Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:10](=[CH:18][N+:19]([O-])=O)[CH2:9][C:8]2=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:23](O)[CH3:24]>[Ni].O1CCCC1>[CH3:23][C:24]1[N:11]2[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:8](=[O:22])[CH2:9][C:10]2=[CH:18][N:19]=1
Reactant: O=C1CC(=C[N+](=O)[O-])Nc2ccccc2N1c1ccccc1
Reactant: CCO
Agent: [Ni]
Solvent: C1CCOC1
Product: Cc1ncc2n1-c1ccccc1N(c1ccccc1)C(=O)C2
Reaction time: 20 h

Procedure:
Raney nickel, 11 g, was added to a solution of 3.5 g (0.0118 m) of 5-phenyl-1,2,3,4-tetrahydro-2-nitromethylene-5H-1,5-benzodiazepin-4-one in 50 ml of tetrahydrofuran, and 150 ml of ethanol. The mixture was then hydrogenated at atmospheric pressure for a period of 20 hours. The catalyst was filtered off and washed with tetrahydrofuran and methylene chloride. The filtrate was evaporated and the remaining oil (3.1 g) was dissolved in 250 ml of xylene and 6.2 ml of triethylorthoacetate. After heating to reflux with stirring for 30 min, the reaction mixture was evaporated. The residue was dissolved in 200 ml of toluene and 19 g of activated manganese dioxide was added to the solution. The mixture was stirred and refluxed for 30 min. The manganese dioxide was filtered off and washed well with tetrahydrofuran and methylene chloride. The filtrate was evaporated, and the residue was crystallized from ethyl acetate to yield crystals with mp 217°-220°. For analysis, the material was recrystallized from methylene chloride/ethyl acetate to give colorless crystals with mp 221°-223°.
Reaction SMILES: [N:1]1([C:7]2C3C(=CC=CC=3)N(C3C=CC(C(F)(F)F)=CC=3)[N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[N+](NC(N)=O)([O-])=[O:27].CN(C)C=O>O>[N:1]1([C:7]([NH2:8])=[O:27])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: NC(=O)N[N+](=O)[O-]
Reactant: FC(F)(F)c1ccc(-n2nc(N3CCNCC3)c3ccccc32)cc1
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)N1CCNCC1

Procedure:
A mixture of 5.5 g of 3-(1-piperazinyl)-1-[4-(trifluoromethyl)phenyl]-1H-indazole, 4.8 g of nitrourea, and 80 ml of dimethylformamide was heated on a steam bath for 15 minutes. The reaction mixture was then poured into water and the resulting precipitate was collected, washed with water, and dried. The precipitate was purified on a Water's Model 500 Preparative High Pressure Liquid Chromatograph (2×) utilizing two silica gel columns and chloroform/methanol (5%) as the eluent. Concentration of the appropriate fractions yielded a solid which was recrystallized from acetonitrile to afford 2.3 g (37%) of 4-[1-(4-trifluoromethyl)phenyl)-1H-indazol-3-yl]-1-piperazine carboxamide, m.p. 138°-140°.
Reaction SMILES: Br.Br[CH2:3][C:4]1[N:5]=[C:6]2[C:11](=[N:12][CH:13]=1)[N:10]=[C:9]([NH2:14])[N:8]=[C:7]2[NH2:15].[C:16]([O:20][C:21](=[O:32])[CH:22]([NH2:31])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)([CH3:19])([CH3:18])[CH3:17].C(=O)(O)[O-]>CN(C)C(=O)C>[C:16]([O:20][C:21](=[O:32])[CH:22]([NH:31][CH2:3][C:4]1[N:5]=[C:6]2[C:11](=[N:12][CH:13]=1)[N:10]=[C:9]([NH2:14])[N:8]=[C:7]2[NH2:15])[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([OH:30])=[CH:28][CH:29]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)C(N)Cc1ccc(O)cc1
Reactant: Nc1nc(N)c2nc(CBr)cnc2n1
Agent: Br
Agent: O=C([O-])O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)C(Cc1ccc(O)cc1)NCc1cnc2nc(N)nc(N)c2n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 36 %

