), 8.93 (1 H, s), 8.14 (1 H, d, J=8.6 Hz), 8.03 (1 H, d, J=9.0 Hz), 7.55-7.64 (1 H, t, J=8.0 Hz) Mass Spectrum (ESI) m/e=302.0 and 304.0 (M+1)
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:4]=[CH:3]1.C([Li])CCC.CN([CH:27]=[O:28])C>C1COCC1>[CH:27]([C:3]1[N:2]([CH3:1])[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[C:5]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:4]=1)=[O:28]
Reactant: Cn1cnc(-c2ccccc2)c1-c1ccncc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1c(C=O)nc(-c2ccccc2)c1-c1ccncc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 1-methyl-4-phenyl-5-[4-pyridinyl]imidazole (0.275 g, 1.17 mmol) in THF at -78° C. was added n-butyllithium (0.56 mL of 2.5M solution, 1.40 mmol). The resulting red-orange solution was allowed to stir at -78° C. for 0.5 h when DMF (0.18 mL, 2.34 mmol) was added. The mixture was allowed to warm to rt and stir for 4 h, then quenched with ice water and partitioned between CH2Cl2 and H2O. The organic extract was washed with aqueous NaCl and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by flash chromatography eluting with 50:1 CH2Cl2 /MeOH. The title compound was obtained as a white solid (0.187 g, 61%): mp 167°-168° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:14][CH2:15][CH2:16][C:17](Cl)=[O:18].C(N(CC)CC)C>C(Cl)Cl>[Cl:14][CH2:15][CH2:16][C:17]([N:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]1)=[O:18]
Reactant: O=C(Cl)CCCl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)CCCl)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.8 %

Procedure:
4-(t-butoxycarbonyl)piperazine (3 g, 16 mmol) was suspended in 10 mL of methylene chloride and cooled in an ice/water bath. 3-Chloropropionyl chloride (2.04 g, 16 mmol) was dissolved in 10 mL of methylene chloride and added slowly, while maintaining the internal temperature below 50° C. Triethylamine (1.63 g, 16 mmol) was then added to the cold (50° C.) solution. The solution was slowly warmed to room temperature and then stirred at room temperature overnight. The reaction mixture was diluted with 150 mL of methylene chloride and washed with 5% aqueous NaHCO3 (2×100 mL), brine (2×100 mL), dried over MgSO4, filtered, concentrated and dried under vacuum to give 3.71 g of crude product. The crude material was purified by flash chromatography on silica gel eluting with ethyl acetate to give 1.85 g (41.8%) of 1-(3-chloropropionyl)-4-(t-butoxycarbonyl)piperazine as a pale yellow solid. 1H NMR (300 MHz/CDCl3): δ 1.47 (s, 9H), 2.82 (t, 2H, J=6.95 Hz), 3.40-3.46 (m, 6H), 3.60-3.63 (m, 2H), 3.84 (t, 2 H, J=6.95 Hz); mass spectrum, m/z=283.1 (M+Li); high-resolution FAB-MS calcd for C12H21N2O3Cl1 276.1240 (M+), found 276.1227.
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:31])=[C:12]([C:26](OCC)=[O:27])[C:13](=[O:25])[N:14]3[CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][C:20]3=[O:24])=[N:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:34][O:35][CH2:36][CH2:37][NH2:38]>C(O)(C)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:31])=[C:12]([C:26]([NH:38][CH2:37][CH2:36][O:35][CH3:34])=[O:27])[C:13](=[O:25])[N:14]3[CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][C:20]3=[O:24])=[N:9][CH:8]=2)=[CH:32][CH:33]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCC2=O)c1=O
Reactant: COCCN
Solvent: CC(C)O
Product: COCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCC2=O)c1=O

