Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(O[C:8](=[O:27])[NH:9][C:10]2[S:11][C:12]3[C:18]([CH:19]4[CH2:24][O:23][CH2:22][CH2:21][O:20]4)=[CH:17][CH:16]=[C:15]([O:25][CH3:26])[C:13]=3[N:14]=2)C=CC=CC=1.[CH3:28][NH:29][C@H:30]1[CH2:35][CH2:34][C@H:33]([OH:36])[CH2:32][CH2:31]1.N1C=CC=CC=1>C(Cl)(Cl)Cl>[O:20]1[CH2:21][CH2:22][O:23][CH2:24][CH:19]1[C:18]1[C:12]2[S:11][C:10]([NH:9][C:8](=[O:27])[N:29]([C@H:30]3[CH2:35][CH2:34][C@H:33]([OH:36])[CH2:32][CH2:31]3)[CH3:28])=[N:14][C:13]=2[C:15]([O:25][CH3:26])=[CH:16][CH:17]=1
Reactant: COc1ccc(C2COCCO2)c2sc(NC(=O)Oc3ccccc3)nc12
Reactant: CN[C@H]1CC[C@H](O)CC1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)N(C)[C@H]3CC[C@H](O)CC3)nc12

Procedure:
From (+)-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-carbamic acid phenyl ester with trans-4-methylamino-cyclohexanol and pyridine in chloroform. [α]D20=+20.5° (c=1.02, CHCl3), ES-MS m/e (%): 422 (M+H+, 100).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH:34]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:34][C:33]3[CH:36]=[CH:37][CH:38]=[C:31]([O:30][CH3:29])[CH:32]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: COc1cccc(C=O)c1
Product: COc1cccc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c1

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 3-methoxy-benzaldehyde according to the procedure of Example 66. MS (ESI) m/z 498.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C@@H:8]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:11]=2[O:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:22][Si]([N-][Si](C)(C)C)(C)C.[Li+].CI>O1CCCC1>[C:1]([O:5][C:6](=[O:21])[NH:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH3:22])[C:12]2[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:11]=2[O:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N[C@H]1COc2ccc(F)cc2NC1=O
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)COc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.3 %

Procedure:
To a solution of 1.62 g (5.46 mmol) ((S)-2-Fluoro-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl)-carbamic acid tert-butyl ester in 20 ml tetrahydrofurane were added at −75° C. 4.57 g (5.46 mmol) lithium bis(trimethylsilyl)amide (20% in tetrahydrofurane) followed after 10 minutes by 0.34 ml (6.55 mmol) methyliodide. Stirring was continued overnight while the mixture was allowed to warm to room temperature. The solvent was removed by distillation and 300 ml saturated aqueous sodium hydrogensulfate solution was added. Extraction with ethylacetate and chromatography on silicagel with ethylacetate/heptane 2:8 yielded 0.87 g (51%) ((S)-2-fluoro-9-methyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl)-carbamic acid tert-butyl ester as white solid, MS m/e (%): 333 (M+Na+, 15), 311 (M+H+, 70), 255 (100).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][C:5]([C:8]2[N:13]=[C:12]3[N:14]([CH3:23])[C:15](=[O:22])[N:16]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:11]3=[CH:10][CH:9]=2)=[CH:4][CH2:3]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:57][N:58]1[CH:62]=[CH:61][N:60]=[C:59]1[C:63](O)=[O:64]>CN1C(=O)CCC1>[CH3:21][C:18]([CH3:20])([CH3:19])[CH2:17][N:16]1[C:11]2[C:12](=[N:13][C:8]([C:5]3[CH2:6][CH2:7][CH:2]([NH:1][C:63]([C:59]4[N:58]([CH3:57])[CH:62]=[CH:61][N:60]=4)=[O:64])[CH2:3][CH:4]=3)=[CH:9][CH:10]=2)[N:14]([CH3:23])[C:15]1=[O:22]
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(C3=CCC(N)CC3)nc21
Reactant: Cn1ccnc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cn1ccnc1C(=O)NC1CC=C(c2ccc3c(n2)n(C)c(=O)n3CC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a round bottom flask were added 5-(4-Aminocyclohex-1-en-1-yl)-1-(2,2-dimethylpropyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (17-2) (0.0010 g, 0.028 mmol), DIPEA (0.050 mL, 0.286 mmol), HATU (0.0013 g, 0.034 mmol), 1-methyl-1H-imidazole-2-carboxylic acid (0.00467 g, 0.037 mmol), and NMP (1 mL). The reaction was stirred at room temperature overnight (˜14 hours), the reaction mixtures were then filtered & purified by reverse-phase chromatography (5-95% 0.1% TFA in H2O:acetonitrile) to give N-{4-[1-(2,2-Dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl]cyclohex-3-en-1-yl}-1-methyl-1H-imidazole-2-carboxamide (17-3). HRMS m/z (M+H): calculated=423.2503; observed=423.2507.
Reaction SMILES: C1([C:6]([OH:24])([C:17]#[C:18][C:19]2[S:20][CH:21]=[CH:22][N:23]=2)[CH2:7][C:8]2[O:13]C(C)(C)O[C:10](=[O:16])[CH:9]=2)CCCC1.[CH:25]1(C(O)(C#CC2C=CC(OC)=CC=2)CC2OC(C)(C)OC(=O)C=2)[CH2:29][CH2:28][CH2:27][CH2:26]1>O>[CH:25]1([CH:9]2[C:8](=[O:13])[CH2:7][CH:6]([C:17]#[C:18][C:19]3[S:20][CH:21]=[CH:22][N:23]=3)[O:24][C:10]2=[O:16])[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CC1(C)OC(=O)C=C(CC(O)(C#Cc2nccs2)C2CCCC2)O1
Reactant: COc1ccc(C#CC(O)(CC2=CC(=O)OC(C)(C)O2)C2CCCC2)cc1
Solvent: O
Product: O=C1CC(C#Cc2nccs2)OC(=O)C1C1CCCC1

