Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C:9]1[C:10]2[CH2:22][C@:21]3([CH3:35])[C@@H:23]([CH3:34])[CH2:24][CH2:25][C@H:26]4[C:27]([CH3:33])([CH3:32])[C:28](=[O:31])[CH2:29][CH2:30][C@@:20]34[O:19][C:11]=2[C:12]2[CH2:13][NH:14][C:15](=[O:18])[C:16]=2[CH:17]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[BH4-].[Na+].O>CO>[Si:1]([O:8][C:9]1[C:10]2[CH2:22][C@:21]3([CH3:35])[C@@H:23]([CH3:34])[CH2:24][CH2:25][C@H:26]4[C:27]([CH3:33])([CH3:32])[C@H:28]([OH:31])[CH2:29][CH2:30][C@@:20]34[O:19][C:11]=2[C:12]2[CH2:13][NH:14][C:15](=[O:18])[C:16]=2[CH:17]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: C[C@H]1CC[C@H]2C(C)(C)C(=O)CC[C@]23Oc2c(c(O[Si](C)(C)C(C)(C)C)cc4c2CNC4=O)C[C@]13C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C[C@H]1CC[C@H]2C(C)(C)[C@H](O)CC[C@]23Oc2c(c(O[Si](C)(C)C(C)(C)C)cc4c2CNC4=O)C[C@]13C
Reaction time: 0.5 h
Yield: 60.6 %

Procedure:
To a solution of the above Compound (12b) (175 mg, 0.35 mmol) in 2 ml of methanol was added 17 mg (0.45 mmol) of sodium borohydride under ice-cooling, and the mixture stirred for 30 min. After addition of water, the reaction mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by a column chromatography (Merck, Lobar column, size A; chloroform:methanol=50:1) to give 106 mg (60%) of Compound (36).
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[C:6]([F:9])[CH:5]=[CH:4][N:3]=1.Br[CH2:11][C:12]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=1[F:19].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[F:18][C:17]1[CH:16]=[CH:15][CH:14]=[C:13]([F:19])[C:12]=1[CH2:11][O:8][C:7]1[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][C:6]=1[F:9]
Reactant: Fc1cccc(F)c1CBr
Reactant: Nc1nccc(F)c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Nc1nccc(F)c1OCc1c(F)cccc1F
Temperature: 50 °C

Procedure:
55 mg (0.43 mmol) of 2-amino-4-fluoropyridin-3-ol Example 267A, 98 mg (0.47 mmol) of 2-(bromomethyl)-1,3-difluorobenzene and 308 mg (0.95 mmol) of caesium carbonate were initially charged in 1 ml of dry DMF and heated for 15 min in an oil bath warmed to 50° C. The mixture was then filtered off and purified by preparative HPLC (Method 9). This gave 70 mg of the title compound (64% of theory).
Reaction SMILES: [CH2:1]([N:4]1[C:21]2[C:20](=[O:22])[NH:19][C:18]([NH2:23])=[N:17][C:16]=2[N:6]([C@@H:7]2[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[C@H:8]2[OH:9])[C:5]1=[O:24])[CH:2]=[CH2:3]>[Pd].C(O)C>[CH2:1]([N:4]1[C:21]2[C:20](=[O:22])[NH:19][C:18]([NH2:23])=[N:17][C:16]=2[N:6]([C@@H:7]2[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[C@H:8]2[OH:9])[C:5]1=[O:24])[CH2:2][CH3:3]
Reactant: C=CCn1c(=O)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2nc(N)[nH]c(=O)c21
Agent: [Pd]
Solvent: CCO
Product: CCCn1c(=O)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2nc(N)[nH]c(=O)c21
Temperature: 25 °C
Reaction time: 3 h
Yield: 55 %

