Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][CH:9]([CH2:21][OH:22])[CH:10]=[CH:11][CH:12]1[C:16]([CH3:18])([CH3:17])[CH2:15][CH2:14][C:13]1([CH3:20])[CH3:19])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:23]OS(OC)(=O)=O.O>C(Cl)Cl>[C:1]([NH:8][CH:9]([CH2:21][O:22][CH3:23])[CH:10]=[CH:11][CH:12]1[C:13]([CH3:20])([CH3:19])[CH2:14][CH2:15][C:16]1([CH3:18])[CH3:17])([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2]
Reactant: COS(=O)(=O)OC
Reactant: CC(C)(C)OC(=O)NC(C=CC1C(C)(C)CCC1(C)C)CO
Solvent: O
Solvent: ClCCl
Product: COCC(C=CC1C(C)(C)CCC1(C)C)NC(=O)OC(C)(C)C

Procedure:
A solution of 2,2,5,5-tetramethylcyclopentylmethyl bromide in ether is added slowly to magnesium turnings until the Grignard begins to form. The remainder of the alkyl bromide is then added and the mixture stirred until all the magnesium dissolved. At 0° C. a solution of N-Boc-0-methyl-D-serinal is quenched with 1M HCl, and extracted with ether, and the extracts are evaporated. The residue is dissolved in dioxane and 2M H2SO4 is added. The mixture is heated until the alcohol is dehydrated as shown by thin layer chromatography. Water is added and the mixture is extracted with ether. The organic layer is dried over MgSO4 and is evaporated to give N-Boc-3-amino-4-methoxy-1-(2,2,5,5-tetramethylcyclopentyl)--butene and some N-Boc-3-amino-4-hydroxy-1-(2,2,5,5-tetramethylcyclopentyl)-1-butene. This mixture is dissolved in methylene chloride and is methylated with dimethylsulfate. Water is added and the mixture is extracted with ether. The organic layer is dried over MgSO4 and is evaporated to give N-Boc-3-amino-4-methoxy-1-(2,2,5,5-tetramethylcyclopentyl)-1-butene.
Reaction SMILES: O1CC[O:3][CH:2]1[C:6]1[CH:7]=[CH:8][C:9]([C:12]2[S:20][C:19]3[C:14](=[N:15][CH:16]=[CH:17][C:18]=3[O:21][C:22]3[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][C:23]=3[F:29])[CH:13]=2)=[N:10][CH:11]=1.[F:30][C:31]1[CH:36]=[CH:35][C:34]([N:37]([CH3:44])[C:38](=[O:43])[CH2:39][C:40](O)=[O:41])=[CH:33][CH:32]=1>CN(C=O)C.O.C(O)(C(F)(F)F)=O>[F:29][C:23]1[CH:24]=[C:25]([NH:26][C:40](=[O:41])[CH2:39][C:38]([N:37]([C:34]2[CH:35]=[CH:36][C:31]([F:30])=[CH:32][CH:33]=2)[CH3:44])=[O:43])[CH:27]=[CH:28][C:22]=1[O:21][C:18]1[CH:17]=[CH:16][N:15]=[C:14]2[CH:13]=[C:12]([C:9]3[CH:8]=[CH:7][C:6]([CH:2]=[O:3])=[CH:11][N:10]=3)[S:20][C:19]=12
Reactant: CN(C(=O)CC(=O)O)c1ccc(F)cc1
Reactant: Nc1ccc(Oc2ccnc3cc(-c4ccc(C5OCCO5)cn4)sc23)c(F)c1
Solvent: CN(C)C=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)CC(=O)Nc1ccc(Oc2ccnc3cc(-c4ccc(C=O)cn4)sc23)c(F)c1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.2 %

Procedure:
To intermediate 38 (0.35 g, 0.86 mmol) in dry DMF (25 mL) was added 3-((4-fluorophenyl)(methyl)amino)-3-oxopropanoic acid (44) [U.S. 2007/0004675 A1] (0.36 g, 1.7 mmol) [Met-036], and EDCHCl (0.33 g, 1.7 mmol) and the mixture was stirred at r.t. for 2 h. The mixture was then partitioned between ethyl acetate and water; the organic phase was collected, washed with water, saturated NaHCO3, and brine, dried (anhydrous MgSO4), filtered and concentrated. The crude product was dissolved in acetone (50 mL) to give a colorless solution. The solution was diluted with water (20 mL) and TFA (2 mL), and heated to reflux for 3 h. It was then cooled and concentrated. The residue was then partitioned between ethyl acetate and water, the organic phase was collected, washed with water, saturated NaHCO3, and brine, dried (anhydrous MgSO4), filtered and concentrated to produce intermediate 45 (0.27 g, 57% yield). MS (m/z): 559.2 (M+H).
Reaction SMILES: [NH2:1][C:2]1[S:10][C:5]2[CH2:6][NH:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1.[CH2:20]([O:22][C:23]([CH2:25]I)=[O:24])[CH3:21]>>[NH2:1][C:2]1[S:10][C:5]2[CH2:6][N:7]([CH2:25][C:23]([O:22][CH2:20][CH3:21])=[O:24])[CH2:8][CH2:9][C:4]=2[C:3]=1[C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1
Reactant: CCOC(=O)CI
Reactant: Nc1sc2c(c1C(=O)c1ccc(Cl)cc1)CCNC2
Product: CCOC(=O)CN1CCc2c(sc(N)c2C(=O)c2ccc(Cl)cc2)C1
Yield: 70 %

Procedure:
The same procedure as in Example 17 was used except an equivalent amount of 2-amino-3-(4-chloro-benzoyl) 4,5,6,7-tetrahydrothieno[2,3-c]pyridine was used in place of 2-amino-3-benzoyl4,5,6,7-tetrahydrothieno[2,3-c]pyridine (2 mmol), and an equivalent amount of ethoxycarbonylmethyl iodide was used in place of methyl iodide (3 mmol). (m.p. 105-106° C.; 70% yield).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]2[CH3:18])[C:5]2[CH2:10][N:9]([CH3:11])[CH2:8][C:6]=2[N:7]=1.[F:19][C:20]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[C:22]([F:35])[C:21]=1[NH:36][C:37]([NH:39][CH2:40][CH3:41])=[O:38]>>[F:19][C:20]1[CH:25]=[C:24]([C:2]2[N:3]=[C:4]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]3[CH3:18])[C:5]3[CH2:10][N:9]([CH3:11])[CH2:8][C:6]=3[N:7]=2)[CH:23]=[C:22]([F:35])[C:21]=1[NH:36][C:37]([NH:39][CH2:40][CH3:41])=[O:38]
Reactant: CCNC(=O)Nc1c(F)cc(B2OC(C)(C)C(C)(C)O2)cc1F
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1CN(C)C2
Product: CCNC(=O)Nc1c(F)cc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CN(C)C3)cc1F
Yield: 9.2 %

Procedure:
Method as example 47 using (S)-4-(2-chloro-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)-3-methylmorpholine (intermediate 12) and 1-(2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-ethylurea as starting materials. The reaction mixture was filtered through a celite 545 pre-packed cartridge (2.5 g), washed with MeOH and the solvent removed in vacuo. The crude material was then purified by prep. HPLC at high pH yielding the title compound (18.5 mg, 0.04 mmol, 9.2%).
Reaction SMILES: Br[C:2]1[N:3]([CH:24]([CH3:26])[CH3:25])[C:4]2[C:9]([N:10]=1)=[C:8]([C:11]1[CH:12]=[N:13][C:14]([NH2:17])=[N:15][CH:16]=1)[N:7]=[C:6]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[N:5]=2.[CH3:27][Zn]C.CO>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:24]([N:3]1[C:2]([CH3:27])=[N:10][C:9]2[C:4]1=[N:5][C:6]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[N:7][C:8]=2[C:11]1[CH:12]=[N:13][C:14]([NH2:17])=[N:15][CH:16]=1)([CH3:26])[CH3:25]
Reactant: C[Zn]C
Reactant: CC(C)n1c(Br)nc2c(-c3cnc(N)nc3)nc(N3CCOCC3)nc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: CO
Product: Cc1nc2c(-c3cnc(N)nc3)nc(N3CCOCC3)nc2n1C(C)C
Yield: 47 %