Procedure:
The title compound was prepared analogously to example 1, except 6-(2-cyclopentyl-2-hydroxy-4-thiazol-2-yl-but-3-ynyl)-2,2-dimethyl-[1,3]dioxin-4-one (from Step 1) was used rather than 6-[2-cyclopentyl-2-hydroxy-4-(4-methoxy-phenyl)-but-3-ynyl]-2,2-dimethyl-[1,3]dioxin-4-one. 1H NMR (CDCl3): δ 1.63-2.05 (bm, 4H), 2.23 (pentet, 1H, J=8.1 Hz), 2.78 (d, 1H, J=17.7 Hz), 3.04 (d, 1H, J=17.7 Hz), 3.51 (d, 1H, J=20.0 Hz), 3.97 (d, 1H, J=20.0 Hz), 7.46 (d, 1H, J=3.2 Hz), 7.89 (d, 2H, J=3.4 Hz). Anal. Calcd. for C15H15N1O3S1.0.25 H2O: C, 57.75; H, 4.93; N, 4.35. Found: C, 58.2; H, 5.34; N, 4.36; ESIMS (M+Na+): 312.0.
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]([C:11]2[O:12][C:13]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:14]=3[CH:15]=2)=[O:10])[CH2:3]1.[CH:21]([N:24]1[CH2:29][CH2:28][CH:27](O)[CH2:26][CH2:25]1)([CH3:23])[CH3:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]([C:11]2[O:12][C:13]3[CH:19]=[CH:18][C:17]([O:20][CH:27]4[CH2:28][CH2:29][N:24]([CH:21]([CH3:23])[CH3:22])[CH2:25][CH2:26]4)=[CH:16][C:14]=3[CH:15]=2)=[O:10])[CH2:3]1
Reactant: C[C@@H]1CN(C(=O)c2cc3cc(O)ccc3o2)C[C@H](C)O1
Reactant: CC(C)N1CCC(O)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)N1CCC(Oc2ccc3oc(C(=O)N4C[C@@H](C)O[C@@H](C)C4)cc3c2)CC1
Reaction time: 3 h
Yield: 64.1 %

Procedure:
The above prepared ((cis)-2,6-dimethyl-morpholin-4-yl)-(5-hydroxy-benzofuran-2-yl)-methanone (0.150 g, 0.545 mmol) was dissolved in 2.7 mL of THF and treated successively at 10° C. with 1-isopropyl-piperidin-4-ol (0.156 g, 2 eq.), triphenylphosphine (0.285 g, 2 eq.) and DIAD (0.212 mL, 2 eq.), and the mixture then kept at ambient temperature for another 3 h. Pouring onto crashed ice/NH4Cl, twofold extraction with AcOEt, washing with water, drying over sodium sulfate, and evaporation of the solvents, followed by two flash chromatographies (SiO2, NEt3/AcOEt=4/96 and CH2Cl2/MeOH=9/1), yielded eventually 0.140 g of the title compound as colorless oil.
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+:15]>CO.O.[Pd]>[C:1]([N:5]1[CH2:10][CH2:9][CH:8]([NH2:15])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [NH4+]
Reactant: CC(C)(C)N1CCC(=O)CC1
Agent: [Pd]
Agent: O=C[O-]
Solvent: CO
Solvent: O
Product: CC(C)(C)N1CCC(N)CC1
Reaction time: 8 h

Procedure:
To a solution of 1-tert-butylpiperidin-4-one (5.0 g) in methanol (100 mL) and water (10 mL) was added ammonium formate (20.3 g) and 0.5 g of Pd/C (10%). The mixture was stirred overnight. The mixture was filtered and the filtrate was concentrated under vacuum and the residue was diluted with ethyl acetate (500 mL) and washed with water and brine. After drying over Na2SO4 and filtration, the solvent was evaporated under vacuum to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.O.[NH3:11].[OH-].[Na+]>C(#N)C>[NH2:11][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[N:3][CH:4]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: NCc1ccc(Cl)nc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 58.1 %

Procedure:
A mixture of 14.99g of 2-chloro-5-(chloromethyl) pyridine, 63.01g of 25% ammonia water and 60ml of acetonitrile in a stainless steel autoclave was stirred for 2 hours in an oil bath of 80° C. After adding 12.3g of 30% sodium hydroxide aqueous solution, the reaction mixture was concentrated. The residue to which 200ml of ethanol were added was dried over anhydrous magnesium sulfate and, filtered to remove insoluble materials. The filtrate was concentrated and purified by a column chromatography [developing solvent: dichloromethane-methanol (4:1)] to afford 7.66g of 5-(aminomethyl)-2- chloropyridine as a yellow solid.
Reaction SMILES: [Br-].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:25])[CH2:10][N+:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[CH3:26][C:27]([CH3:39])([CH3:38])[C:28](=[O:37])[C:29]#[C:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>CN(C=O)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:10]2[N:11]3[C:12]([CH:13]=[C:14]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[CH:15]=[CH:16]3)=[C:29]([C:28](=[O:37])[C:27]([CH3:39])([CH3:38])[CH3:26])[C:30]=2[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:25])=[CH:5][CH:4]=1
Reactant: O=C(C[n+]1ccc(OCc2ccccn2)cc1)c1ccc(Cl)cc1
Reactant: CC(C)(C)C(=O)C#Cc1ccccc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Br-]
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)c1c(-c2ccccc2)c(C(=O)c2ccc(Cl)cc2)n2ccc(OCc3ccccn3)cc12
Temperature: 70 °C
Reaction time: 18 h
Yield: 12.9 %

Procedure:
To a suspension of 1-[2-(4-chlorophenyl)-2-oxoethyl]-4-(pyridin-2-ylmethoxy)pyridinium bromide (750 mg, 1.79 mmol) and 4,4-dimethyl-1-phenylpent-1-yn-3-one (333 mg, 1.79 mmol) in DMF (10.0 mL) is added TEA (0.37 mL, 2.68 mmol). The mixture is stirred at 70° C. for 18 h then treated with DDQ (406 mg, 1.79 mmol) and stirred for an additional 1 h. The mixture is then cooled to 23° C. and partitioned between water and EtOAc. The organics are collected, dried with MgSO4, filtered, and concentrated in vacuo. Purification of the crude by flash chromatography (SiO2, hexanes to 50% EtOAc in hexanes) gives the title compound (121 mg, 13%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.[Br:13][C:14]1[CH:15]=[CH:16][C:17]([N+]([O-])=O)=[N:18][CH:19]=1.CC([O-])(C)C.[K+]>CN(C=O)C>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[N+:10]([O-:12])=[O:11])=[N:18][CH:19]=1
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(Nc2ccc(Br)cn2)c([N+](=O)[O-])c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 7 %