Procedure:
A mixture of 7-allyl-8-oxoguanosine (Example 8; 1.0 g, 2.9 mM) 10% Pd/C (100 mg) and ethanol (100 ml) was stirred at room temperature under an atmosphere of hydrogen for 3 hours. The catalyst was filtered through a pad of Celite and washed with ethanol (100 ml). The combined filtrate was concentrated in vacuo. The residue was dissolved in methanol (20 ml) and treated with ether (200 ml). The resulting solid was filtered and dried at 60° C. to provide the title compound in 55% yield as a white powder, mp 151°-153° C. NMR(DMSO-d6): δ 10.8(bs, 1H); 6.5(bs, 2H); 5.5(d J=5.5 Hz, 1H); 0.8(d, J=7 Hz, 3H). IR (KBr): 1680 and 1640 cm-1.
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[CH:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][C@@:9]1([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C@:10](/[CH:24]=[CH:25]\[CH2:26]O)([OH:23])[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1>O>[CH2:1]([N:8]1[C@H:13]2[CH2:12][CH2:11][C@@:10]3([CH:24]=[CH:25][CH2:26][O:23]3)[C@:9]1([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:15][CH:14]2[C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)C1C[C@]2(c3ccccc3)N(Cc3ccccc3)[C@H]1CC[C@]2(O)/C=C\CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1C[C@]2(c3ccccc3)N(Cc3ccccc3)[C@H]1CC[C@@]21C=CCO1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81 %

Procedure:
The mixture of (1R*,2S*,5S*,6RS)-8-benzyl-6-(tert-butoxycarbonyl)-2-[(Z)-3-hydroxypropenyl]-1-phenyl-8-azabicylco[3.2.1]octan-2-ol (Description 26; a 3:1 mixture of C6 epimers, 4.0 g, 8.9 mmol), diethyl azodicarboxylate (1.8 ml, 11.4 mmol), triphenylphosphine (3.6 g, 13.7 mmol), tetrahydrofuran (30 ml) was stirred at room temperature for 15 minutes. The mixture was treated with water (0.1 ml) and concentrated in vacuo. The residue was treated with diethyl ether followed by iso-hexane. The solid was filtered off and the filtrate was concentrated and purified by chromatography on silica gel (iso-hexane:diethyl ether 0-20%) to give the title compound (3.1 g, 81%) as a 3:1 mixture of C6 epimers.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]([CH2:25][CH3:26])[NH:20][CH2:19][CH2:18]2>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:20]3[CH2:19][CH2:18][C:17]4[C:22](=[CH:23][CH:24]=[C:15]([F:14])[CH:16]=4)[CH:21]3[CH2:25][CH3:26])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CCC1NCCc2cc(F)ccc21
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: CCC1c2ccc(F)cc2CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-fluoro-1-ethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=O)[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=O.Cl.[CH2:15]([O:17][C:18](=[O:21])[CH2:19][NH2:20])[CH3:16]>>[CH2:15]([O:17][C:18](=[O:21])[CH2:19][N:20]1[C:11](=[O:13])[C:4]2[C:5](=[CH:9][CH:10]=[C:2]([OH:1])[CH:3]=2)[C:6]1=[O:8])[CH3:16]
Reactant: CCOC(=O)CN
Reactant: O=C(O)c1ccc(O)cc1C(=O)O
Agent: Cl
Product: CCOC(=O)CN1C(=O)c2ccc(O)cc2C1=O

Procedure:
Prepared in analogy to example D-100 c) from 4-hydroxy-phthalic acid and glycine ethyl ester HCl salt. 1H NMR (200 MHz, DMSO-d6) δ 11.0 (br s, 1 H), 7.74 (d, J=7.8 Hz, 1 H), 7.17 (m, 2 H), 4.35 (s, 2 H), 4.13 (q, J=7.0 Hz, 2 H), 1.20 (t, J=7.0 Hz, 3 H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[C:7]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH2:17])([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[C:19](N1C=CN=C1)(N1C=CN=C1)=[O:20]>C1COCC1>[C:1]([O:5][C:6](=[O:18])[C:7]([CH3:9])([N:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:17][C:19]1=[O:20])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)C(C)(C)Nc1ccccc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(C)(C)n1c(=O)[nH]c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.7 %