Procedure:
To a solution of 6-bromomethyl-2,4-pteridinediamine hydrobromide (31.2 mg, 0.116 mmol) in anhydrous N,N dimethylacetamide was added 2-amino-3-(4-hydroxy-phenyl)-propionic acid tert-butyl ester (30.22 mg, 0.127 mmol). The reaction mixture was stirred at 50° C. overnight. The crude product was poured into saturated bicarbonate solution. The resulted precipitate was collected and purified by preparative HPLC. 17.2 mg product was obtained. Yield: 71%; 1H NMR (500 MHz, DMSO-d6): δ 1.33577 (s, 9H), 2.94185–3.02295 (m, 2H), 3.6550(b, 1H), 4.0878 (s, 2H), 6.70174–6.72384 (dd, J1=8.545 Hz, J2=2.59 Hz, 2H), 7.02394–7.04103 (d, J=8.545 Hz, 2H); 9.38501 (s, 1H); ESI-MS: 412 (M++1)
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][C:15]2[NH:19][C:18]3[C:20]([O:28][CH3:29])=[C:21]([CH3:27])[C:22]([CH3:26])=[C:23]([O:24][CH3:25])[C:17]=3[N:16]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12].[CH3:30][O:31][C:32](=[O:41])[C:33]1[CH:38]=[CH:37][C:36]([CH2:39]Br)=[CH:35][CH:34]=1>CN(C=O)C>[CH3:30][O:31][C:32](=[O:41])[C:33]1[CH:38]=[CH:37][C:36]([CH2:39][N:19]2[C:18]3[C:20]([O:28][CH3:29])=[C:21]([CH3:27])[C:22]([CH3:26])=[C:23]([O:24][CH3:25])[C:17]=3[N:16]=[C:15]2[CH:14]=[CH:13][C:7]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:5]([O:4][CH3:3])[CH:6]=2)=[CH:35][CH:34]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: COc1ccc(C=Cc2nc3c(OC)c(C)c(C)c(OC)c3[nH]2)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cn2c(C=Cc3ccc(OC)c(OC)c3)nc3c(OC)c(C)c(C)c(OC)c32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.9 %

Procedure:
To a suspension of sodium hydride, 60% dispersion in oil (150 mg; 3.5 mmol) in 20 mL of DMF, {2-[2-(3,4-dimethoxyphenyl)-vinyl]-4,7-dimethoxy-5,6-dimethyl-1H-benzoimidazole (1.2 g; 3.25 mmol) in DMF (20 mL) was added dropwise over 5 minutes. After addition, the reaction mixture was stirred at ambient temperature for 30 minutes, then methyl-4-(bromomethyl)benzoate (745 mg; 3.25 mmol) in DMF (10 mL) was added. The reaction mixture was stirred at ambient temperature for 4 hours. The DMF was concentrated to a residue, and H2O was added. The solid was collected by filtration. Recrystallization from MeOH gave 620 mg (37% yield) of the title compound as a light yellow solid, hemihydrate, m.p. 111-114° C. Anal. Calcd. for C30H32N2O6—0.5 H2O: C, 68.56, H, 6.33; N, 5.33. Found: C, 68.51; H, 6.27; N, 5.28. Mass spectrum: (EI; M+) m/z 516.1H-NMR (DMSO-d6; 400 MHz) δ7.9(d, 2H), 7.72-7.78(d, 1H), 7.31(d, 1H), 7.2-7.26 (m, 4H), 6.95 (d, 1H), 5.9 (s, 2H), 4.12 (s, 3H), 3.81 (s 3H), 3.79 (s, 3H),3.77 (s, 3H), 3.53 (s, 3H), 2.1 ppm (d, 6H).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12](I)[CH:13]=1)(=[O:3])[CH3:2].[F:27][C:28]1[CH:33]=[CH:32][C:31]([S:34]([O-:36])=[O:35])=[CH:30][CH:29]=1>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([S:34]([C:31]2[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=2)(=[O:36])=[O:35])[CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(I)c1
Reactant: O=S([O-])c1ccc(F)cc1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(S(=O)(=O)c2ccc(F)cc2)c1

Procedure:
By following a procedure analogous to Example 139 starting from 5-iodo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside and 4-fluorophenyl sulfinate, 5-[(4-fluorophenyl)sulfonyl]-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of a white solid (yield=24%).
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:19]1[CH2:26][C@H:25]2[C@H:21]([CH2:22][CH2:23][C:24]2=[O:27])[CH2:20]1)C1C=CC=CC=1>ClCCl>[CH2:1]([O:8][C:9]([N:19]1[CH2:26][C@H:25]2[C@H:21]([CH2:22][CH2:23][C:24]2=[O:27])[CH2:20]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C1CC[C@@H]2CN(Cc3ccccc3)C[C@H]12
Solvent: ClCCl
Product: O=C1CC[C@@H]2CN(C(=O)OCc3ccccc3)C[C@H]12
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.9 %

