Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[C:28]([C:30]1[CH:31]=[C:32]([CH:40]([CH2:44][CH:45]2[CH2:49][CH2:48][CH2:47][CH2:46]2)[C:41](O)=[O:42])[CH:33]=[CH:34][C:35]=1[S:36]([CH3:39])(=[O:38])=[O:37])#[N:29].[NH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][N:52]=1>C(Cl)Cl>[C:28]([C:30]1[CH:31]=[C:32]([CH:40]([CH2:44][CH:45]2[CH2:46][CH2:47][CH2:48][CH2:49]2)[C:41]([NH:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][N:52]=2)=[O:42])[CH:33]=[CH:34][C:35]=1[S:36]([CH3:39])(=[O:38])=[O:37])#[N:29]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1C#N
Reactant: Nc1ccccn1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2ccccn2)cc1C#N
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 76.7 %

Procedure:
A solution of triphenylphosphine (98 mg, 0.37 mmol) in methylene chloride (1 mL) was cooled to 0° C. and then slowly treated with N-bromosuccinimide (67 mg, 0.37 mmol). The reaction mixture was stirred at 0° C. for 15 min and then treated with 2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 75, 100 mg, 0.31 mmol). The resulting reaction mixture was stirred at 0° C. for 5 min and then allowed to warm to 25° C. where it was stirred for 30 min. The reaction mixture was then treated with 2-aminopyridine (64 mg, 0.68 mmol). The resulting reaction mixture was stirred at 25° C. for 15 h. The crude reaction mixture was then directly purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethyl acetate) to afford 2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide (94.5 mg, 76%) as a yellow foam: mp 87-90° C. (foam to gel); EI-HRMS m/e calcd for C21H23N3O3S (M+) 397.1460, found 397.1460.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([O:10][CH2:11][C@@H:12]2[CH2:15][CH2:14][N:13]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:6]=[N:7][C:8]=1[Cl:9].C(N(CC)CC)C.[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl>[C:30]([NH:1][CH2:2][C:3]1[CH:4]=[C:5]([O:10][CH2:11][C@@H:12]2[CH2:15][CH2:14][N:13]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:6]=[N:7][C:8]=1[Cl:9])(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cnc(Cl)c(CN)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cnc(Cl)c(CNC(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.3 %

Procedure:
To 5-aminomethyl-6-chloro-3-(1-BOC-2-(S)-azetidniylmethoxy)pyridine from step 92b (0.262 g, 0.80 mmol) was added CH2Cl2 (10 mL), triethylamine (0.1619 g, 1.60 mmol) and benzoyl chloride (0.1349 g, 1.0 mmol). The mixture was stirred at room temperature overnight, then concentrated under vacuum. The residue was chromatographed (silica gel; CH2Cl2 /MeOH, 9/1) to afford a light brown foam (0.267 g, 77%). MS (CI/NH3) m/z 432.00 (M+H+), 449.00 (M+NH4+). 