Procedure:
A mixture of ethyl 7-(4-fluorobenzyl)-4-hydroxy-2-oxo-1-[2-(2-oxopyrrolidin-1-yl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate (1.13 g, 2.50 mmol) and 2-methoxyethylamine (1.1 mL, 12.5 mmol) in isopropanol (20 mL) was heated at reflux for 3 hrs. After cooling, the resulting slurry was diluted with isopropanol (10 mL) and filtered. The precipitate was partitioned between CH2Cl2 and 1N NaHSO4. After separating the layers, the aqueous phase was back-extracted with CH2Cl2 and the combined organics were dried over Na2SO4, filtered and evaporated in vacuo to provide the product as a white solid. The isopropanol was evaporated in vacuo and the residue was partitioned between CH2Cl2 and 1N NaHSO4. After separating the layers, the aqueous phase was back-extracted with CH2Cl2 and the combined organics were dried over Na2SO4, filtered and evaporated in vacuo to provide an additional crop of the product as a white solid: 1H NMR (CDCl3) δ 10.27 (1H, br m), 8.55 (1H, s), 8.06 (1H, s), 7.24 (2H, m), 6.99 (2H, t, J=8.6 Hz), 4.35 (2H, t, J=7 Hz), 4.14 (2H, s), 3.65 (2H, m), 3.59 (2H, m), 3.50 (2H, t, J=7 Hz), 3.44 (2H, m), 3.42 (3H, s), 2.31 (2H, t, J=8 Hz), 1.97 (2H, m); ES+ MS: 483 (M+H+).
Reaction SMILES: Cl.[NH:2]1[CH:6]=[C:5]([CH2:7][N:8]2[C:14]3[CH:15]=[CH:16][C:17]([C:19]#[N:20])=[CH:18][C:13]=3[CH2:12][N:11]([S:21]([CH3:24])(=[O:23])=[O:22])[C@H:10]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:9]2)[N:4]=[CH:3]1.[C:32]1([C:38](Cl)([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(#N)C>[C:32]1([C:38]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)[N:2]2[CH:6]=[C:5]([CH2:7][N:8]3[C:14]4[CH:15]=[CH:16][C:17]([C:19]#[N:20])=[CH:18][C:13]=4[CH2:12][N:11]([S:21]([CH3:24])(=[O:22])=[O:23])[C@H:10]([CH2:25][C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH2:9]3)[N:4]=[CH:3]2)[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CS(=O)(=O)N1Cc2cc(C#N)ccc2N(Cc2c[nH]cn2)C[C@H]1Cc1ccccc1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CC#N
Product: CS(=O)(=O)N1Cc2cc(C#N)ccc2N(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)C[C@H]1Cc1ccccc1
Reaction time: 8 h

Procedure:
To a solution of 1.2 g (2.85 mmol) of the free base of Example 225 in 20 ml of acetonitrile, at rt and under argon, was added 1.2 ml (8.55 mmol) of TEA, followed by 1.2 g (4.3 mmol) of triphenylmethyl chloride. Stirring was continued overnight. The resulting cloudy solution was evaporated to dryness and the residue subjected to flash chromatography on a 100 cc column of silica gel (50% ethyl acetate-hexane) to afford 1.2 g (64%) of Cmpd A as a viscous white foam.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:10])=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[OH-].[Na+].[CH:13](O)=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][CH:13]=[N:9][C:4]=2[C:3]=1[F:10]
Reactant: Nc1ccc(Br)c(F)c1N
Reactant: O=CO
Agent: [Na+]
Agent: [OH-]
Product: Fc1c(Br)ccc2[nH]cnc12
Yield: 92 %