Procedure:
A solution of benzyloxycarbonyl chloride (4.28 ml, 30.0 mmol) in dichloromethane (15 ml) was added dropwise to a solution of (1R,5S)-7-benzyl-2-oxo-7-azabicyclo[3.3.0]octane (1.31 g, 6.10 mmol) in dichloromethane (20 ml) while cooling with ice, and the mixture was stirred at room temperature for 16 hours. The solvent was removed by evaporation, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1) to give 1.36 g (5.24 mmol, 86%) of the title compound as a colorless oily substance.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[C:9](=[O:10])[N:8]([CH3:11])[C:7]2[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=2[C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]1=2.[C:20](O)(=[O:24])[C@H:21]([CH3:23])[OH:22]>>[OH:22][C@@H:21]([CH3:23])[C:20]([NH:2][C@H:3]1[C:9](=[O:10])[N:8]([CH3:11])[C:7]2[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=2[C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]1=2)=[O:24]
Reactant: CN1C(=O)[C@H](N)c2ccccc2-c2ccccc21
Reactant: C[C@H](O)C(=O)O
Agent: Cl
Product: C[C@H](O)C(=O)N[C@H]1C(=O)N(C)c2ccccc2-c2ccccc21

Procedure:
The title compound, MS: m/e=311.3 (M+H+), was prepared in analogy to example 1a) from (+)-(R)-7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one hydrochloride and L-(+)-lactic acid.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:19]=[CH:20][C:21]=1[S:22](=[O:36])(=[O:35])[NH:23][CH2:24][C:25]1[CH:26]=[C:27]2[CH:33]=[CH:32][N:31]([CH3:34])[C:28]2=[N:29][CH:30]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15]>>[Cl:10][C:11]1[CH:12]=[C:13]([CH:19]=[CH:20][C:21]=1[S:22](=[O:35])(=[O:36])[N:23]([C:3]1[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][N:4]=1)[CH2:24][C:25]1[CH:26]=[C:27]2[CH:33]=[CH:32][N:31]([CH3:34])[C:28]2=[N:29][CH:30]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: Fc1ncc(Cl)cc1Cl
Reactant: CCOC(=O)c1ccc(S(=O)(=O)NCc2cnc3c(ccn3C)c2)c(Cl)c1
Product: CCOC(=O)c1ccc(S(=O)(=O)N(Cc2cnc3c(ccn3C)c2)c2ncc(Cl)cc2Cl)c(Cl)c1

Procedure:
The titled compound was prepared according to the procedure described in step-2 of Example 1 from 3,5-dichloro-2-fluoropyridine and ethyl 3-chloro-4-(N-((1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)sulfamoyl)benzoate (step-2 of Example 35).
Reaction SMILES: [CH3:1][C:2]([C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][NH:29][C:30]([NH:32][CH2:33][CH3:34])=[O:31])[CH:23]=2)=[C:18]([OH:35])[CH:17]=1)([CH3:15])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[O:8].IC.[C:38]([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:33]([NH:32][C:30]([NH:29][CH2:28][C:24]1[CH:23]=[C:22]([C:19]2[CH:20]=[CH:21][C:16]([C:2]([CH3:1])([CH2:3][CH2:4][CH2:5][CH2:6][C:7]([N:9]3[CH2:10][CH2:11][O:12][CH2:13][CH2:14]3)=[O:8])[CH3:15])=[CH:17][C:18]=2[O:35][CH3:38])[CH:27]=[CH:26][CH:25]=1)=[O:31])[CH3:34]
Reactant: CCNC(=O)NCc1cccc(-c2ccc(C(C)(C)CCCCC(=O)N3CCOCC3)cc2O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CCNC(=O)NCc1cccc(-c2ccc(C(C)(C)CCCCC(=O)N3CCOCC3)cc2OC)c1
Temperature: 60 °C
Yield: 23 %