Procedure:
A mixture of 4-methoxy-2-nitrobenzenamine (8 g, 47.62 mmol), 5-bromo-2-nitropyridine (7.2 g, 35.47 mmol), and potassium 2-methylpropan-2-olate (6 g, 53.57 mmol) in DMF (180 ml) was allowed to stir for 5 hours at 30° C. and overnight at 60° C. After being cooled down to room temperature, the reaction mixture was quenched by the addition of H2O (200 mL) and the resulting solution was extracted three times with 400 ml of EtOAc, washed with 200 ml of H2O and 200 ml of brine. The mixture was dried and concentrated under reduced pressure. The crude material such obtained was purified by solvating gas chromatography (SGC) using 1:10-1:5 EtOAc/PE as eluents to provide 800 mg (5%) of (5-Bromo-pyridin-2-yl)-(4-methoxy-2-nitro-phenyl)-amine (z) as a red solid.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[F:20][C:21]1[CH:51]=[CH:50][C:24]([O:25][C:26]2[CH:31]=[CH:30][C:29]([S:32]([N:35]3[CH2:44][CH2:43][C:42]4[C:37](=[CH:38][CH:39]=[C:40]([OH:45])[CH:41]=4)[CH:36]3[C:46]([O:48][CH3:49])=[O:47])(=[O:34])=[O:33])=[CH:28][CH:27]=2)=[CH:23][CH:22]=1.[N:52]1([CH2:58][CH2:59]O)[CH2:57][CH2:56][O:55][CH2:54][CH2:53]1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[F:20][C:21]1[CH:22]=[CH:23][C:24]([O:25][C:26]2[CH:27]=[CH:28][C:29]([S:32]([N:35]3[CH2:44][CH2:43][C:42]4[C:37](=[CH:38][CH:39]=[C:40]([O:45][CH2:59][CH2:58][N:52]5[CH2:57][CH2:56][O:55][CH2:54][CH2:53]5)[CH:41]=4)[CH:36]3[C:46]([O:48][CH3:49])=[O:47])(=[O:33])=[O:34])=[CH:30][CH:31]=2)=[CH:50][CH:51]=1
Reactant: OCCN1CCOCC1
Reactant: COC(=O)C1c2ccc(O)cc2CCN1S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C1c2ccc(OCCN3CCOCC3)cc2CCN1S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Reaction time: 1 h
Yield: 53 %

Procedure:
667 mg (2.0 mmol) of polymer-bound PPh3 (3 mmol/g) are introduced into 2 ml of THF and, at room temperature, 229 mg (0.5 mmol) of methyl 2-[4-(4-fluorophenoxy)-benzenesulfonyl]-6-hydroxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylate (3B), 242 μl (2.0 mmol) of 2-morpholin-4-ylethanol and 311 μl (2.0 mmol) of DEAD are added. After one hour, the mixture is filtered and the filtrate is concentrated in vacuo. The residue is chromatographed on silica gel (dichloromethane→dichloromethane/methanol 98:2), resulting in 53% of the title compound.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:10]([C:14]([C:16]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]([F:25])[CH:19]=3)=[O:17])=[O:15])[CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[CH3:32][S:33]([O-:35])=[O:34].[Na+]>CN(C)C=O>[CH3:32][S:33]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:10]([C:14]([C:16]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]([F:25])[CH:19]=3)=[O:17])=[O:15])[CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1)(=[O:35])=[O:34]
Reactant: Cc1ccc(C(=O)C(=O)c2cccc(-c3ccc(F)cc3)c2-c2ccccc2)cc1F
Reactant: CS(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)C(=O)c2cccc(-c3ccc(S(C)(=O)=O)cc3)c2-c2ccccc2)cc1F
Yield: 25.8 %