Procedure:
A mixture of 2-(2-amino-phenylamino)-2-methyl-propionic acid tert-butyl ester (570 mg, 2.3 mmol) in THF (25 mL) was added 1,1′-carbonyldiimidazole (560 mg, 3.5 mmol). The solution was stirred at room temperature for 16 hours. The reaction mixture was concentrated. The resulting residue was purified by CombiFlash with 50% EtOAc in Hexane as the eluent to afford the desired 2-methyl-2-(2-oxo-2,3-dihydro-benzimidazol-1-yl)-propionic acid tert-butyl ester (462 mg, 72%).
Reaction SMILES: [Cl:1][C:2]1[CH2:10][C:9]([F:12])(F)[C:8]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]2=[O:25])=[CH:7][C:3]=1[C:4]([O-:6])=[O:5].[K+].[CH2:27]([CH:29]1[O:31][CH2:30]1)Cl.O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[C:9]([F:12])[C:8]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[N:15]([CH3:24])[C:14]2=[O:25])=[CH:7][C:3]=1[C:4]([O:6][CH2:27][CH:29]1[O:31][CH2:30]1)=[O:5]
Reactant: ClCC1CO1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(C2=CC(C(=O)[O-])=C(Cl)CC2(F)F)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(C(=O)OCC3CO3)c(Cl)cc2F)c1=O

Procedure:
3.0 g of potassium 2-chloro-4-fluoro-5-[3,6-dihydro-2,6-dioxo-3-methyl-4-trifluoromethyl-1(2H)-pyrimidinyl]-4-fluorobenzoate and 0.6 ml of epichlorohydrin are heated at 70° C. for 3 hours in 25 ml of dimethylformamide. Thereafter, the reaction solution is added to 500 ml of water and adjusted to pH 10 to 11 with a small amount of saturated potassium carbonate solution. It is extracted twice with 300 ml of ethyl acetate. The organic phases are washed twice with 200 ml of water, dried over anhydrous magnesium sulphate and concentrated. The residue is purified by chromatography on silica gel with ethyl acetate/n-hexane. There is obtained 2,3-epoxypropyl 2-chloro-5-[3,6-dihydro-2,6-dioxo-3-methyl-4 -trifluoromethyl-1(2H)-pyrimidinyl]-4-fluorobenzoate as a pale yellow oil, 1H-NMR(D6 -DMSO, 400 MHz): 2.73 (m,1H), 2.85 (m,1H), 32 (m,1H), 3.42 (s,3H), 4.10 (m,1H), 4.69 (m,1H), 6.62 (s,1H), 7.92 (d,1H), 8.11 (d,1H), mass spectrum (m/e): M+ 422(16).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([O:9]CC)=O.[NH2:12][NH2:13].C(OCC)C>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([NH:12][NH2:13])=[O:9]
Reactant: NN
Reactant: CCOC(=O)c1ccccn1
Solvent: CCOCC
Solvent: CCO
Product: NNC(=O)c1ccccn1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A mixture of ethyl pyridin-2-carboxylate (90 gm) and hydrazine (60 gm) in ethanol (400 ml) was stirred at 80° C. over a period of 4 h. Solvent was evaporated under vacuum to provide a crude mass. The crude mass was stirred with diethyl ether and the suspension was filtered and the wet cake washed with small quantity of ethanol (50 ml) to provide title compound in 76 gm quantity (93%) as a white solid.
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([CH3:11])[CH:9]=[CH:10][C:4]=2[N:3]=1.[F:12][C:13]([F:27])([F:26])[C:14]1[C:15]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[N:16][CH:17]=[CH:18][CH:19]=1>>[CH3:11][C:8]1[CH:9]=[CH:10][C:4]2[N:3]=[C:2]([N:23]3[CH2:24][CH2:25][N:20]([C:15]4[C:14]([C:13]([F:27])([F:12])[F:26])=[CH:19][CH:18]=[CH:17][N:16]=4)[CH2:21][CH2:22]3)[NH:6][C:5]=2[CH:7]=1
Reactant: Cc1ccc2nc(Cl)[nH]c2c1
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Product: Cc1ccc2nc(N3CCN(c4ncccc4C(F)(F)F)CC3)[nH]c2c1