1H NMR (CDCl3, 300 MHz): 1.57 (s, 9H), 2.25-2.37 (m, 2H), 3.87 (t, J=7.1 Hz, 2H), 4.11 (dd, J=2.7, 9.80 Hz, 1H), 4.31-4.39 (m, 1H), 4.49-4.55 (m, 1H), 4.68 (d, J=8.5 Hz, 2H), 6.75 (m, 1H), 7.42-7.56 (m, 4H), 7.79-7.82 (m, 2H), 8.03 (d, J=3.1 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:12]=[CH:13][C:14]2[C:20](=[O:21])[N:19]([CH2:22][CH3:23])[CH2:18][CH2:17][N:16]([CH2:24][CH3:25])[C:15]=2[CH:26]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][C:11]2[CH:12]=[CH:13][C:14]3[C:20](=[O:21])[N:19]([CH2:22][CH3:23])[CH2:18][CH2:17][N:16]([CH2:24][CH3:25])[C:15]=3[CH:26]=2)[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CCN1CCN(CC)c2cc(N)ccc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN1CCN(CC)c2cc(Nc3nc(Cl)ncc3Cl)ccc2C1=O
Temperature: 80 °C
Yield: 54.1 %

Procedure:
To a mixture of 2,4,5-Trichloro-pyrimidine (0.315 g, 0.00172 mol), 8-Amino-1,4-diethyl-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one (0.40 g, 0.0017 mol) in anhydrous N,N-Dimethylformamide (10 mL, 0.1 mol) was added Potassium carbonate (0.35 g, 0.0025 mol) and heated at 80° C. for 17 hours. The reaction was evaporated, water added and tan solid collected. This was chromatographed on a SiO2 prep plates with hexane/acetonitrile (1-1) giving 8-(2,5-Dichloro-pyrimidin-4-ylamino)-1,4-diethyl-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one as a cream colored solid (0.35 g, 54%); Mp 71-74° C.; LCMS (m/e) 380 (M); 1H-NMR (DMSO, 400 MHz) 9.50 (s, 1H), 8.42 (s, 1H), 7.45-7.43 (d, 1H, J=7.83 Hz), 7.35 (s, 1H), 7.21-7.19 (d, 1H, J=8.34 Hz), 3.54-3.48 (q, 2H, J=7.08 Hz), 3.43-3.41 (t, 2H, J=5.31 Hz), 3.32-3.28 (t, 2H, J=4.04 Hz), 3.21-3.16 (q, 2H, J=6.32 Hz), 1.16-1.11 (t, 3H, J=7.07 Hz), 1.20-1.18 (t, 3H, J=6.82 Hz).
Reaction SMILES: [C:1]1(=O)[NH:6][CH:5]=[CH:4][N:3]2[CH:7]=[CH:8][CH:9]=[C:2]12.P(Cl)(Cl)([Cl:13])=O.C(=O)(O)[O-].[Na+]>>[Cl:13][C:1]1[C:2]2[N:3]([CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:5][N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]ccn2cccc12
Agent: O=C([O-])O
Agent: [Na+]
Product: Clc1nccn2cccc12
Reaction time: 16 h
Yield: 71 %

Procedure:
To pyrrolo[1,2-a]pyrazin-1(2H)-one (0.35 g, 2.61 mmol) was added phosphorous oxychloride (4.0 g, 26.1 mmol). The reaction mixture was agitated for approximately 16 hours. The reaction mixture was then made alkaline by the addition of sodium bicarbonate. The reaction mixture was then extracted with hexane, washed with a saturated sodium bicarbonate solution, dried over MgSO4 and evaporated. The product was purified by recrystallization in hexane and cooled with a mixture of dry ice and acetone to give the title compound, 1-chloropyrrolo[1,2-a]pyrazine (71%), m.p. 56°-57° C.
Reaction SMILES: [CH2:1]([C:3]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][N:9]=2)[N:4]=1)[CH3:2].BrN1C(C)(C)C(=O)N(Br)C1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(=O)(O)[O-].[Na+].BrC(C1C(C2C=CC=CC=2)=CC2C(=CC=CN=2)N=1)C.[K].[C:73]1(=[O:83])[NH:77][C:76](=[O:78])[C:75]2=[CH:79][CH:80]=[CH:81][CH:82]=[C:74]12>C(Cl)(Cl)(Cl)Cl.CN(C=O)C>[C:13]1([C:12]2[C:3]([CH:1]([N:77]3[C:73](=[O:83])[C:74]4[C:75](=[CH:79][CH:80]=[CH:81][CH:82]=4)[C:76]3=[O:78])[CH3:2])=[N:4][C:5]3[C:10]([CH:11]=2)=[N:9][CH:8]=[CH:7][CH:6]=3)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCc1nc2cccnc2cc1-c1ccccc1
Agent: CC(Br)c1nc2cccnc2cc1-c1ccccc1
Agent: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: ClC(Cl)(Cl)Cl
Product: CC(c1nc2cccnc2cc1-c1ccccc1)N1C(=O)c2ccccc2C1=O

Procedure:
2-Ethyl-3-phenyl-1,5-naphthyridine (112 mg, 0.43 mmol) and 1,3-dibromo-5,5-dimethylhydantoin (85 mg, 0.7 eq) were suspended in carbon tetrachloride (5 mL). To the mixture was added benzoyl peroxide (10.3 mg, 0.1 eq) and the mixture was heated at reflux for 3 h. To the mixture was added saturated aqueous sodium bicarbonate solution (3 mL). The layers were separated and the aqueous layer was extracted with CH2CH2 (3 mL×2). The combined organic layers were washed with brine (3 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give an orange syrup. The material is used as such for the next step. LC-MS (ESI) m/z 314 [M+H]+. A mixture of 2-(1-bromoethyl)-3-phenyl-1,5-naphthyridine (120 mg, 0.38 mmol) in DMF (2.0 mL) was treated with phthalimide potassium salt (142 mg, 2.0 eq) at 60° C. for 2 h. LCMS showed completion. The reaction mixture was partitioned between water and EtOAc, worked up and purified by silica gel column chromatography using EtOAc-hexane (0/1 to 2/1) as eluent to give a white solid. 1H NMR (500 MHz, CDCl3) δ ppm 8.88 (1H, dd, J=5.0, 1.6 Hz), 8.31 (1H, J=10 Hz), 8.1 (1H, s), 7.63-7.54 (5H, m), 7.27-7.17 (8H, m), 5.88 (1H, dd, J=10, 5.0 Hz), 1.76 (3 H, J=10 Hz); LC-MS (ESI) m/z 380 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=1)[CH2:9][C:10]([C:12]1[CH:13]=[N:14][C:15]([O:18]C)=[CH:16][CH:17]=1)=[O:11].Cl>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:21]=[CH:22][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:24][CH:25]=1)[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15](=[O:18])[NH:14][CH:13]=1)=[O:11]
Reactant: COc1ccc(C(=O)CC(c2ccc(S(C)(=O)=O)cc2)c2ccccc2Cl)cn1
Agent: Cl
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(C(CC(=O)c2ccc(=O)[nH]c2)c2ccccc2Cl)cc1

Procedure:
In analogy to example 162, step 2, 3-(2-chloro-phenyl)-3-(4-methanesulfonyl-phenyl)-1-(6-methoxy-pyridin-3-yl)-propan-1-one was reacted with concentrated aqueous HCl in 1,4-dioxane to give the title compound as a colorless solid, MS (ESI+): m/z=416.0 [M+H]+.
Reaction SMILES: OS(O)(=O)=O.[NH2:6][C:7]1[C:8]([N+:17]([O-:19])=[O:18])=[C:9]([CH:13]=[C:14]([Cl:16])[CH:15]=1)[C:10]([OH:12])=[O:11].[C:20]([O-])([O-])=O.[Na+].[Na+]>CO>[NH2:6][C:7]1[C:8]([N+:17]([O-:19])=[O:18])=[C:9]([CH:13]=[C:14]([Cl:16])[CH:15]=1)[C:10]([O:12][CH3:20])=[O:11]
Reactant: Nc1cc(Cl)cc(C(=O)O)c1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(Cl)cc(N)c1[N+](=O)[O-]
Yield: 88.5 %

Procedure:
Concentrated H2SO4 (1.5 ml) was added to a mixture of 3-amino-5-chloro-2-nitrobenzoic acid (70; 3.5 g, 16.2 mmol) in MeOH (120 ml). The resulting reaction mixture was stirred under reflux for 3 days. It was then neutralized with saturated aqueous Na2CO3 and extracted with EtOAc. The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. Purification by chromatography afforded methyl 3-amino-5-chloro-2-nitrobenzoate 71 (3.3 g, 88.5%) as a yellow solid.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Br:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH:28]([CH2:39][O:40][Si](C(C)(C)C)(C)C)[CH2:29][N:30]2[CH:34]=[C:33]([N+:35]([O-:37])=[O:36])[N:32]=[C:31]2[Br:38])=[CH:22][N:21]=1>C1COCC1>[Br:38][C:31]1[N:30]([CH2:29][CH:28]([CH2:27][O:26][C:23]2[CH:22]=[N:21][C:20]([Br:19])=[CH:25][CH:24]=2)[CH2:39][OH:40])[CH:34]=[C:33]([N+:35]([O-:37])=[O:36])[N:32]=1
Reactant: CC(C)(C)[Si](C)(C)OCC(COc1ccc(Br)nc1)Cn1cc([N+](=O)[O-])nc1Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cn(CC(CO)COc2ccc(Br)nc2)c(Br)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.9 %

Procedure:
Tetra-n-butylammonium fluoride (13.0 mL of a 1M solution in THF, 13.0 mmol) was added dropwise to a stirred solution of silyl ether 189 (6.78 g, 12.3 mmol) in anhydrous THF (140 mL) and the mixture was stirred at room temperature for 4 h. The resulting solution was concentrated under reduced pressure, and then diluted with ice-water (120 mL) and extracted with EtOAc (5×120 mL). The extracts were washed with brine (100 mL) and then evaporated to dryness and the residue was chromatographed on silica gel. Elution with 0-80% Et2O/petroleum ether, petroleum ether and 0-1% MeOH/CH2Cl2 firstly gave foreruns, and then further elution with 2-3% MeOH/CH2Cl2 gave 3-(2-bromo-4-nitro-1H-imidazol-1-yl)-2-{[(6-bromo-3-pyridinyl)oxy]methyl}-1-propanol (190) (5.36 g, 100%) as a pale yellow foam; 1H NMR (CDCl3) δ 8.07 (d, J=3.0 Hz, 1H), 7.89 (s, 1H), 7.40 (d, J=8.7 Hz, 1H), 7.09 (dd, J=8.7, 3.2 Hz, 1H), 4.32 (d, J=7.2 Hz, 2H), 4.09 (d, J=5.5 Hz, 2H), 3.87 (dd, J=10.7, 4.7 Hz, 1H), 3.75 (dd, J=10.8, 4.8 Hz, 1H), 2.57 (m, 1H); HRESIMS calcd for C12H13Br2N4O4 z [M+H]+ 438.9258, 436.9278, 434.9298. found 438.9262, 436.9279, 434.9299.
Reaction SMILES: [CH3:1][O:2][CH:3]=[CH:4][C:5]1[CH:6]=[C:7]([C:11]2[N:12]([CH3:20])[C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:8]=[N:9][CH:10]=1>[Pd].CO>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[N:12]([CH3:20])[C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:8]=[N:9][CH:10]=1
Reactant: COC=Cc1cncc(-c2cc3ccccc3n2C)c1
Agent: [Pd]
Solvent: CO
Product: COCCc1cncc(-c2cc3ccccc3n2C)c1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
A flask is charged with 2-[5-(2-methoxy-vinyl)-pyridin-3-yl]-1-methyl-1H-indole (0.550 g, 2.08 mmol) and methanol (5 mL). Palladium on carbon (0.221 g, 0.208 mmol) is added and the reaction mixture is stirred at 50° C. under H2 for 16 h. It is then cooled to room temperature and filtered through celite. The celite layer is thoroughly washed with methanol. The filtrate is concentrated in vacuo, to give a residue which is purified by silica gel flash chromatography (heptane-ethyl acetate, 7:3) to afford 2-[5-(2-methoxy-ethyl)-pyridin-3-yl]-1-methyl-1H-indole as an oil. MS (ESI) m/z 267.36 (M+H)+.
Reaction SMILES: [BrH:1].[OH:2][C@H:3]([CH2:14]O)[CH2:4][NH:5][C:6]([C:8]1[S:9][C:10]([Cl:13])=[CH:11][CH:12]=1)=[O:7].C(OC(=O)C)(=O)C.CO>C(O)(=O)C>[Br:1][CH2:14][C@@H:3]([OH:2])[CH2:4][NH:5][C:6]([C:8]1[S:9][C:10]([Cl:13])=[CH:11][CH:12]=1)=[O:7]
Reactant: O=C(NC[C@H](O)CO)c1ccc(Cl)s1
Reactant: Br
Solvent: CO
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C(NC[C@H](O)CBr)c1ccc(Cl)s1
Temperature: 62.5 °C
Reaction time: 3 h

Procedure:
301.7 ml of a 33% solution of hydrobromic acid in acetic acid are added to a suspension of 100 g of N-((S)-2,3-dihydroxypropyl)-5-chlorothiophene-2-carboxamide (VIII) in 250 ml of glacial acetic acid at from 21 to 26° C. over a period of 30 minutes. Subsequently, 40 ml of acetic anhydride are added and the reaction mixture is stirred at from 60 to 65° C. for three hours. At 20 to 25° C., 960 ml of methanol are then added over a period of 30 minutes. The reaction mixture is stirred under reflux for 2.5 hours and then overnight at from 20 to 25° C. For workup, the solvents are distilled off under reduced pressure at approx. 95 mbar. The remaining suspension is admixed with 50 ml of 1-butanol and 350 ml of water. The precipitated product is filtered off with suction, washed with water and dried.
Reaction SMILES: CN.[F:3][C:4]([F:29])([F:28])[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH:13]2[N:17]2C(=O)C3C(=CC=CC=3)C2=O)[CH:6]=1>C(O)C>[F:29][C:4]([F:3])([F:28])[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH:13]2[NH2:17])[CH:6]=1
Reactant: O=C1c2ccccc2C(=O)N1C1CCCC1Cc1cc(C(F)(F)F)ccn1
Agent: CN
Solvent: CCO
Product: NC1CCCC1Cc1cc(C(F)(F)F)ccn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methanamine (40% aq, 1 ml, 11.55 mmol) was added to a solution of 2-(2-{[4-(trifluoromethyl)pyridin-2-yl]methyl}cyclopentyl)-2,3-dihydro-1H-isoindole-1,3-dione (0.100 g, 0.27 mmol) in ethanol (6 ml) in a microwave vial. The vial was sealed and stirred at room temperature for 18 hours and then heated to 60° C. for 5 hours. The reaction was cooled to room temperature and concentrated in vacuo. This was then purified by SCX chromatography (2M ammonia in methanol) to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8]O)[CH:3]=1.S(Cl)([Cl:12])=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][Cl:12])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cc(Cl)ccn1
Solvent: ClCCl
Product: ClCc1cc(Cl)ccn1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
4-Chloro-2-pyridinemethanol (1.0 g, 6.965 mmol) was dissolved in dichloromethane (25 cm3), heated to reflux and then treated slowly with a solution of thionyl chloride (1.50 cm3, d=1.631 gcm−3, 0.0206 mmol) in DCM (25 cm3). The reaction mixture was then stirred at 60° C. for 3 h, soon turning pink. After this time the DCM was evaporated off and the pale pink residue carefully neutralised with saturated sodium bicarbonate solution (40 cm3). The product was then extracted into DCM (3×30 cm3) and dried over sodium carbonate for 30 min. After filtration the product solution was then concentrated to a low volume and filtered through a short silica column (1:4 methanol/DCM as eluent), giving a pale yellow solution. This was then concentrated down to a red/brown oil, dried at 50° C., which was the desired product 4-chloro-2-chloromethylpyridine (934 mg, 83%); 1H NMR (CDCl3); δH 8.40 (d, 1H, J=5.5), 7.44 (d, 1H, J=1.5), 7.19 (dd, 1H, J=5.5, 1.5), and 4.58 (s, 2H) ppm.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:13][CH:12]2[O:27][CH2:28][C:29]2[CH:30]=[CH:31][C:32]3[O:37][CH2:36][C:35](=[O:38])[N:34]([CH2:39][CH2:40][CH2:41][O:42][CH3:43])[C:33]=3[CH:44]=2)=[CH:7][CH:6]=1)C=C.C(=O)([O-])[O-].[K+].[K+]>CO.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>[OH:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:18])[CH2:13][CH:12]2[O:27][CH2:28][C:29]2[CH:30]=[CH:31][C:32]3[O:37][CH2:36][C:35](=[O:38])[N:34]([CH2:39][CH2:40][CH2:41][O:42][CH3:43])[C:33]=3[CH:44]=2)=[CH:7][CH:6]=1
Reactant: C=CCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCc2ccc3c(c2)N(CCCOC)C(=O)CO3)cc1
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: [K+]
Solvent: CO
Product: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(O)cc3)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The solution of 10.0 g of benzyl 4-(4-allyloxyphenyl)-3-[4-(3-methoxypropyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate in 160 ml of methanol is admixed successively with 0.57 g of tetrakis(triphenylphosphine)palladium(0) and potassium carbonate. The reaction mixture is stirred at room temperature over 2 hours and subsequently concentrated by evaporation. The residue is admixed slowly with 2M HCl (70 ml) and extracted with dichloromethane (2×250 ml). The organic phases are washed with water (150 ml) and brine (150 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.20 (3:2 EtOAc-heptane); Rt=4.54.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.ON1C2C=CC=CC=2N=N1.[F:42][C:43]1[CH:50]=[CH:49][C:46]([CH2:47][NH2:48])=[CH:45][CH:44]=1>O1CCCC1>[Br:1][C:2]1[S:3][C:4]([C:8]([NH:48][CH2:47][C:46]2[CH:49]=[CH:50][C:43]([F:42])=[CH:44][CH:45]=2)=[O:10])=[C:5]([CH3:7])[N:6]=1
Reactant: NCc1ccc(F)cc1
Reactant: Cc1nc(Br)sc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(Br)sc1C(=O)NCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
To a solution of 2-bromo-4-methylthiazole-5-carboxylic acid (2.00 g, 9.00 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.41 g, 12.6 mmol) and N,N-diisopropylethylamine (4.67 mL, 27.0 mmol) in tetrahydrofuran (40 mL) was added 1-hydroxybenzotriazole (1.70 g, 12.6 mmol). The resulting mixture was stirred at ambient temperature for 30 minutes and 4-fluorobenzylamine (1.43 mL, 12.6 mmol) was added. The reaction mixture was kept stirring at ambient temperature for 17 hours, then concentrated in vacuo. The residue was dissolved ethyl acetate and washed with water and brine. The organic solution was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography to afford 2-bromo-N-(4-fluorobenzyl)-4-methylthiazole-5-carboxamide in 81% yield (2.38 g): 1H NMR (300 MHz, CDCl3) δ 7.30-7.26 (m, 2H), 7.05-7.00 (m, 2H), 5.99-5.87 (m, 1H), 4.54 (d, J=5.7 Hz, 2H), 2.63 (s, 3H).
Reaction SMILES: O1CCOCC1.C([NH:10][C:11]1[C:12]([N+:24]([O-:26])=[O:25])=[CH:13][C:14]2[O:19][C:18]([CH3:21])([CH3:20])[CH:17]3[O:22][CH:16]3[C:15]=2[CH:23]=1)(=O)C.[OH-].[Na+].Cl>O>[NH2:10][C:11]1[C:12]([N+:24]([O-:26])=[O:25])=[CH:13][C:14]2[O:19][C:18]([CH3:21])([CH3:20])[CH:17]3[O:22][CH:16]3[C:15]=2[CH:23]=1
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])OC(C)(C)C1OC21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC1(C)Oc2cc([N+](=O)[O-])c(N)cc2C2OC21
Temperature: 25 °C
Reaction time: 4 h
Yield: 22 %

Procedure:
A mixed solution of a 1,4-dioxane (152 mL) and water (76 mL) in which a 6-acetoamido-3,4-epoxy-3,4-dihydro-2,2-dimethyl-7-nitro-2H-1-benzopyran (synthesized according to the method of Evans, J. M., et al., J. Med. Chem. 1984, 27, 1127) (7.6 g, 27 mmol) and sodium hydroxide (5.6 g, 5.0 eq.) were dissolved was stirred at room temperature for four hours. After the mixture was neutoralized with hydrochloric acid, the resulting product was diluted by a saturated saline water, extracted with an ethyl acetate and then, dried over a sodium sulfate anhydride. After the solvent was distilled off, the resulting product was recrystallized from a mixed solvent of ethanol and hexane to obtain a 6-amino-3,4-epoxy-3,4-dihydro-2,2-dimethyl-7-nitro-2H-1-benzopyran (1.4 g, 22%) as orange crystals.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:23][CH2:24][CH3:25])[CH2:5][N:6]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]2[CH:13]=[N:14][N:15]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[CH:16]=2)=[N:7]1)[CH3:2].Br[C:27]1[CH:32]=[C:31]([N+:33]([O-:35])=[O:34])[CH:30]=[CH:29][C:28]=1[CH3:36].C(=O)([O-])[O-].[Cs+].[Cs+].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>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:3][CH:4]([O:23][CH2:24][CH3:25])[CH2:5][N:6]1[C:10]([NH:11][C:27]2[CH:32]=[C:31]([N+:33]([O-:35])=[O:34])[CH:30]=[CH:29][C:28]=2[CH3:36])=[CH:9][C:8]([C:12]2[CH:13]=[N:14][N:15]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[CH:16]=2)=[N:7]1)[CH3:2]
Reactant: CCOC(Cn1nc(-c2cnn(C3CCCCO3)c2)cc1N)OCC
Reactant: Cc1ccc([N+](=O)[O-])cc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CCOC(Cn1nc(-c2cnn(C3CCCCO3)c2)cc1Nc1cc([N+](=O)[O-])ccc1C)OCC
Temperature: 25 °C

Procedure:
Under argon, 12.3 g (35.2 mmol) of the compound of Example 1A, 9.9 g (45.8 mmol) of 2-bromo-4-nitrotoluene, 0.79 g (3.52 mmol) of palladium(II) acetate, 22.9 g (70.4 mmol) of caesium carbonate and 2.04 g (3.52 mmol) of xantphos [4,5-bis(diphenylphosphino)-9,9-dimethylxanthene] in 170 ml of 1,4-dioxane were heated at reflux for 4 h. After cooling to RT, the mixture was filtered through kieselguhr and the filtrate was concentrated on a rotary evaporator. The residue was taken up in ethyl acetate and the mixture was washed with semiconcentrated sodium bicarbonate solution and then with concentrated sodium chloride solution. The organic phase was dried over anhydrous sodium sulphate and concentrated. The crude product was purified chromatographically on silica gel (mobile phase gradient dichloromethane/ethyl acetate 2:1→1:3). This gave 15.9 g (92% of theory) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][N:8]=[C:7]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[C:6]=2[CH:16]=1.[C:17]([O:21][C:22](=[O:33])[NH:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([CH2:30][CH:31]=O)[CH2:26][CH2:25]1)([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:17]([O:21][C:22](=[O:33])[NH:23][C@H:24]1[CH2:25][CH2:26][C@H:27]([CH2:30][CH2:31][N:13]2[CH2:12][CH2:11][CH:10]([C:7]3[C:6]4[CH:16]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=4[O:9][N:8]=3)[CH2:15][CH2:14]2)[CH2:28][CH2:29]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: Fc1ccc2onc(C3CCNCC3)c2c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCC(c3noc4ccc(F)cc34)CC2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 5-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (1.3 g, 5 mmol), trans-[4-(2-oxo-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester (example 1, intermediate C) (1.6 g, 6 mmol), triethylamine (0.64 mL, 5 mmol) in 1,2 dichloroethane (27 mL) was stirred for 4 h at room temperature and sodium triacetoxyborohydride (1.9 g, 9 mmol) was added slowly and the resulting solution was stirred for 12 hours until the TLC indicated completion of the reaction. The mixture was filtrated and concentrated to dryness and purified with column chromatography on silica gel using CH2Cl2—CH2Cl2/MeOH (1-9:1). The product fractions were concentrated to give 2.3 g (5.1 mmol, 100% yield) of a off-white solid. MS (m/e): 446.3 (M+H+).