Procedure:
Following the procedure of Example 53, Step 4 using the benzil from Step 3 (2.15 g 8.2 mmol) and sodium methylsulfinate (1.05 g, 10 mmol) in dimethylformamide (20 ml), there was obtained 1 g (50%) of the desired sulfone: mp 146-147° C., after recrystallization from ethyl acetate and hexane. Anal. Calc'd. for C16H13FO4S (MW 320.34): C, 59.99; H, 4.09; S, 10.01. Found: C, 59.68; H, 4.17; S, 10.13.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][CH2:7][CH:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1.CC(C)([O-])C.[Na+].[Br:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29]Br)[N:24]=1>CS(C)=O>[Br:22][C:23]1[N:24]=[C:25]([CH2:29][N:8]2[CH2:7][CH:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]3[N:3]=[C:2]([Cl:1])[N:11]=[CH:10][C:9]2=3)[CH:26]=[CH:27][CH:28]=1
Reactant: Clc1ncc2c(n1)N1CCOCC1CN2
Reactant: BrCc1cccc(Br)n1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Clc1ncc2c(n1)N1CCOCC1CN2Cc1cccc(Br)n1

Procedure:
The title compound was prepared in a manner similar to PREPARATION x9 using 2-chloro-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x2, 300 mg, 1.324 mmol) in DMSO (20 mL) followed by sodium tert-butoxide (153 mg, 1.588 mmol) and 2-bromo-6-(bromomethyl)pyridine (332 mg, 1.324 mmol). 1H NMR (400 MHz, DMSO-d6) δ 2.92-3.04 (m, 1 H), 3.12-3.24 (m, 2 H), 3.40-3.53 (m, 2 H), 3.62-3.72 (m, 1 H), 3.86-4.00 (m, 2 H), 4.19-4.28 (m, 1 H), 4.42-4.64 (m, 2 H), 7.31 (s, 4 H), 7.36-7.43 (m, 4 H), 7.56 (s, 3 H), 7.72 (d, J=7.83 Hz, 4 H). ESI-MS m/z [M+H]+ calc'd for C15H15BrClN5O, 396.01; found 396.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[Br:9]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[N:3][CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(F)nc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(CBr)cn1
Reaction time: 2.5 h
Yield: 35 %

Procedure:
2-fluoro-5-methylpyridine in an amount of 500 mg (4.50 mmol) was dissolved in 50 mL of carbon tetrachloride, following which 1.20 g (6.76 mmol) of N-bromosuccinimide and 20 mg of benzoyl peroxide were added and refluxing under heating was carried out for 2.5 hours. Following reaction completion, the reaction mixture was returned to room temperature, the solvent was removed by distillation under reduced pressure, and purification was carried out by silica gel column chromatography (hexane/ethyl acetate=19:1), giving 300 mg of 5-bromomethyl-2-fluoropyridine (yield, 35%).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[C:8]3[NH:16][N:15]=[N:14][C:9]=3[N:10]=[C:11]([NH2:13])[N:12]=2)=[CH:4][CH:3]=1.[Br:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25]Br)[N:20]=1>CCCCCC.CCOC(C)=O>[Br:17][CH2:18][C:19]1[N:20]=[C:21]([CH2:25][N:14]2[C:9]3[N:10]=[C:11]([NH2:13])[N:12]=[C:7]([C:5]4[O:6][C:2]([CH3:1])=[CH:3][CH:4]=4)[C:8]=3[N:16]=[N:15]2)[CH:22]=[CH:23][CH:24]=1
Reactant: Cc1ccc(-c2nc(N)nc3nn[nH]c23)o1
Reactant: BrCc1cccc(CBr)n1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1ccc(-c2nc(N)nc3c2nnn3Cc2cccc(CBr)n2)o1