Procedure:
The reaction of 2-chloro-6-methyl-1H-benzoimidazole (0.261 g, 1.57 mmol, Example14b) with 1-(3-trifluoromethylpyridin-2-yl)piperazine (0.54 g, 1.6 mmol, Maybridge) under the conditions of Example 3c afforded the title compound as a white solid. M.p. 216-217° C. MS (ESI, pos. ion) m/z: 362 (M+1).
Reaction SMILES: O.O.O.[N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]([C:14]([OH:16])=O)[C:5]=1[C:17]([OH:19])=[O:18]>C(OC(=O)C)(=O)C>[N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]2[C:14]([O:19][C:17](=[O:18])[C:5]=12)=[O:16]
Reactant: O=C(O)c1cc2ccccc2nc1C(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: O=C1OC(=O)c2nc3ccccc3cc21
Temperature: 85 °C
Reaction time: 1 h

Procedure:
A mixture of 2,3-quinolinedicarboxylic acid-trihydrate (0.141 mol) in acetic anhydride (125 ml) is heated at 85° C. for 1/2 hour and then at 100° C. for 1 hour. The reaction mixture is then cooled to room temperature, filtered and the solids washed with ethyl ether to afford the desired 2,3-quinolinedicarboxylic anhydride, mp 225°-228° C.
Reaction SMILES: C(OC([NH:8][C:9]1([CH3:35])[C:13]2([CH2:15][CH2:14]2)[CH2:12][N:11]([C:16]2[C:17]([F:34])=[CH:18][C:19]3[C:29](=[O:30])[C:28]([C:31]([OH:33])=[O:32])=[CH:27][N:21]4[C@@H:22]([CH3:26])[CH2:23][O:24][C:25]=2[C:20]=34)[CH2:10]1)=O)(C)(C)C>Cl>[NH2:8][C:9]1([CH3:35])[C:13]2([CH2:15][CH2:14]2)[CH2:12][N:11]([C:16]2[C:17]([F:34])=[CH:18][C:19]3[C:29](=[O:30])[C:28]([C:31]([OH:33])=[O:32])=[CH:27][N:21]4[C@@H:22]([CH3:26])[CH2:23][O:24][C:25]=2[C:20]=34)[CH2:10]1
Reactant: C[C@H]1COc2c(N3CC4(CC4)C(C)(NC(=O)OC(C)(C)C)C3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Agent: Cl
Product: C[C@H]1COc2c(N3CC(C)(N)C4(CC4)C3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.6 %

Procedure:
(3S)-10-[7-(tert-butoxycarbonylamino)-7-methyl-5-azaspiro[2.4]heptane-5-yl]-9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid (761 mg, 1.56 mmol) was dissolved in concentrated hydrochloric acid (6.5 mL) in an ice bath, and the mixture was stirred at room temperature for 120 minutes. The reaction mixture was washed with chloroform, and saturated aqueous solution of sodium hydroxide was added to the aqueous layer in an ice bath to a pH of 12.0. Hydrochloric acid was then added to adjust pH to 7.4, end the solution was extracted with lower layer of a mixed solution (chloroform:methanol water, 7:3:1). After combining the organic layers, and drying with anhydrous sodium sulfate, the solvent was removed by distillation under reduced pressure. Chloroform was added to the residue, and the insoluble content was removed by filtration. The filtrate distilled under reduced pressure. The residue was purified by crystallization from ethanol, and dried under reduced pressure to obtain 260 mg (0.68 mmol, 43%) of the title compound as a yellow powder.
Reaction SMILES: [N+:1]([N:4]=[C:5]([NH2:15])[NH:6][C:7]1[CH:8]=[C:9]([CH2:13][NH2:14])[CH:10]=[CH:11][CH:12]=1)([O-:3])=[O:2].C[N:17](N=O)[C:18]([NH:20][N+:21]([O-:23])=[O:22])=N>>[N+:21]([N:20]=[C:18]([NH2:17])[NH:14][CH2:13][C:9]1[CH:8]=[C:7]([NH:6][C:5]([NH:4][N+:1]([O-:3])=[O:2])=[NH:15])[CH:12]=[CH:11][CH:10]=1)([O-:23])=[O:22]
Reactant: CN(N=O)C(=N)N[N+](=O)[O-]
Reactant: NCc1cccc(NC(N)=N[N+](=O)[O-])c1
Product: N=C(Nc1cccc(CNC(N)=N[N+](=O)[O-])c1)N[N+](=O)[O-]
Yield: 25 %