Procedure:
A mixture of 20 (0.1 g, 0.208 mmol, 1.0 eq), iodomethane (0.05 mL, 0.832 mmol, 4.0 eq), and K2CO3 (0.115 g, 0.832 mmol, 4.0 eq) in acetone (3 mL) was heated to 60° C. overnight. LC/MS showed SM/product ˜1/1. More K2CO3 (0.2 g, 1.45 mmol, 7 eq) and iodomethane (0.2 mL, 3.21 mmol, 15.4 eq) were added, and the mixture was heated again to 60° C. overnight. Acetone was removed under reduced pressure, and the residue was partitioned in water/ethyl acetate. The aqueous layer was extracted with ethyl acetate (2×20 mL), and the combined organic layer was washed by water (20 mL), brine (20 mL) and dried over anhydrous K2CO3. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (silica gel, 60-100% ethyl acetate in hexane). Yield: 23%, 98% pure. M+1=496
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[C:8]([OH:11])([CH3:10])[CH3:9].C([Li])CCC.Cl[CH2:18][C:19]([OH:21])=[O:20].O>C1(C)C=CC=CC=1>[CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[C:8]([O:11][CH2:18][C:19]([OH:21])=[O:20])([CH3:9])[CH3:10]
Reactant: O=C(O)CCl
Reactant: CC(C)(O)C1CC2C=CC1C2
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(OCC(=O)O)C1CC2C=CC1C2
Temperature: 25 °C
Yield: 31.4 %

Procedure:
2-(5-norbornen-2-yl)-2-propanol (15.20 g, 0.10 mole) (JSR Corp., Japan) and toluene (100 ml) were added to a three-necked 500 ml round bottomed flask equipped with a magnetic stirrer, an addition funnel, and a condenser with a nitrogen inlet. The addition funnel was charged with n-butyl lithium (1.6M in hexane, 62.50 ml, 0.10 mole). The n-butyl lithium was added drop wise while stirring at room temperature. An exothermic reaction occurred. Afterwards, chloroacetic acid (4.75 g, 0.05 mole) in toluene (100 ml) was added drop wise. The contents were heated to reflux for about 20 hours. After cooling to room temperature, water (200 ml) was added cautiously and stirred. The water phase was collected, washed with ether (100 ml) and neutralized with 2 molar hydrochloric acid solution. The cloudy solution was extracted twice with ether (100 ml) and the combined ether solutions was washed with brine (100 ml) and dried over anhydrous magnesium sulfate. The solvent was removed and the residue was recrystallized from a small amount of hexane to give 3.3 g of white crystalline material (Melting Point: 48.5-49.50° C.).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH3:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1B(O)O.[F-].[K+]>C1COCC1>[CH3:9][O:8][C:6]([C:5]1[CH:10]=[CH:11][C:2]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH3:12])=[CH:3][CH:4]=1)=[O:7]
Reactant: COC(=O)c1ccc(Cl)cc1
Reactant: Cc1ccccc1B(O)O
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2ccccc2C)cc1
Yield: 91.5 %

Procedure:
Methyl 4-chlorobenzoate (172 mg, 1.01 mmol) reacted with 2-methylphenylboronic acid (210 mg, 1.54 mmol) using 1/2 mol % of Pd(dba)2/Ph5FcP(t-Bu)2 and KF (190 mg, 3.39 mmol) in THF at 100° C. to give the title compound (209 mg, 92%) as a colorless oil: 1H-NMR (400 MHz, CDCl3): δ 8.13 (d, 2H, J=8.24 Hz), 7.44 (d, 2H, J=8.20 Hz), 7.33-7.25 (m, 4H), 3.98 (s, 3H), 2.30 (s, 3H). 13C{1H}-NMR (100 MHz, CDCl3): δ 166.98, 146.69, 140.79, 135.10, 130.44, 129.47, 129.36, 129.21, 128.53, 127.78, 125.85, 52.06, 20.33. GC/MS(EI): m/z 226 (M+), 195, 165, 152. Anal. Calcd for C15H14O2: C, 79.62; H, 6.24. Found C, 79.33; H, 6.26.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)[N:10]2[CH2:13][C:12]([C@H:15]([C:20]3[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=3)[S:16]([CH3:19])(=[O:18])=[O:17])(O)[CH2:11]2)=[CH:5][CH:4]=1.CS(Cl)(=O)=O>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([C:28]2[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=2)[N:10]2[CH2:13][C:12](=[C:15]([C:20]3[CH:21]=[C:22]([F:27])[CH:23]=[C:24]([F:26])[CH:25]=3)[S:16]([CH3:19])(=[O:18])=[O:17])[CH2:11]2)=[CH:5][CH:4]=1
Reactant: CS(=O)(=O)[C@@H](c1cc(F)cc(F)c1)C1(O)CN([C@@H](c2ccc(Cl)cc2)c2ccc(CCl)cc2)C1
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CS(=O)(=O)C(=C1CN([C@@H](c2ccc(Cl)cc2)c2ccc(CCl)cc2)C1)c1cc(F)cc(F)c1