Procedure:
Prepared from 7-(5-methyl-2-furyl)-1H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine and 2,6-bis(bromomethyl)pyridine by the alkylation method described in Example 36; NMR δH (400 MHz, DMSO) 2.46 (3H, s), 4.64 (2H, s), 5.75 (2H, s), 6.50 (1H, d, J 3.5 Hz), 7.04 (1H, d, J 8.0 Hz), 7.31 (2H, s), 7.49 (1H, d, J 7.5 Hz), 7.80 (1H, t, J 7.5 Hz), 7.88 (1H, d, J 3.5 Hz). TLC (Hexane:EtOAc (1:1)) Rf=0.28**
Reaction SMILES: [OH:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH:18]=[CH:19][C:20]=2[CH3:21])[C:12]([NH:14][CH:15]2[CH2:17][CH2:16]2)=[O:13])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38]Br)[N:33]=1.O>C(#N)C>[Br:30][CH2:31][C:32]1[N:33]=[C:34]([CH2:38][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]3[CH:10]=[C:11]([CH:18]=[CH:19][C:20]=3[CH3:21])[C:12]([NH:14][CH:15]3[CH2:16][CH2:17]3)=[O:13])=[O:7])=[CH:22][CH:23]=2)[CH:35]=[CH:36][CH:37]=1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(O)cc1
Reactant: BrCc1cccc(CBr)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(OCc2cccc(CBr)n2)cc1
Temperature: 25 °C
Yield: 60.6 %

Procedure:
To 3-{[4-(hydroxy)benzoyl]amino}-N-cyclopropyl-4-methylbenzamide (1.50 g, 4.84 mmol) and potassium carbonate (3.34 g, 24.2 mmol) in refluxing acetonitrile (20 mL) was added a solution of 2,6-bis(bromomethyl)pyridine (5.13 g, 19.4 mmol) in acetonitrile (10 mL) over 25 mins. The reaction was cooled to room temperature and water (20 mL) was added. The mixture was extracted with DCM (3×30 mL) and the organic layers were combine and evaporated to leave a solid which was triturated with hot ethyl acetate to give 3-[(4-{[6-(bromomethyl)pyridin-2-yl]methoxy}benzoyl)amino]-N-cyclopropyl-4-methylbenzamide as a white solid (1.449 g, 61%); NMR Spectrum: (DMSOd6) 0.58 (m, 2H), 0.70 (m, 2H), 2.27 (s, 3H), 2.85 (m, 1H), 4.73 (s, 2H), 5.30 (s, 2H), 7.19 (d, 2H), 7.32 (d, 1H), 7.49 (d, 1H), 7.55 (d, 1H), 7.65 (d, 1H), 7.81 (s, 1H), 7.90 (t, 1H) 7.98 (d, 2H), 8.38 (d, 1H), 9.85 (s, 1H); Mass Spectrum: M+H+ 494, 496 Br pattern.
Reaction SMILES: [NH2:1][C:2](=[S:10])[CH:3]([CH3:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5].Cl[CH2:12][C:13](=O)[CH3:14].C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:14][C:13]1[N:1]=[C:2]([CH:3]([CH3:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[S:10][CH:12]=1
Reactant: CCOC(=O)C(C)C(N)=S
Reactant: CC(=O)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)c1nc(C)cs1
Temperature: 80 °C
Reaction time: 5 h
Yield: 92.9 %

Procedure:
A mixture of Intermediate 103 (6.6 g, 40.9 mmol) and chloroacetone (FLUKA, 3.27 mL, 40.9 mmol) in DMF (50 mL) was stirred at 80° C. for 5 h. Reaction mixture was cooled to room temperature, treated with NaHCO3 (150 mL) and extracted with ethyl ether (2×200 mL). Organic layer was washed with brine, dried over Na2SO4 and evaporated to give title compound (7.57 g, 38.0 mmol, 93% yield) as yellow oil. 1H NMR (300 MHz, DMSO-d6) δ ppm: 7.19 (s, 1H), 4.23-4.06 (m, 3H), 2.31 (s, 3H), 1.48 (d, 3H), 1.16 (t, 3H). [ES+MS] m/z 200 (MH+). It was subsequently observed that this compound undergoes autooxidation at the stereogenic centre to form ethyl 2-hydroxy-2-(4-methyl-1,3-thiazol-2-yl)propanoate. Once the presence of this compound had been observed, the compound was actively synthesised, hereinbelow described as Intermediate 106.
Reaction SMILES: Br.[NH2:2][CH2:3][CH2:4][C:5]1[CH:12]=[CH:11][C:9]([OH:10])=[C:7]([OH:8])[CH:6]=1.[C:13](O)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=1.C1(N=C=NC2CCCCC2)CCCCC1>N1C=CC=CC=1>[C:13]([NH:2][CH2:3][CH2:4][C:5]1[CH:12]=[CH:11][C:9]([OH:10])=[C:7]([OH:8])[CH:6]=1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=1
Reactant: NCCc1ccc(O)c(O)c1
Reactant: O=C(O)c1cccnc1
Agent: Br
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Product: O=C(NCCc1ccc(O)c(O)c1)c1cccnc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 70 %