Procedure:
Using the compound obtained in Example 34 as a starting material and also using N-methyl-N′-nitro-N-nitrosoguanidine as a reagent, reaction was performed as in Example 83 to give the titled compound (yield, 25%).
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[N:12]=[CH:11][N:10]=[C:9]2[C:5]=1[NH:6][CH:7]=[N:8]2.[O:13]1[C@@H:15]([CH3:16])[CH:14]1[N:17]1[CH2:22][CH2:21][N:20]([CH:23]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH2:19][CH2:18]1>CN(C=O)C>[F:30][C:27]1[CH:28]=[CH:29][C:24]([CH:23]([C:31]2[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=2)[N:20]2[CH2:19][CH2:18][N:17]([CH2:14][C@H:15]([OH:13])[CH2:16][S:3][C:4]3[N:12]=[CH:11][N:10]=[C:9]4[C:5]=3[NH:6][CH:7]=[N:8]4)[CH2:22][CH2:21]2)=[CH:25][CH:26]=1
Reactant: C[C@@H]1OC1N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Reactant: Sc1ncnc2nc[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O[C@H](CSc1ncnc2nc[nH]c12)CN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To NaH (0.56 g, 11.6 mmol, 50% suspension in mineral oil prewashed with pentane) in DMF (12 mL) at 0° C. 6-mercaptopurine (1.97 g, 11.6 mmol) was added in portions over 10 min. (2S)-(-)-(1,2-Epoxypropyl)-4-[bis(4-fluorophenyl)methyl]piperazine (4.0 g, 11.6 mmol) in DMF (10 mL) was added dropwise at 0° C. over a 5 min period. The reaction mixture was allowed to warm to room temperature after an additional 5 min and was stirred for 72 h. DMF was removed in vacuo (1 mm Hg, 55° C.) and the residue was dissolved in CH2Cl2 (100 mL). The solution was filtered through celite, concentrated and the residue was purified by flash chromatography on silica gel using 10% MeOH:CH2Cl2 to give the title compound as a white solid, 1.37 g (23%), mp 118°-120° C. (dec.); DCI/MS (M+1) 497. 400 MHz 1H NMR (CDCl3)δ: 8.65 (s, 1H), 8.2 (s, 1H), 7.35 (m, 4H), 6.98 (m, 4H), 4.2 (s, 1H), 4.18 (m, 1H), 3.65-3.45 (m, 2H), 2.7-2.4 (m, 10H); [δ]D22 +7.3° (0.5% in EtOH).
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[CH2:11][C:12]([CH3:17])([CH3:16])[C:13](=[O:15])[CH3:14]>C(Cl)(Cl)Cl>[Br:1][CH2:14][C:13](=[O:15])[C:12]([CH3:17])([CH3:16])[CH2:11][C:5]1[CH:6]=[CH:7][C:8]([Cl:10])=[CH:9][C:4]=1[Cl:3]
Reactant: BrBr
Reactant: CC(=O)C(C)(C)Cc1ccc(Cl)cc1Cl
Solvent: ClC(Cl)Cl
Product: CC(C)(Cc1ccc(Cl)cc1Cl)C(=O)CBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
13.4 ml (0.26 mol) of bromine are slowly added dropwise to a solution of 64.5 g (0.26 mol) of 4-(2,4-dichlorophenyl)-3,3-dimethyl-2-butanone in 600 ml of chloroform at room temperature. The reaction solution is subsequently stirred at room temperature for 1 hour. It is then concentrated by distilling off the solvent. 84.3 g (100% of theory) of crude 1-bromo-4-(2,4-dichlorophenyl)-3,3-dimethyl-2-butanone are obtained as an oil, which is further reacted directly. ##STR11##
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[C:9]([N:17]=[C:18]=[S:19])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:18]([NH:17][C:9](=[O:16])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[S:19])[CH:3]=1
Reactant: Nc1cc(Br)ccn1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CC(C)=O
Product: O=C(NC(=S)Nc1cc(Br)ccn1)c1ccccc1
Yield: 74.3 %