Procedure:
To a solution of 5-(8-bromo-9-isopropyl-2-morpholin-4-yl-9H-purin-6-yl)-pyrimidin-2-ylamine, (30 mg, 0.072 mmol) and Pd(dppf)Cl2, (3 mg, 5% mmol) in 3 ml of anhydrous dioxane, was added slowly dimethyl zinc (210 μl, 1.0 M in heptane solution) in a sealed tube. The mixture was heated to about 65′C. MeOH was added drop wise and the solvents removed in vacuo. EtOAc was added to the residue and the resulting solution washed with 1 M HCl, water, brine and then dried over Na2SO4. The solvent was removed and the crude mixture was subjected to flash chromatography on silica gel to obtain 5-(9-isopropyl-8-methyl-2-morpholin-4-yl-9H-purin-6-yl)-pyrimidin-2-ylamine 8 mg in a yield of 47%. 1H NMR, MeOD: 9.40 (s, 2H), 4.81 (m, 1H), 3.89 (m, 4H), 3.82 (s, 4H), 3.71 (s, 3H), 1.73 (d, 6H). m/z: 355.16 [MH]+.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.C([O-])(=O)C.[Na+].[OH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]1[C:33](=[O:34])[C:32]([O:35][CH3:36])=[C:31]([O:37][CH3:38])[C:30](=[O:39])[C:29]=1[CH3:40]>ClCCl>[CH:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]1[C:33](=[O:34])[C:32]([O:35][CH3:36])=[C:31]([O:37][CH3:38])[C:30](=[O:39])[C:29]=1[CH3:40])=[O:17]
Reactant: COC1=C(OC)C(=O)C(CCCCCCCCCCO)=C(C)C1=O
Agent: O=[Cr](=O)([O-])Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(CCCCCCCCCC=O)=C(C)C1=O
Temperature: 0 °C
Yield: 38.7 %

Procedure:
Pyridinium chlorochromate (3.3 g) and sodium acetate (0.5 g) were suspended in dichloromethane (2.5 ml). To the suspension was added a solution of 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (3.38 g) in dichloromethane (20 ml) at room temperature. The mixture was stirred for an hour. Then, additional amount of pyridinium chlorochromate (1 g) and sodium acetate (0.5 g) were added and the mixture was stirred for another 1.5 hours. The reaction mixture was poured into an ice water and the mixture was extracted with ethyl acetate. The extract was treated in a conventional manner and the residue obtained was purified by column chromatography using silica gel. Elution was carried out with dichloroethane-ethyl acetate (9:1) and then with carbon tetrachloride-ethyl acetate (9:1), and the eluate was recrystallized from ethyl acetate-hexane to give 6-(9-formylnonyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (1.3 g), melting at 44.5°-46.5° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([C@@H:19]3[CH2:23][CH2:22][CH2:21][C@H:20]3[C:24]([OH:26])=[O:25])=[O:18])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].[CH3:29]I.O>CN(C=O)C>[CH3:29][N:16]([C:13]1[CH:14]=[CH:15][C:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[CH:11][CH:12]=1)[C:17]([C@@H:19]1[CH2:23][CH2:22][CH2:21][C@H:20]1[C:24]([OH:26])=[O:25])=[O:18]
Reactant: O=C(O)[C@@H]1CCC[C@H]1C(=O)Nc1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C(=O)[C@@H]1CCC[C@H]1C(=O)O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of rac-trans-2-(4′-nitro-biphenyl-4-ylcarbamoyl)-cyclopentanecarboxylic acid (3.54 g, 10 mmol) in DMF cooled at 0° C. was added sodium hydride (0.48 g, 12 mmol) gradually. The mixture was stirred at room temperature for 15 min followed by the addition of methyl iodide (0.7 mL). The reaction mixture was stirred for 2 h. The reaction was then mixed with water and extracted with ethyl acetate. The organic layer was washed with water and brine. The organic layer dried over sodium sulfate, filtered and concentrated to give rac-trans-2-[methyl-(4′-nitro-biphenyl-4-yl)-carbamoyl]-cyclopentanecarboxylic acid as a yellow solid. With a method similar to that used above, trans-2-[(4′-amino-biphenyl-4-yl)-methyl-carbamoyl]-cyclopentanecarboxylic acid was prepared by the hydrogenation of trans-2-[methyl-(4′-nitro-biphenyl-4-yl)-carbamoyl]-cyclopentanecarboxylic acid. This material was directly used in the next step without further purification. LCMS calcd for C20H22N2O3 (m/e) 338, obsd 339 (M+H).
Reaction SMILES: [C:1]([CH2:3][CH:4]1[O:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[O:6][CH2:5]1)#[N:2].[CH2:14]([OH:16])[CH3:15].[ClH:17]>C(OCC)C>[ClH:17].[O:9]1[C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[O:6][CH2:5][CH:4]1[CH2:3][C:1](=[NH:2])[O:16][CH2:14][CH3:15]
Reactant: N#CCC1COc2ccccc2O1
Reactant: CCO
Agent: Cl
Solvent: CCOCC
Product: CCOC(=N)CC1COc2ccccc2O1
Reaction time: 96 h
Yield: 59 %

Procedure:
17.5 g (0.10 mole) 2-cyanomethyl-1,4-benzodioxane, prepared as described by Augstein, et al, J. Med. Chem. 8: 446 (1965), was dissolved in a mixture containing 7 g ethanol and 50 ml diethyl ether. 4.5 g (0.15 moles) of dry HCl was bubbled though the mixture, which was then capped. The mixture was allowed to stand at 5° C. for 4 days, followed by 3 days at room temperature. The crude product imidate hydrochloride (IV) precipitated out and was harvested by filtration, and washed with 100 ml ether, followed by 3×100 ml portions of methylene chloride. The solid was then purified by thin layer chromatography using 10% methanol in chloroform as a developing solvent. The product has an Rf value of 0.7-0.8; starting material moves farther in this solvent system, and none was present in the crude product. The yield of product was 15.3 g, as the hydrochloride, or 59% yield.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:19]=[C:18]([C:20](=[O:31])[NH:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=4)[CH:17]=[CH:16][C:15]=3[F:32])=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.CC1(C)C(C)(C)OB([C:41]2[CH:42]=[CH:43][C:44]([CH:47]=[O:48])=[N:45][CH:46]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+].C(Cl)Cl>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:30][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][C:26]=1[F:29])[CH2:22][NH:21][C:20]([C:18]1[CH:17]=[CH:16][C:15]([F:32])=[C:14]([NH:13][C:11]([C:8]2[N:5]3[CH:6]=[CH:7][C:2]([C:41]4[CH:46]=[N:45][C:44]([CH:47]=[O:48])=[CH:43][CH:42]=4)=[CH:3][C:4]3=[N:10][CH:9]=2)=[O:12])[CH:19]=1)=[O:31]
Reactant: O=C(NCc1ccc(F)c(F)c1)c1ccc(F)c(NC(=O)c2cnc3cc(Br)ccn23)c1
Reactant: CC1(C)OB(c2ccc(C=O)nc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Solvent: O
Product: O=Cc1ccc(-c2ccn3c(C(=O)Nc4cc(C(=O)NCc5ccc(F)c(F)c5)ccc4F)cnc3c2)cn1
Temperature: 100 °C