Procedure:
To a pyridine solution containing 11.7 g (0.05 mol) dopamine hydrobromide and 6.15 g (0.05 mol) nicotinic acid at 0° C. were added 10.3 g (0.05 mol) dicyclohexylcarbodiimide (DCC). The reaction mixture was stirred at room temperature for 24 hours and the formed dicyclohexylurea was removed by filtration. The pyridine was removed in vacuo and the residue was crystallized from water at 0° C. The product was isolated by filtration and dried over phosphorous pentoxide. Recrystallization from isopropanol gave 9.0 g (0.035 mol), 70% N-nicotinoyldopamine, m.p. 159°-162° C.; aqueous solution of the compound gave a green color with Fe+3 and reduced AgNO3 ; ir (KBr) 3300, 2960, 1725, 1630, 1590, 1520, 1430, 1290, 1190, 1115, 720 and 710 cm-1 ; NMR (d6 -DMSO) δ 9.25-6.25 (m, 7H), 3.3 (m, 2H) and 2.65 (m, 2H) ppm. Anal. (C14H14N2O 3) C, H, N.
Reaction SMILES: [S:1]([O-:4])([O-])=[O:2].[Na+].[Na+].[Cl:7][C:8]1[CH2:16][C:15]([Cl:21])(S(Cl)(=O)=O)[CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11].[OH-].[Na+]>O>[Cl:21][C:15]1[CH:16]=[C:8]([Cl:7])[C:9]([C:10]([OH:12])=[O:11])=[CH:13][C:14]=1[S:1]([OH:4])=[O:2]
Reactant: O=S([O-])[O-]
Reactant: O=C(O)C1=C(Cl)CC(Cl)(S(=O)(=O)Cl)C=C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc(S(=O)O)c(Cl)cc1Cl

Procedure:
This compound is prepared following substantially the same procedure described in Example 1, Step A, using the following substances:sodium sulfite 75 g.water 200 ml.2,4-dichloro-4-chlorosulfonylbenzoic acid 58 g.10N sodium hydroxide 50 ml.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:14]([CH:15]2[CH2:20][CH2:19][CH2:18][O:17][CH2:16]2)[C:13]2[CH:21]=[CH:22][CH:23]=[CH:24][C:12]=2[N:11]=1)[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:17]1[CH2:18][CH2:19][CH2:20][CH:15]([N:14]2[C:13]3[CH:21]=[CH:22][CH:23]=[CH:24][C:12]=3[N:11]=[C:10]2[C@@H:8]([NH2:7])[CH3:9])[CH2:16]1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccccc2n1C1CCCOC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](N)c1nc2ccccc2n1C1CCCOC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 59.8 %

Procedure:
To a solution of {(S)-1-[1-(tetrahydropyran-3-yl)-1H-benzoimidazol-2-yl]ethyl}carbamic acid tertbutyl ester (720 mg, 2.08 mmol) in DCM (5 mL) was added TFA (15 mL) and the mixture was stirred at RT for 20 min. Volatiles were removed under reduced pressure and the resulting residue was partitioned between DCM and a saturated solution of NaHCO3. The aqueous phase was further extracted with DCM (×2) and the combined organic layers were dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM). The product containing fractions were concentrated in vacuo affording (S)-1-[1-(Tetrahydropyran-3-yl)-1H-benzoimidazol-2-yl]ethylamine as an oil (305 mg, 60%). LCMS: RT 1.85 min [M−NH2]+ 229.1.