Procedure:
2.500 g (14.01 mmol) 4-bromopyridine-2-amine was dissolved in 20 mL acetone, and 1.92 mL (14.01 mmol) undiluted benzoyl isothiocyanate was added dropwise. The solution turned an orange color. The reaction mixture was then heated for 1 hr under reflux with stirring. Half of the added quantity of acetone was removed under vacuum, and the precipitated solid was filtered under vacuum and washed with diethyl ether. After drying of the crystallizate, 3.500 g (10.410 mmol, 74%) pure N-{[(4-bromopyridin-2-yl)amino]carbonothioyl}benzamide was obtained which was directly used for further reaction.
Reaction SMILES: [SH:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.Cl.Cl[CH2:13][C:14]1[C:19]([CH3:20])=[C:18]([S:21][CH2:22][CH2:23][CH2:24][N:25]2[CH:29]=[CH:28][N:27]=[CH:26]2)[CH:17]=[CH:16][N:15]=1>>[N:25]1([CH2:24][CH2:23][CH2:22][S:21][C:18]2[CH:17]=[CH:16][N:15]=[C:14]([CH2:13][S:1][C:2]3[NH:6][C:5]4[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=4[N:3]=3)[C:19]=2[CH3:20])[CH:29]=[CH:28][N:27]=[CH:26]1
Reactant: Sc1nc2ccccc2[nH]1
Reactant: Cc1c(SCCCn2ccnc2)ccnc1CCl
Agent: Cl
Product: Cc1c(SCCCn2ccnc2)ccnc1CSc1nc2ccccc2[nH]1

Procedure:
Following the procedure described in Example 1, the reaction of 2-mercapto-1H-benzimidazole with 2-chloromethyl-4-[3-(imidazol-1-yl)propylthio]-3-methylpyridine hydrochloride gives the title compound as a colorless solid after crystallization from diisopropyl ether; m.p. 145°-146° C.
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[Cl-].[Al+3].[Cl-].[Cl-].Cl.[CH:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClC1C=CC=CC=1Cl>[Cl:3][C:2]1[N:4]=[C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:7]=[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:1]=1
Reactant: c1ccccc1
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Product: Clc1nc(-c2ccccc2)nc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirring mixture of 1 eq of cyanuric chloride and 3 eq of aluminum chloride in o-dichlorobenzene at ice bath temperature was added concentrated HCl (13 wt % based on cyanuric chloride). After 10 minutes, 1.95 eq of benzene was added and the reaction mixture stirred at ice bath temperature for 10 minutes. The cooling bath was removed, the reaction was allowed to warm to room temperature, and stirred. After 26 h at room temperature, an HPLC analysis indicated about 86% cyanuric chloride conversion to 2-chloro-2,6-bisphenyl-1,3,5-triazine. The stirring was continued for 24 h at room temperature. The HPLC analysis showed the cyanuric chloride conversion to 92% with >96% being 2-chloro-4,6-bisphenyl-1,3,5-triazine and less than 2% of 2,4,6-trisphenyl-1,3,5-triazine. The result was confirmed by LCMS.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[C@@H:6]([CH2:14][CH3:15])[N:5]([CH:16]3[CH2:18][CH2:17]3)[C:4]=2[N:3]=1.[C:19]1([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][C:30]=2B2OC(C)(C)C(C)(C)O2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH:16]1([N:5]2[C:4]3[N:3]=[C:2]([C:30]4[CH:29]=[CH:28][N:27]=[CH:26][C:25]=4[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:11]=[CH:10][C:9]=3[N:8]([CH3:12])[C:7](=[O:13])[C@H:6]2[CH2:14][CH3:15])[CH2:18][CH2:17]1
Reactant: CC1(C)OB(c2ccncc2-c2ccccc2)OC1(C)C
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Cl)nc2N1C1CC1
Product: CC[C@@H]1C(=O)N(C)c2cnc(-c3ccncc3-c3ccccc3)nc2N1C1CC1

Procedure:
The title compound was prepared similarly to the methods described in Example 5, with Intermediate O instead of Intermediate B and with 3-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (Boronic Acid 2) instead of pyridin-4-ylboronic acid. LCMS: 386.2 m/z (M+H)+; ret. Time: 6.04 min (Analytical Method C).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:7]2=[N:6][C:5]=1[CH3:16].[Cl:17][C:18]1[CH:19]=[C:20]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:21]=[CH:22][CH:23]=1>C1(C)C=CC=CC=1>[Cl:17][C:18]1[CH:19]=[C:20]([N:24]2[CH2:29][CH2:28][N:27]([CH2:2][CH2:3][C:4]3[C:9](=[O:10])[N:8]4[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:7]4=[N:6][C:5]=3[CH3:16])[CH2:26][CH2:25]2)[CH:21]=[CH:22][CH:23]=1
Reactant: Cc1ccc2nc(C)c(CCCl)c(=O)n2c1
Reactant: Clc1cccc(N2CCNCC2)c1
Solvent: Cc1ccccc1
Product: Cc1ccc2nc(C)c(CCN3CCN(c4cccc(Cl)c4)CC3)c(=O)n2c1
Yield: 40.7 %

Procedure:
A mixture of 2.2 g of 3-(2-chloroethyl)-2,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one, 4.5 g of 1-(m-chlorophenyl)piperazine and 25 ml of toluene was refluxed for 30 hours. After completion of the reaction, the reaction mixture was then treated in the same manner as in Example 10. The crude crystals thus obtained were recrystallized from a mixture of ethanol and n-hexane to give 1.5 g of the desired compound as pale yellow powders, m.p. 127° - 128°C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8]OS(C)(=O)=O)[CH:5]=[C:4]([CH3:14])[N:3]=1.[N-:15]=[N+:16]=[N-:17].[Na+]>CN(C=O)C>[N:15]([CH2:8][C:6]1[CH:5]=[C:4]([CH3:14])[N:3]=[C:2]([Br:1])[CH:7]=1)=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc(COS(C)(=O)=O)cc(Br)n1
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(CN=[N+]=[N-])cc(Br)n1
Reaction time: 15 h

Procedure:
To a solution of methanesulfonic acid 2-bromo-6-methyl-pyridin-4-ylmethyl ester (410 mg, 1.46 mmol) in DMF (2.0 mL) was added sodium azide (238 mg, 3.66 mmol). After 15 hours, the reaction was quenched with water (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with water (10 mL) and brine (10 mL), dried over MgSO4, filtered and concentrated. The residue was passed through a pad of silica gel eluting with 30% ethyl acetate in heptane to afford 4-azidomethyl-2-bromo-6-methyl-pyridine.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[CH2:12][CH2:11][C@:10]3([CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:19])[CH2:13]3)[C:9]2=[O:28])[CH2:4][CH2:3]1.CN(C)C=O.N1C=CN=C1.Cl[Si:40]([CH2:45][CH3:46])([CH2:43][CH3:44])[CH2:41][CH3:42]>>[O:28]=[C:9]1[C@@:10]2([CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:19])[CH2:13]2)[CH2:11][CH2:12][N:8]1[C@H:5]1[CH2:4][CH2:3][C@H:2]([O:1][Si:40]([CH2:45][CH3:46])([CH2:43][CH3:44])[CH2:41][CH3:42])[CH2:7][CH2:6]1
Reactant: CC[Si](Cl)(CC)CC
Reactant: O=C(OCc1ccccc1)N1CCC[C@]2(CCN([C@H]3CC[C@H](O)CC3)C2=O)C1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)O[C@H]1CC[C@H](N2CC[C@]3(CCCN(C(=O)OCc4ccccc4)C3)C2=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of benzyl (5S)-2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]decane-7-carboxylate (2.0 g, 0.0052 mol) in N,N-dimethylformamide (5 mL, 0.06 mol) were added 1H-imidazole (0.986 g, 0.0145 mol) and chlorotriethylsilane (1.13 mL, 0.00673 mol) at rt. After stirring for 2 h ice-water was added and the resulting mixture was stirred at room temperature for 30 minutes and extracted three times with AcOEt. The combined extracts were washed with brine, dried over sodium sulfate, and concentrated. The residual oil was purified by column chromatography using 30% by volume AcOEt in hexanes.