Procedure:
1-{(R*)-[4-(chloromethyl)phenyl](4-(chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine, form B isomer, may be prepared by carrying out the operation as described in Example 87, starting with 7.3 g of the mixture of the 2 diastereoisomers (B forms) 1-{(R*)-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(R)-(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidin-3-ol and 1-{(R*)-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(S)-(3,5-difluorophenyl)(methylsulfonyl)methyl]azetidin-3-ol, 8.2 g of 4-dimethylaminopyridine, 150 cm3 of dichloromethane and 3.2 cm3 of methanesulfonyl chloride. The crude product is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 3 cm, height 30 cm), at an argon pressure of 0.2 bar, eluting with dichloromethane and collecting 100 cm3 fractions. Fractions 15 to 30 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 2.50 g of 1-{(R*)-[4-(chloromethyl)phenyl]-(4-chlorophenyl)methyl}-3-{(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine, form B isomer, are obtained in the form of a white foam.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([O:12][CH:13]([CH3:15])[CH3:14])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:19])[CH:5]=[C:6]([S:16]([CH3:18])=O)[O:7]2.[OH:20][C:21]1[CH:26]=[CH:25]C(S)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O>[OH:1][C:2]1[CH:11]=[C:10]([O:12][CH:13]([CH3:15])[CH3:14])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:19])[CH:5]=[C:6]([S:16][C:18]1[CH:25]=[CH:26][C:21]([OH:20])=[CH:22][CH:23]=1)[O:7]2
Reactant: Oc1ccc(S)cc1
Reactant: CC(C)Oc1cc(O)c2c(=O)cc(S(C)=O)oc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)Oc1cc(O)c2c(=O)cc(Sc3ccc(O)cc3)oc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.4 %

Procedure:
A mixture consisting of 7.01 g (24.59 mmol) 5-hydroxy-7-isopropoxy-2-methylsulfinylchromone, 3.72 g (29.51 mmol) 4-hydroxybenzenethiol, 4.07 g (29.51 mmol) potassium carbonate, and 170 ml acetone was stirred over 1 hour at room temperature. The solution thus reacted was neutralized by addition of dilute hydrochloric acid. Subsequently, the product was extracted twice with chloroform. The organic layer was washed with saturated salt water and dried over sodium sulfate anhydride. The solvent was distilled out under reduced pressure. The resulting crude product was subjected to recrystallization from ethanol-methanol, whereby 6.64 g of 5-hydroxy2-(4-hydroxyphenylthio)-7-isopropoxychromone was obtained (yield: 78%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].C(N(CC)CC)C.[Cl:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1>C(Cl)Cl>[Cl:21][C:22]1[CH:28]=[CH:27][C:25]([NH:26][C:7](=[O:8])[C:6]2[CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[N+:11]([O-:13])=[O:12])=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Nc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)cc1)c1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 96.4 %

Procedure:
To a solution of 5-chloro-2-nitrobenzoyl chloride (23 g, 100 mmol) in methylene chloride (200 mL) at 0° C. was added triethylamine (16 mL, 115 mmol), followed by 4-chloroaniline (14 g, 110 mmol). The mixture was stirred for 20 minutes at 0° C., then warmed to ambient temperature. After 5 hours, the mixture was concentrated of all volatiles in vacuo. The residual solid was dissolved in ethyl acetate (400 mL) and washed with water (200 mL), 1M hydrochloric acid (2×200 mL), 1M sodium bicarbonate (200 mL) and brine (200 mL) and dried over MgSO4. Concentration and drying in vacuo afforded 30 g (93% yield) of N-(4-chlorophenyl)-5-chloro-2-nitrobenzamide; NMR (CDCl3) 8.1 (d, 1), 7.7 (br, 1), 7.6 (m, 2), 7.5 (d, 2), 7.3 (d, 2) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)=[CH:17][C:9]1=2.[Cl:32][C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH2:35][NH2:36]>>[Cl:32][C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH2:35][NH:36][C:21](=[O:23])[C:20]1[CH:24]=[CH:25][CH:26]=[C:18]([C:16]2[CH:15]=[N:14][C:10]3[NH:11][CH2:12][CH2:13][N:8]([CH2:7][C:6]4[CH:27]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[C:28]([F:30])([F:31])[F:29])[C:9]=3[CH:17]=2)[CH:19]=1
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Reactant: NCc1ccccc1Cl
Product: O=C(NCc1ccccc1Cl)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 2-chlorobenzylamine as in General Procedure 10 to give the title compound. LCMS: m/z=570.9 (M+H+); retention time=0.98 minutes.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH:11]=O)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:19]1[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]1[CH3:28])=[N:6][C:7]=2[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[CH3:29][S:30]([CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][C:36]1([CH3:42])[CH3:41])(=[O:32])=[O:31].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:41][C:36]1([CH3:42])[N:35]([CH2:34][CH2:33][S:30]([CH3:29])(=[O:31])=[O:32])[CH2:40][CH2:39][N:38]([CH2:11][C:10]2[N:2]([CH3:1])[C:3]3[C:8]([N:9]=2)=[C:7]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)[N:6]=[C:5]([N:19]2[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=[C:20]2[CH3:28])[N:4]=3)[CH2:37]1
Reactant: CC1(C)CNCCN1CCS(C)(=O)=O
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(CCS(C)(=O)=O)C(C)(C)C3)n(C)c2n1
Reaction time: 64 h

