Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:3]=1[O:4][C:5]1[CH:15]=[CH:14][C:8]([O:9][CH:10]([CH3:13])[CH2:11][OH:12])=[CH:7][CH:6]=1.S(OC)(O[CH3:25])(=O)=O.O>[OH-].[Na+]>[CH3:25][O:12][CH2:11][CH:10]([O:9][C:8]1[CH:14]=[CH:15][C:5]([O:4][C:3]2[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:2]=2[Cl:1])=[CH:6][CH:7]=1)[CH3:13]
Reactant: COS(=O)(=O)OC
Reactant: CC(CO)Oc1ccc(Oc2ccc(Cl)cc2Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COCC(C)Oc1ccc(Oc2ccc(Cl)cc2Cl)cc1
Temperature: 60 °C
Yield: 47.9 %

Procedure:
6 g of β-[4-(2,4-dichlorophenoxy)phenoxy]propanol was dissolved in 3.4 g of 30% aqueous sodium hydroxide. The solution was heated at a temperature of 60° C., then 3.1 g of dimethyl sulfate was added dropwise to the solution with stirring and the mixture was allowed to react for 1.5 hours. The reaction mixture was poured into an appropriate amount of water, and the mixture was extracted with diethyl ether. The extract was washed with water and dried over anhydrous sodium sulfate, and the ether was removed by distillation. The residue was distilled under reduced pressure to obtain 3.0 g of the desired product having a boiling point of 182° to 185° C./1.5 mmHg.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[N:13]([CH3:17])[C:14](=[O:16])[NH:15][C:8]=23)=[CH:4][C:3]=1[F:20].[H-].[Na+].I[CH3:24].O>C1COCC1>[NH2:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[N:13]([CH3:17])[C:14](=[O:16])[N:15]([CH3:24])[C:8]=23)=[CH:4][C:3]=1[F:20]
Reactant: Cn1c(=O)[nH]c2c(Oc3ccc(N)c(F)c3)ccnc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(=O)n(C)c2c(Oc3ccc(N)c(F)c3)ccnc21
Reaction time: 0.33 h

Procedure:
To a solution of 7-(4-amino-3-fluorophenoxy)-3-methyl-1H-imidazo[4,5-b]pyridin-2(3H)-one (100 mg, 0.365 mmol) in THF (4 mL) at 0° C. under argon, NaH (16.77 mg, 0.419 mmol) was added in one portion. The resulting solution was stirred for 20 minutes and iodomethane (0.025 mL, 0.401 mmol) was added. After 1 hour, water was added, and the solution evaporated and extracted with DCM (3×20 mL) to give the title compound.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([N:8]2[CH2:12][C@:11]3([CH:17]4[CH2:18][CH2:19][N:14]([CH2:15][CH2:16]4)[CH2:13]3)[O:10][C:9]2=[O:20])[S:5][C:6]=1Br.C([Sn](CCCC)(CCCC)[C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1)CCC>>[N:29]1[CH:30]=[CH:31][C:26]([C:2]2[N:3]=[C:4]([N:8]3[CH2:12][C@:11]4([CH:17]5[CH2:18][CH2:19][N:14]([CH2:15][CH2:16]5)[CH2:13]4)[O:10][C:9]3=[O:20])[S:5][CH:6]=2)=[CH:27][CH:28]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Reactant: O=C1O[C@]2(CN3CCC2CC3)CN1c1nc(Br)c(Br)s1
Product: O=C1O[C@]2(CN3CCC2CC3)CN1c1nc(-c2ccncc2)cs1

Procedure:
The title compound was prepared by a method analogous to that described in Example 14 from the reaction of the mixture of(R)-3′-(4-bromothiazol-2-yl)spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one and (R)-3′-(4,5-dibromothiazol-2-yl)spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one with 4-(tri-n-butylstannyl)pyridine. Separation by reverse phase HPLC separation followed by conversion to the free base as described in Example 14 to give the title compound, m/z 343 (MH+); and (R)-3′-[4,5-di(4-pyridyl)thiazol-2-yl]spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one, m/z 420 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C@H:4]([CH2:6][S:7][C:8]([CH3:11])([CH3:10])[CH3:9])[NH2:5].[C:13]([S:16][CH2:17][CH:18]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:19](O)=[O:20])(=[O:15])[CH3:14]>CO>[CH3:1][O:2][C:3](=[O:12])[C@H:4]([CH2:6][S:7][C:8]([CH3:9])([CH3:11])[CH3:10])[NH:5][C:19](=[O:20])[CH:18]([CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:17][S:16][C:13](=[O:15])[CH3:14]
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)O
Reactant: COC(=O)[C@@H](N)CSC(C)(C)C
Solvent: CO
Product: COC(=O)[C@H](CSC(C)(C)C)NC(=O)C(CSC(C)=O)Cc1ccccc1

Procedure:
React S-(t-butyl)-L-cysteine methyl ester (2.32 g) and 3-acetylthio-2-benzylpropionic acid (3.22 g) in the manner described in Example 1, Step 1 to give an orange solid. Chromatograph this solid on a column of silica gel (2L, 60-200 mesh) and elute with ethyl acetate:hexane 3:17 to give Isomer A, a clear oil (1.09 g), [α]D26 =-44.9° (MeOH); overlap Isomer A and Isomer B (0.52 g); and Isomer B, a clear oil (0.75 g), [α]D26 =+8.3° (MeOH).
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C:3]([S:5][CH2:6][CH3:7])=[NH:4].C(=O)([O-])[O-].[K+].[K+].[P:15](=[S:21])(Cl)([O:18][CH3:19])[O:16][CH3:17]>C(#N)C>[CH3:17][O:16][P:15]([O:18][CH3:19])([N:4]=[C:3]([S:5][CH2:6][CH3:7])[N:2]([CH3:8])[CH3:1])=[S:21]
Reactant: COP(=S)(Cl)OC
Reactant: CCSC(=N)N(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCSC(=NP(=S)(OC)OC)N(C)C
Temperature: 40 °C
Reaction time: 2 h

Procedure:
To a mixture of 13.2 g of N,N-dimethylcarbamimidothioic acid, ethyl ester, 27.6 g of finely powdered potassium carbonate and 250 ml of acetonitrile, 16.1 g of phosphorochloridothioic acid, O,O-dimethyl ester was added. The mixture was stirred and heated to 40° C. for 4 hours. The salts were removed by filtration and the filtration concentrated in a rotary evaporator. The residue was taken up in methylene chloride, the methylene chloride solution washed thrice with 50 ml portions of water and dried over anhydrous magnesium sulfate. The solvent was removed in a rotary evaporator, leaving 20.0 g of crude product. To remove some lower boiling impurity the sample was placed in a Kugelrohr (bath temperature 95° C., pressure 0.2 mm) for 2 hours. The residue was exhaustively extracted with hexane and the hexane solution concentrated under vacuum, leaving N'-(dimethoxyphosphinothioyl)-N,N-dimethylcarbamimidothioic acid, ethyl ester as a nearly colorless oil. The product has a refractive index of nd25 =1.5610. The IR and NMR spectra were in agreement with the structural assignment.
Reaction SMILES: [CH2:1]([O:3][P:4]([NH:9][CH:10]1[CH:15]([CH3:16])[CH2:14][CH2:13][N:12](C(OCC2C=CC=CC=2)=O)[CH2:11]1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]>CO.[Pd]>[CH3:16][CH:15]1[CH2:14][CH2:13][NH:12][CH2:11][CH:10]1[NH:9][P:4](=[O:5])([O:6][CH2:7][CH3:8])[O:3][CH2:1][CH3:2]
Reactant: CCOP(=O)(NC1CN(C(=O)OCc2ccccc2)CCC1C)OCC
Agent: [Pd]
Solvent: CO
Product: CCOP(=O)(NC1CNCCC1C)OCC
Reaction time: 1 h
Yield: 83 %

Procedure:
To a solution of benzyl 3-(diethoxyphosphorylamino)-4-methylpiperidine-1-carboxylate (1.0 equiv.) in degassed MeOH was added Pd/C (10% by weight) and the reaction was stirred under a hydrogen atmosphere for 1 h. The solution was filtered, then concentrated to yield diethyl 4-methylpiperidin-3-ylphosphoramidate in 83% yield. LCMS (m/z): 251.1 (MH+).
Reaction SMILES: CS(O[CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1)(=O)=O.[I-:19].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>CC(C)=O>[I:19][CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCCC(OS(C)(=O)=O)C1
Reactant: [I-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC(I)C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
tert-Butyl 3-(methylsulfonyloxy)piperidine-1-carboxylate (0.54 g, 1.94 mmol) and sodium iodide (0.87 g, 5.8 mmol) were dissolved in acetone (10 ml) and the solution was refluxed under an inert gas for 6 h and then stirred at room temperature for 15 h. After thin layer chromatography control, the reaction mixture was heated in three portions in a microwave oven (CEM Discover): 10 min 100° C. 150 watt, 15 min 150° C. 200 watt, 20 min 100° C. 150 watt. After thin layer chromatography control, the three portions were combined, sodium thiosulfate solution (20 ml, 5 mmol/l) was added, the phases were separated and the aqueous phase was extracted with ethyl acetate (2×20 ml). The combined organic phases were washed with saturated sodium chloride solution (10 ml), dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (silica gel) with hexane/diethyl ether (3:1). Yield: 0.14 g (23%)
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[CH:15]1([CH2:21][N:22]2[CH2:26][CH2:25][CH:24]([C:27](O)=[O:28])[C:23]2=[O:30])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>ClCCl.CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:27]([CH:24]1[CH2:25][CH2:26][N:22]([CH2:21][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]2)[C:23]1=[O:30])=[O:28]
Reactant: O=C(O)C1CCN(CC2CCCCC2)C1=O
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)C1CCN(CC2CCCCC2)C1=O
Yield: 38.4 %

Procedure:
This compound was prepared according to method E with 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g; 0.433 mmol), 1-(cyclohexylmethyl)-2-oxopyrrolidine-3-carboxylic acid (0.097; 0.433 mmol), PyBOP (0.225 g; 0.433 mmol), N,N diisopropylethylamine (0.186 mL; 1.08 mmol) in dichloromethane (2 mL) and DMF (3 mL). The crude mixture was purified flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.0668 g (38%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-1-(cyclohexylmethyl)-2-oxopyrrolidine-3-carboxamide as a white solid.
Reaction SMILES: [NH2:1][C:2]1[S:25][C:5]2=[N:6][C:7]([CH3:24])=[C:8](C(O)=O)[C:9]([NH:10][S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)(=[O:13])=[O:12])=[C:4]2[C:3]=1[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=1.N1C2C(=CC=CC=2)C=CC=1>[Cu]>[NH2:1][C:2]1[S:25][C:5]2=[N:6][C:7]([CH3:24])=[CH:8][C:9]([NH:10][S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)(=[O:12])=[O:13])=[C:4]2[C:3]=1[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=1
Reactant: COc1cccc(-c2c(N)sc3nc(C)c(C(=O)O)c(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Agent: [Cu]
Solvent: c1ccc2ncccc2c1
Product: COc1cccc(-c2c(N)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Temperature: 200 °C
Yield: 35.9 %

Procedure:
A mixture of 2-amino-4-{[(3-chlorophenyl)sulfonyl]amino}-6-methyl-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridine-5-carboxylic acid (Description 84) (388 mg, 0.770 mmol), copper (245 mg, 3.85 mmol) and quinoline (3 mL, 25.3 mmol) was heated at 200° C. for ca. 1 h. After cooling to RT, the mixture was purified by normal phase chromatography, eluting with a gradient of 50-70% ethyl acetate in cyclohexane followed by 10% MeOH in DCM, to give the title compound (127 mg). LCMS (A) m/z: 460 [M+1]+, Rt 1.10 min (acidic).
Reaction SMILES: [CH:1]1[C:6]([CH2:7][CH2:8][C:9]2[C:13]3[C:14]([NH:16][C:17]([NH2:19])=[N:18][C:12]=3[NH:11][CH:10]=2)=[O:15])=[CH:5][CH:4]=[C:3]([C:20]([NH:22][C@@H:23]([C:29]([OH:31])=[O:30])[CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[O:21])[CH:2]=1.[OH-].[Na+:33]>CCO>[CH:5]1[C:6]([CH2:7][CH2:8][C:9]2[C:13]3[C:14]([NH:16][C:17]([NH2:19])=[N:18][C:12]=3[NH:11][CH:10]=2)=[O:15])=[CH:1][CH:2]=[C:3]([C:20]([NH:22][C@@H:23]([C:29]([O-:31])=[O:30])[CH2:24][CH2:25][C:26]([O-:28])=[O:27])=[O:21])[CH:4]=1.[Na+:33].[Na+:33]
Reactant: Nc1nc2[nH]cc(CCc3ccc(C(=O)N[C@H](CCC(=O)O)C(=O)O)cc3)c2c(=O)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1nc2[nH]cc(CCc3ccc(C(=O)N[C@H](CCC(=O)[O-])C(=O)[O-])cc3)c2c(=O)[nH]1
Reaction time: 2 h

Procedure:
A suspension of Pemetrexed in EtOH containing 0% to 2% water (v/v) is heated to reflux and 1.85 eq of aq. NaOH (30% w/w) are added. The mixture is stirred at reflux until PXRD shows complete conversion. 0.15 eq of aq. NaOH (30% w/w) are added and stirring under reflux is continued for 2 h before the suspension is cooled to 20° C. to 30° C. Pemetrexed Disodium Form IV is isolated by filtration, washed with EtOH and dried in vacuo to constant weight.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]3[CH:13]=[CH:14][C:15]([N+:17]([O-:19])=[O:18])=[CH:16][C:9]=3[CH2:8][O:7][C:6]=2[CH:20]=1.Cl[C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[F:29].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC([O-])(C)C.[K+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2].CC(O)(C)C>[F:28][C:25]1[CH:24]=[C:23]([F:29])[CH:22]=[CH:27][C:26]=1[NH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]3[CH:13]=[CH:14][C:15]([N+:17]([O-:19])=[O:18])=[CH:16][C:9]=3[CH2:8][O:7][C:6]=2[CH:20]=1
Reactant: Nc1ccc2c(c1)OCc1cc([N+](=O)[O-])ccc1C2=O
Reactant: Fc1ccc(Cl)c(F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: O=C1c2ccc([N+](=O)[O-])cc2COc2cc(Nc3ccc(F)cc3F)ccc21
Temperature: 100 °C

Procedure:
In accordance with general method Z, 0.50 g (1.85 mmol) of (6), 0.28 g (1.89 mmol) of 1-chloro-2,4-difluorobenzene, 2 spatula tips of Pd(OAc)2, 0.09 g of 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (phosphine ligand), 0.50 g of KOt-Bu, 1.5 ml of t-BuOH are weighed out and dissolved in 10 ml of toluene (anhydrous). The mixture is refluxed at 100° C. under an argon atmosphere for 4 h. The crude product is purified by chromatography over silica gel with MC/EtOH (98/2). Yield: 0.05 g (7.0%); melting point: 210-214° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:18]1[N:23]=[C:22]([NH:24][C@@H:25]2[CH2:30][CH2:29][C@H:28]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH2:27][CH2:26]2)[C:21]([Cl:36])=[CH:20][N:19]=1>>[Cl:36][C:21]1[C:22]([NH:24][C@@H:25]2[CH2:26][CH2:27][C@H:28]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH2:29][CH2:30]2)=[N:23][C:18]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:19][CH:20]=1
Reactant: CS(=O)(=O)N[C@H]1CC[C@@H](Nc2nc(Cl)ncc2Cl)CC1
Reactant: COCCN1CCc2ccc(N)cc2CC1
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(N[C@H]4CC[C@@H](NS(C)(=O)=O)CC4)n3)cc2CC1

Procedure:
cis-N-(4-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-cyclohexyl)-methanesulfonamide was prepared from 3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and cis-N-[4-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide in an analogous manner to Example 308c. Product isolated as a white foam (99 mg, 55%). LCMS (m/e) 523 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 7.91 (s, 1H), 7.36-7.23 (m, 2H), 7.02 (d, 1H, J=8.1 Hz), 6.78 (s, 1H), 5.18 (d, 1H, J=7.0 Hz), 4.36-4.30 (m, 1H), 4.18-4.08 (m, 1H), 3.70-3.61 (m, 1H), 3.56 (t, 2H, J=5.6 Hz), 3.39 (s, 3H), 3.03 (s, 3H), 2.96-2.88 (m, 4H), 2.80-2.69 (m, 6H), 2.01-1.84 (m, 4H), 1.84-1.70 (m, 4H).
Reaction SMILES: [Br:1]Br.[CH3:3][N:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N:14]3[CH:18]=[C:17]([CH3:19])[CH:16]=[N:15]3)[CH:10]=2)[C:5]1=[O:20]>C(O)(=O)C>[Br:1][C:12]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N:14]3[CH:18]=[C:17]([CH3:19])[CH:16]=[N:15]3)[CH:10]=2)[C:5](=[O:20])[N:4]([CH3:3])[CH:13]=1
Reactant: Cc1cnn(-c2ccc3c(=O)n(C)ccc3c2)c1
Reactant: BrBr
Solvent: CC(=O)O
Product: Cc1cnn(-c2ccc3c(=O)n(C)cc(Br)c3c2)c1
Temperature: 25 °C
Reaction time: 0.28 h
Yield: 64.7 %

Procedure:
Bromine (94 mg, 0.59 mmol) in acetic acid (2 mL) was added drop-wise to a solution of 2-methyl-6-(4-methylpyrazol-1-yl)isoquinolin-1-one (140.0 mg, 0.583 mmol) in acetic acid (4 mL) at 0° C. The mixture was then stirred at room temperature for 17 min and quenched with water (10 mL). The pH was adjusted to about 7-8 with aqueous 1M NaOH. Extractive work up with ethyl acetate followed by purification using silica gel chromatography (PE:EA=1:1) gave the title compound of step 2 (120.0 mg, 56%) as a light yellow solid. 1H NMR (CDCl3, 400 MHz) δ 8.51 (d, J=8.8 Hz, 1H), 8.06 (d, J=2.0 Hz, 1H), 7.89 (s, 1H), 7.87 (dd, J1=8.8 Hz, J2=2.0 Hz, 1H), 7.63 (s, 1H), 7.42 (s, 1H), 3.62 (s, 3H), 2.20 (s, 3H). LCMS: 319.8 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C@H:4]([CH2:22][CH2:23][S:24][CH3:25])[NH:5][C:6](=[O:21])[C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[O:14])=[CH:9][C:8]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[BH4-].[Na+]>C(O)C>[CH3:1][O:2][C:3](=[O:26])[C@H:4]([CH2:22][CH2:23][S:24][CH3:25])[NH:5][C:6](=[O:21])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][C:8]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(C=O)cc1-c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(CO)cc1-c1ccccc1
Temperature: 0 °C

Procedure:
To a solution of the resultant compound from Example 16E in ethanol at 0° C. is added sodium borohydride (0.5 equivalent), and the reaction is stirred at 0° C. until TLC analysis shows the reaction to be complete. The reaction mixture is extracted with ether, which is washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue is then purified by column chromatography on silica gel to afford the title product.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[Na].Cl[CH2:8][C:9]([N:11]1[CH2:15][CH2:14][S:13][CH:12]1[CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[O:24][CH3:25])=[O:10]>CS(C)=O>[N:1]1([CH2:8][C:9]([N:11]2[CH2:15][CH2:14][S:13][CH:12]2[CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[O:10])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COc1ccccc1OCC1SCCN1C(=O)CCl
Reactant: [Na]c1ncc[nH]1
Solvent: CS(C)=O
Product: COc1ccccc1OCC1SCCN1C(=O)Cn1ccnc1
Yield: 79.6 %

Procedure:
Imidazolyl sodium (3.58 g) is added to a stirred solution of 3-chloroacetyl-2-(o-methoxyphenoxy)methylthiazolidine (5.8 g) in DMSO (35 ml). After 1 hour the mixture is poured in ice and water (200 ml) and the separated oil is extracted with EtOAc (3×30). The organic phases are collected, washed with water, dried on Na2SO4. After evaporation, the crude residue is purified by filtration on a short column of SiO2 using EtOAc and EtOAc/MeOH 85:15 as the eluent to give 3-(imidazol-1-yl)acetyl-2-(o-methoxyphenoxy)methyl-thiazolidine (5.1 g) as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[C:14]([OH:18])([CH3:17])([CH3:16])[CH3:15].N1C=CC=CC=1.O>C(Cl)Cl>[C:14]([O:18][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CC(C)(C)O
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 78.7 %

Procedure:
A solution of 4-chloro-3-nitrobenzoylchloride (8.80 g, 40 mmol) in CH2Cl2 (20 mL) was added to a solution of tert-butyl alcohol (7.6 mL, 80 mmole) and pyridine (6.6 mL, 80 mmole) at 25° C. The mixture was stirred at 25° C. for 12 h then H2O (30 mL) was added. The aqueous solution was extracted with ethyl ether (3×100 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo to give a yellowish solid residue. Purification of the residue by flash column chromatography (gradient elution 0 to 15% EtOAc/hexanes) provided the title compound (8.11 g, 79%): TLC (Rf =0.50; 15% EtOAc/hexanes); 1H NMR (CDCl3) δ 8.41 (s, 1H), 8.13 (d, 1H, J=8.0), 7.63 (d, 1H, J=8.3), 1.63 (s, 9H); 13C NMR (CDCl3)δ 162.4, 147.6, 133.2, 131.6, 130.5, 126.0, 124.4, 82.6, 27.8; Anal. (C11H12N1O4Cl) C, H, N.
Reaction SMILES: [BH4-].[Na+].[Cl-].[Ca+2].[Cl-].[Cl:6][C:7]1[CH:8]=[C:9]([CH:14]2[CH2:20][O:19][CH2:18][CH2:17][N:16]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:15]2[C:28](OCC)=[O:29])[CH:10]=[CH:11][C:12]=1[Cl:13].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CCO>[Cl:6][C:7]1[CH:8]=[C:9]([CH:14]2[CH2:20][O:19][CH2:18][CH2:17][N:16]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH:15]2[CH2:28][OH:29])[CH:10]=[CH:11][C:12]=1[Cl:13]
Reactant: CCOC(=O)C1C(c2ccc(Cl)c(Cl)c2)COCCN1C(=O)OC(C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Ca+2]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCOCC(c2ccc(Cl)c(Cl)c2)C1CO
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 97.2 %

Procedure:
To a solution of sodium borohydride (49 mg) in THF (1.25 mL)-EtOH (0.9 mL) was added calcium chloride (72 mg), and the mixture was stirred at room temperature for 20 min. To this reaction mixture was added a solution of 4-tert-butyl 5-ethyl (5RS,6SR)-6-(3,4-dichlorophenyl)-1,4-oxazepane-4,5-dicarboxylate (135 mg) in THF (1.25 ml), and the mixture was stirred at room temperature for 16 hr. The reaction mixture was poured into 10% aqueous citric acid solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (118 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.[CH3:21][N:22]1[C:26]2[C:27]([CH3:42])=[CH:28][C:29]([C:31]([C:33]3[CH:34]=[C:35]([CH:38]=[C:39](F)[CH:40]=3)[C:36]#[N:37])=[O:32])=[CH:30][C:25]=2[O:24][C:23]1=[O:43]>CN(C=O)C>[CH3:21][N:22]1[C:26]2[C:27]([CH3:42])=[CH:28][C:29]([C:31]([C:33]3[CH:34]=[C:35]([CH:38]=[C:39]([N:17]4[CH2:18][CH2:19][CH:14]([N:10]5[CH2:9][CH2:8][C:7]6[CH:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=6[NH:12][C:11]5=[O:13])[CH2:15][CH2:16]4)[CH:40]=3)[C:36]#[N:37])=[O:32])=[CH:30][C:25]=2[O:24][C:23]1=[O:43]
Reactant: Cc1cc(C(=O)c2cc(F)cc(C#N)c2)cc2oc(=O)n(C)c12
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C#N)cc(C(=O)c4cc(C)c5c(c4)oc(=O)n5C)c3)CC1)C(=O)N2
Temperature: 300 °C

Procedure:
0.22 g (0.80 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one and 0.12 g (0.40 mmol) 3-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-5-fluoro-benzonitrile were combined and heated to 300° C. for approx. 10 min. Then the mixture was dissolved in DMF and purified by preparative HPLC-MS. The fractions containing the product were combined and the organic solvent was evaporated down. The residue was neutralised with 1N aqueous sodium hydroxide solution, the precipitate formed was suction filtered, washed with water and dried i. vac.
Reaction SMILES: [CH:1]1([N:7]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:8](=[O:18])[NH:9][C:10]2[S:11][C:12]([C:15](O)=[O:16])=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:25]([O:27][C:28](=[O:37])[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=1)[CH3:26]>>[CH2:25]([O:27][C:28](=[O:37])[CH2:29][C:30]1[CH:31]=[CH:32][C:33]([NH:36][C:15]([C:12]2[S:11][C:10]([NH:9][C:8]([N:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]3)=[O:18])=[N:14][CH:13]=2)=[O:16])=[CH:34][CH:35]=1)[CH3:26]
Reactant: O=C(O)c1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Product: CCOC(=O)Cc1ccc(NC(=O)c2cnc(NC(=O)N(C3CCCCC3)C3CCCCC3)s2)cc1

Procedure:
Prepared as described in general procedure (K) using 2-(3,3-dicyclohexyl-ureido)-thiazole-5-carboxylic acid and 4-aminophenylacetic acid ethylester.