Procedure:
A mixture of 142 (25 g, 0.121 mol) and formic acid (75 mL) was heated to reflux for 1.5 h. After the completion of the reaction the reaction was cooled and made basic with 10% NaOH. The resulting solid was filtered and washed with water. Drying overnight under suction afforded 24 g (92%) of 5-bromo-4-fluoro-1H-benzoimidazole (144) as pale yellow solid which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]3[C:13](=[C:14]([C:15]4[CH:20]=[C:19]([CH3:21])[C:18]([OH:22])=[C:17]([CH3:23])[CH:16]=4)[C:4]=2[C:3]=1[CH3:24])[CH:12]=[CH:11][CH:10]=[CH:9]3.Cl[S:26]([C:29]1[CH:37]=[CH:36][C:32]([C:33]([OH:35])=[O:34])=[C:31]([OH:38])[CH:30]=1)(=[O:28])=[O:27]>>[CH3:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]3[C:13](=[C:14]([C:15]4[CH:20]=[C:19]([CH3:21])[C:18]([O:22][S:26]([C:29]5[CH:37]=[CH:36][C:32]([C:33]([OH:35])=[O:34])=[C:31]([OH:38])[CH:30]=5)(=[O:28])=[O:27])=[C:17]([CH3:23])[CH:16]=4)[C:4]=2[C:3]=1[CH3:24])[CH:12]=[CH:11][CH:10]=[CH:9]3
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Reactant: Cc1cc(-c2c3ccccc3cc3sc(C)c(C)c23)cc(C)c1O
Product: Cc1cc(-c2c3ccccc3cc3sc(C)c(C)c23)cc(C)c1OS(=O)(=O)c1ccc(C(=O)O)c(O)c1
Yield: 62.4 %

Procedure:
The title compound was prepared according to the procedure in Example 1, step 9, using 4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenol (2.052 g, 6.171 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (5.840 g, 24.68 mmol). Purification on 2% H3PO4 /MeOH treated Biotage KP-Sil, eluting with a 15 & 25% EtOAc/hexane step gradient gave 2.05 g (62%) of the title compound. 1H NMR (DMSO-d6) δ 1.60 (s, 3 H), 2.16 (s, 6 H), 2.42 (s, 3 H), 7.17 (s, 2 H), 7.38-7.40 (m, 2 H), 7.47-7.56 (m, 3 H), 7.98 (d, 1 H), 8.09 (d, 1 H), 8.50 (s, 1 H).
Reaction SMILES: [CH3:1][N:2]([CH2:14][CH:15](O)[CH3:16])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1.S(Cl)([Cl:20])=O>>[CH3:1][N:2]([CH2:14][CH:15]([Cl:20])[CH3:16])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1
Reactant: CC(O)CN(C)CCc1ccc([N+](=O)[O-])cc1
Reactant: O=S(Cl)Cl
Product: CC(Cl)CN(C)CCc1ccc([N+](=O)[O-])cc1

Procedure:
Thionyl chloride (50 ml) was added dropwise with stirring and cooling in an ice/water bath to 1-(N-methyl-N-(4-nitrophenethyl)amino)-2-hydroxypropane (1.5 g). After stirring at room temperature for 1 hour, the solution was refluxed on a steam bath for a further 2 hours. The solution was evaporated to dryness and the residual oil partitioned between 2N aqueous sodium carbonate solution and ethyl acetate. After two further extractions with ethyl acetate, the organic portions were combined, washed with a saturated brine solution, dried over anhydrous magnesium sulphate, filtered and evaporated to dryness. The resultant brown oil was chromatographed on silica ("Kieselgel 60"- Trade Mark) eluting with ethyl acetate followed by collection and evaporation of suitable fractions to give the title compound as a yellow oil, (0.75 g).
Reaction SMILES: [CH2:1]([C@@:4]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[OH2:26]>CN(C=O)C.Cl[Cu].Cl[Pd]Cl>[Br:19][C:16]1[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]2[CH2:6][CH2:5][C@:4]([CH2:1][C:2](=[O:26])[CH3:3])([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:9][C:8]2=[O:10])[CH3:12])=[CH:18][CH:17]=1
Reactant: C=CC[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Reactant: O
Agent: Cl[Cu]
Agent: Cl[Pd]Cl
Solvent: CN(C)C=O
Product: CC(=O)C[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Temperature: 25 °C
Yield: 58 %