Procedure:
A mixture of 9-methyl-2-(2-methylbenzoimidazol-1-yl)-6-morpholin-4-yl-9H-purine-8-carbaldehyde (80 mg, 0.21 mmol), 1-(2-methanesulfonylethyl)-2,2-dimethylpiperazine (56 mg, 0.25 mmol) and 4 Å powdered molecular sieves (100 mg) in DCE (5 mL) was stirred at room temperature for 4 h before the addition of sodium triacetoxyborohydride (90 mg, 0.42 mmol). The reaction mixture was stirred for 64 h then filtered through celite, washing with DCM. The organic phase was washed with brine (×1) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-15%). The resulting oil was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH affording 330 as a white solid (70 mg, 58%). LCMS (Method G): RT 6.62 min [M+H]+ 582.3. 1H NMR (CDCl3, 400 MHz): δ 8.12-8.07 (m, 1 H); 7.74-7.70 (m, 1 H); 7.29-7.25 (m, 2 H); 4.35 (m, 4 H); 3.91-3.83 (m, 7 H); 3.69 (s, 2 H); 3.11 (m, 2 H); 3.06 (s, 3 H); 2.95 (s, 3 H); 2.63 (m, 2 H); 2.54 (m, 2 H); 2.30 (s, 2 H); 1.78 (m, 2 H) and 1.10 (s, 6 H)
Reaction SMILES: [C:1]1([CH:7]2[C:19]3[NH:18][C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:11]=3[CH2:10][CH2:9][N:8]2[C:20](=[O:31])/[CH:21]=[CH:22]/[C:23]2[CH:28]=[CH:27][C:26]([CH:29]=[O:30])=[CH:25][CH:24]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C-]#N.[Na+].[C:35](O)(=[O:37])C.C(Cl)Cl.CO>CO.O=[Mn]=O>[O:31]=[C:20]([N:8]1[CH2:9][CH2:10][C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:18][C:19]=2[CH:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)/[CH:21]=[CH:22]/[C:23]1[CH:28]=[CH:27][C:26]([C:29]([O:37][CH3:35])=[O:30])=[CH:25][CH:24]=1
Reactant: O=Cc1ccc(/C=C/C(=O)N2CCc3c([nH]c4ccccc34)C2c2ccccc2)cc1
Reactant: CC(=O)O
Agent: O=[Mn]=O
Agent: [C-]#N
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1ccc(/C=C/C(=O)N2CCc3c([nH]c4ccccc34)C2c2ccccc2)cc1
Reaction time: 5 h
Yield: 70.1 %

Procedure:
To a solution of Example 9 (0.2 g, 0.49 mmol) in 20 mL of MeOH was added activated MnO2 (0.59 g, 14 equiv.), sodium cyanide (0.05 g, 2 equiv.) and acetic acid (0.05 g, 1.7 equiv.). The resulting mixture was stirred for 5 hours. Tlc monitoring showed a new compound (SiO2, DCM:MeOH (95:5), Rf=0.82). The mixture was filtered through a short column of celite using 150 mL of a mixture of MeOH:EtOAc:CHCl3 (1:25:25). After evaporation in vacuo the residue was purified via flash chromatography on a 2×20 cm2 column using DCM as eluting solvent. Evaporation and recrystallization from EtOH gave the title compound (0.15 g, 70%) as yellow crystals.