Procedure:
A mixture comprising 7-bromo-N-(5-(3,4-difluorobenzylcarbamoyl)-2-fluorophenyl)imidazo[1,2-a]pyridine-3-carboxamide (Intermediate 3A) (2.7 g, 5.36 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinaldehyde (1.375 g, 5.90 mmol) and cesium carbonate (6.99 g, 21.46 mmol) in DME (30 ml) and water (3 ml) was treated with PdCl2(dppf).CH2Cl2 adduct (0.219 g, 0.268 mmol). The mixture was placed under nitrogen and heated at 100° C. for 1 hr. The resulting mixture was concentrated in vacuo and the residue was dissolved in 10% trifluoroethanol/CHCl3. The organics were washed with water and NaHCO3 and concentrated in vacuo. Purification by chromatography on silica eluting with 0-30% 2M NH3 in MeOH/DCM afforded the title product;
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1.C(N(C(C)C)C(C)C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH2:47]([O:49][C:50]1[CH:51]=[C:52]([C@@H:58]2[C@H:63]([NH2:64])[CH2:62][CH2:61][O:60][CH2:59]2)[CH:53]=[CH:54][C:55]=1[O:56][CH3:57])[CH3:48]>ClCCl>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:64][C@@H:63]2[CH2:62][CH2:61][O:60][CH2:59][C@@H:58]2[C:52]2[CH:53]=[CH:54][C:55]([O:56][CH3:57])=[C:50]([O:49][CH2:47][CH3:48])[CH:51]=2)=[O:10])=[CH:11][CH:12]=1
Reactant: CCOc1cc([C@H]2COCC[C@H]2N)ccc1OC
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1cc([C@H]2COCC[C@H]2NC(=O)c2ccc(C(=O)OC)cc2)ccc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1 mmol of terephthalic acid monomethyl ester, 5 mmol of ethyl di-isopropylamine and 1.1 mmol of O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluoro-phosphate (HBTU) in 20 ml of dichloromethane is stirred for 30 min at RT. After addition of 1.1 mmol of (3R,4R)-3-(3-ethoxy-4-methoxy-phenyl)-tetrahydro-pyran-4-ylamine the suspension is stirred over night at RT. The mixture is concentrated under reduced pressure and the solid residue is purified by column chromatography on SiO2 (dichloromethane/ethyl acetate 85/15 vol/vol), the main product fraction is separated and concentrated yielding the title compound as grayish solid residue. M.p. 166-167.5° C.
Reaction SMILES: Br[C:2]1[N:3]([CH2:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:4]2[C:9]([N:10]=1)=[C:8]([NH2:11])[N:7]=[C:6]([NH:12][CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[N:5]=2.Cl.C([OH:32])CCC>>[NH2:11][C:8]1[N:7]=[C:6]([NH:12][CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[N:5]=[C:4]2[C:9]=1[NH:10][C:2](=[O:32])[N:3]2[CH2:20][CH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: CCCCO
Reactant: Nc1nc(NCC2CCCCC2)nc2c1nc(Br)n2CC1CCOCC1
Agent: Cl
Product: Nc1nc(NCC2CCCCC2)nc2c1[nH]c(=O)n2CC1CCOCC1
Temperature: 100 °C

Procedure:
To a solution of 8-bromo-N2-(cyclohexylmethyl)-9-(tetrahydro-2H-pyran-4-ylmethyl)-9H-purine-2,6-diamine (110 mg) in dry n-butanol (1.5 ml) was added 37% grade hydrochloric acid (1.5 ml) at RT. The reaction was heated to 100° C. for six hours. The reaction was concentrated in vacuo, taken up in water (5 ml) and neutralised by the addition of 2.0M sodium hydroxide solution. The resulting white precipitate was filtered. This was purified by C18 reverse phase chromatography using water (containing 0.1% formic acid)-acetonitrile (containing 0.05% formic acid) as eluant (20-60%) to afford a white solid (20 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:32])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20](Cl)=[C:19](Cl)[CH:18]=3)[CH2:15][N:14]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.C(N1C[C@@H](C2C=CC([F:51])=CC=2)[C@H](NC)C1)C1C=CC=CC=1.ClC(OC1C=CC(F)=CC=1)=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:32])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([F:51])=[CH:19][CH:18]=3)[CH2:15][N:14]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: CN[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(F)cc1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(Cl)c(Cl)c1
Agent: O=C(Cl)Oc1ccc(F)cc1
Product: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(F)cc1

Procedure:
In analogy to the procedure described for the synthesis of [(3S,4R)-1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester (example 265, a) the title compound was prepared from rac-[(3S,4R)-1-Benzyl-4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-methyl-amine (WO2008128891) and 4-fluorophenyl chloroformate. MS m/e: 423.3 [M+H]+. This was followed by column chromatography on Chiralpak AD eluting with a gradient formed from ethanol and heptane. The product containing fractions were evaporated to yield the title compound as off-white solid. MS m/e: 423.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>N1C=CC=CC=1>[C:13]1([S:19]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2ccccc2)n1
Reaction time: 0.83 h
Yield: 58.3 %

Procedure:
To a solution of ethyl 2-aminothiazol-4-ylacetate (18.6 g.) in pyridine (140 ml.) was added benzenesulfonyl chloride (17.7 g.), and the mixture was stirred for 50 minutes at 90° to 100° C., and then pyridine was distilled off under reduced pressure. To the residue was added 10% hydrochloric acid (200 ml.), and then extracted with ethyl acetate (100 ml.). The extract was washed with a saturated sodium chloride aqueous solution (50 ml.×2) and treated with an activated carbon and then dried. After distillation of ethyl acetate from the extract, the precipitated crystals were collected by filtration and washed with diethyl ether and dried to give ethyl 2-benzenesulfonamidothiazol-4-ylacetate (19.0 g.), mp 129° to 130° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[NH2:19][CH:20]1[CH2:26][C:25]([CH3:28])([CH3:27])[CH:24]=[N:23][C:22]2[CH:29]=[CH:30][CH:31]([CH3:34])[C:32](=[O:33])[C:21]1=2>CO.C(Cl)(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:19][CH:20]2[CH2:26][C:25]([CH3:27])([CH3:28])[CH:24]=[N:23][C:22]3[CH:29]=[CH:30][CH:31]([CH3:34])[C:32](=[O:33])[C:21]2=3)=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: CC1C=CC2=C(C1=O)C(N)CC(C)(C)C=N2
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC1C=CC2=C(C1=O)C(NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)CC(C)(C)C=N2

Procedure:
Following General Procedure D and using N-(3,5-difluorophenylacetyl)-L-alanine (Ex. B) and 5-amino-3,3,7-trimethyl-5,7-dihydro-6H-benz[b]azepin-6-one hydrochloride (Example 6-C), the title compound was prepared. The reaction was monitored by tlc (Rf=0.4, 5% MeOH/CHCl3) and product was purified by chromatography (silica, 5% MeOH/CHCl3) and crystallization from acetonitrile.
Reaction SMILES: [CH3:1][C@@H:2]1[N:7]2[C:8]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[N:11]=[CH:10][C:9]=3[N:18]=[C:6]2[CH2:5][N:4]([S:19]([CH3:22])(=[O:21])=[O:20])[CH2:3]1.C1C=C(Cl)C=C(C(OO)=[O:31])C=1.C([O-])([O-])=O.[Na+].[Na+]>ClCCl>[CH3:1][C@@H:2]1[N:7]2[C:8]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[N+:11]([O-:31])=[CH:10][C:9]=3[N:18]=[C:6]2[CH2:5][N:4]([S:19]([CH3:22])(=[O:21])=[O:20])[CH2:3]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C[C@H]1CN(S(C)(=O)=O)Cc2nc3cnc4ccccc4c3n21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: C[C@H]1CN(S(C)(=O)=O)Cc2nc3c[n+]([O-])c4ccccc4c3n21
Reaction time: 8 h
Yield: 100 %

Procedure:
(11S)-11-Methyl-9-(methylsulfonyl)-8,9,10,11-tetrahydropyrazino[1′,2′:1,2]imidazo[4,5-c]quinoline (1.01 g, 3.19 mmol) was dissolved in dichloromethane (40 mL) and treated with MCPBA (0.94 g, 77% max). After stirring overnight, the reaction was treated with 20 mL of 2% Na2CO3 solution and the layers were separated. The aqueous layer was then extracted with dichloromethane (10×10 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give (11S)-11-methyl-9-(methylsulfonyl)-8,9,10,11-tetrahydropyrazino[1′,2′:1,2]imidazo[4,5-c]quinoline 5-oxide (1.06 g) as a tan solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[NH:8][C:7](=[O:13])[C:6]([CH3:14])=[N:5]2.S(=O)(=O)(O)O.[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1>CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[NH:8][C:7](=[O:13])[C:6]([CH:14]=[CH:25][C:24]1[CH:27]=[CH:28][C:21]([F:20])=[CH:22][CH:23]=1)=[N:5]2
Reactant: Cc1nc2cc(Cl)c(Cl)cc2[nH]c1=O
Reactant: O=Cc1ccc(F)cc1
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: O=S(=O)(O)O
Product: O=c1[nH]c2cc(Cl)c(Cl)cc2nc1C=Cc1ccc(F)cc1
Temperature: 85 °C
Yield: 97.6 %

Procedure:
6,7-Dichloro-3-methyl-1H-quinoxalin-2-one (5 g, 22 mmol) (prepared as described in: Collins, J. L.; Dambek, P. J.; Goldstein, S. W.; Faraci, W. S. Bioorg. Med. Chem. Lett. 1992, 2, 915-8) was dissolved in a mixture of glacial acetic add (100 ml) and 98% sulfuric acid (10 ml). 4-Fluorobenzaldehyde (2.3 ml, 22 mmol) was added and the resulting mixture was stirred at reflux temperature for 3.5 hours. The mixture was allowed to cool to 85° C. and then poured onto ice (500 ml). The solid was filtered, washed with water and ethyl acetate and dried in vacuo at 30° C. overnight to afford 7.2 g (99%) of 6,7-dichloro-3-[2-(4-fluorophenyl)vinyl]-1H-quinoxalin-2-one.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[N:10]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:11](=[O:29])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([N:24]1[CH:28]=[CH:27][N:26]=[N:25]1)=[CH:14][CH:13]=2)(C)(C)C.[ClH:35]>C(OCC)(=O)C>[ClH:35].[NH2:7][CH2:8][C:9]1[N:10]([CH2:30][CH:31]([CH3:32])[CH3:33])[C:11](=[O:29])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([N:24]1[CH:28]=[CH:27][N:26]=[N:25]1)=[CH:14][CH:13]=2
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(-n3ccnn3)cc12
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCCOc1c(CN)n(CC(C)C)c(=O)c2ccc(-n3ccnn3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.3 %

Procedure:
tert-butyl[4-butoxy-2-isobutyl-1-oxo-6-(1H-1,2,3-triazol-1-yl)-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.14 g, 0.3 mmol) was dissolved in a solution of 4N hydrogen chloride in ethyl acetate (5 ml,) and the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to give 3-(aminomethyl)-4-butoxy-2-isobutyl-6-(1H-1,2,3-triazol-1-yl)-1(2H)-isoquinolinone hydrochloride (81 mg, 62.3%) as an amorphous.