Procedure:
To a solution of (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (20 g, 50 mmol) and CuCl (12.4 g, 125 mmol) in dry DMF (50 mL) was added H2O (12 mL) and PdCl2 (2.66 g, 15 mmol) at 0˜−5° C. After addition, the mixture was allowed to warm to rt gradually for 48 h under O2. After TLC showing the stating material had disappeared, the solid was filtered off. Water (200 mL) and EtOAc (50 mL) were added. The layers were separated and the aqueous layer was extracted with EtOAc (3×40 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give a residue, which was purified by column chromatography to give (S)-3-((S)-1-(4-bromo-phenyl)ethyl)-6-(2-oxopropyl)-6-phenyl-1,3-oxazinan-2-one (12 g, 58%).
Reaction SMILES: [NH2:1][C:2]1[C:3](OC2C=CC(F)=CC=2F)=[C:4](C2C3C=CN(S(C4C=CC(C)=CC=4)(=O)=O)C=3C(=O)N(C)C=2)[CH:5]=[CH:6][C:7]=1[NH2:8].[CH:39]([O-])([O-])OCC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1>[N:1]1[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=2[NH:8][CH:39]=1
Reactant: CCOC([O-])[O-]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4ccc(N)c(N)c4Oc4ccc(F)cc4F)cn(C)c(=O)c32)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Product: c1ccc2[nH]cnc2c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A solution of 4-[3,4-diamino-2-(2,4-difluorophenoxyl)phenyl]-6-methyl-1-[(4-methylphenyl)sulfonyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (31.0 mg, 0.058 mmol) in tetrahydrofuran (0.50 mL) was treated with ethyl orthoformate (28.8 μL, 0.173 mmol) followed by p-toluenesulfonic acid monohydrate (1.1 mg, 5.8 μmol) and stirred at 50° C. for 1 h. The reaction mixture was concentrated to give the intermediate benzimidazole which was used immediately without further purification. The intermediate benzimidazole was dissolved in ethanol (1.0 mL), treated with 1.0 M sodium hydroxide in water (300 μL, 0.90 mmol), and heated at 60° C. overnight. The reaction mixture was purified via preparative LCMS (XBridge C18 column, eluting with a gradient of methanol/water containing 0.1% trifluoroacetic acid, at flow rate of 60 mL/min) to give the desired product (6 mg, 26%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 12.01 (s, 1H), 8.72 (br s, 1H), 7.65 (d, J=8.4 Hz, 1H), 7.44 (d, J=8.3 Hz, 1H), 7.32-7.15 (m, 3H), 6.80-6.65 (m, 1H), 6.63-6.48 (m, 1H), 6.20-6.03 (m, 1H), 3.48 (s, 3H); LCMS calculated for C21H15F2N4O2 (M+H)+: m/z=393.1. found: 393.1.
Reaction SMILES: Cl.[NH2:2][C:3]1([CH2:8]Cl)[CH2:7][CH2:6][CH2:5][CH2:4]1.[CH:10]([C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1[N:22]=[C:23]=[S:24])([CH3:12])[CH3:11]>>[CH:10]([C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1[N:22]=[C:23]1[S:24][CH2:8][C:3]2([CH2:7][CH2:6][CH2:5][CH2:4]2)[NH:2]1)([CH3:12])[CH3:11]
Reactant: CC(C)c1cc([N+](=O)[O-])ccc1N=C=S
Reactant: NC1(CCl)CCCC1
Agent: Cl
Product: CC(C)c1cc([N+](=O)[O-])ccc1N=C1NC2(CCCC2)CS1

Procedure:
2-Isoropylaniline was converted to 2-isopropylacetanilide according to Method A2a, Step 1. The acetanilide was converted to 2-isopropyl-4-nitroacetanilide according to Method A2a, Step 2. The acetanilide was deprotected according to Method A2a, Step 3 to give 2-isopropyl-4-nitroaniline. The aniline was converted to 2-isopropyl-4-nitrophenyl isothiocyanate according to Method A2a, Step 3. 1-Amino-1-(hydroxymethyl)cyclopentane was synthesized as described in Method B1c. The 2-hydroxyethylamine was reacted with SOCl2 according to Method B7a to give 1-amino-1-(chloromethyl)cyclopentane HCl salt. The 2-chloroethylamine was reacted with 2-isopropyl-4-nitrophenyl isothiocyanate according to Method C1a to give 2-(2-isopropyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford 1-isobutyl-2-(2-isopropyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane.