Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[F:30][CH:31]1[CH2:34][N:33]([CH:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH2:32]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][N:38]4[CH2:39][CH2:40][CH:35]([N:33]5[CH2:32][CH:31]([F:30])[CH2:34]5)[CH2:36][CH2:37]4)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: FC1CN(C2CCNCC2)C1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(N4CC(F)C4)CC3)n(C)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (0.155 g, 0.395 mmol), 4-(3-fluoroazetidin-1-yl)piperidine (0.075 g, 0.474 mmol) and 4 Å molecular sieves (0.5 g) in DCE (6 mL) was stirred for 3 h at room temperature. Sodium triacetoxyborohydride (0.168 g, 0.79 mmol) was added and the reaction mixture was stirred for 72 h at room temperature. The reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, MeOH:DCM, gradient 0:100 to 15:85) to give 608 as a white solid (0.177 g, 84%). LCMS (Method I): RT=2.25 min, [M+H]+ 534.2 1H NMR (400 MHz, DMSO-d6): δ 8.03-7.98 (m, 1 H), 7.65-7.60 (m, 1 H), 7.27-7.21 (m, 2 H), 5.20-5.00 (m, 1 H), 4.50-3.96 (m, 4 H), 3.80 (s, 3 H), 3.80-3.74 (m, 4 H), 3.75 (s, 2 H), 3.56-3.45 (m, 2 H), 3.26 (q, J=7.4 Hz, 2 H), 3.06-2.94 (m, 2 H), 2.78-2.68 (m, 2 H), 2.19-2.09 (m, 2 H), 2.07 (s, 1 H), 1.66-1.57 (m, 2 H), 1.33 (t, J=7.4 Hz, 3 H), 1.25-1.12 (m, 2 H)
Reaction SMILES: [F:1][C:2]1[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:3]=1[CH2:4][S:5][C:6]1[N:11]=[C:10]([NH:12][S:13]([N:16]2[CH2:19][CH2:18][CH2:17]2)(=[O:15])=[O:14])[CH:9]=[C:8]([O:20][C@H:21]([C@H:23]2[CH2:27][O:26]C3(CCCCC3)[O:24]2)[CH3:22])[N:7]=1.O>C(Cl)Cl.O.O.O.O.O.O.[Fe](Cl)(Cl)Cl>[F:1][C:2]1[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:3]=1[CH2:4][S:5][C:6]1[N:11]=[C:10]([NH:12][S:13]([N:16]2[CH2:19][CH2:18][CH2:17]2)(=[O:15])=[O:14])[CH:9]=[C:8]([O:20][C@@H:21]([CH3:22])[C@H:23]([OH:24])[CH2:27][OH:26])[N:7]=1
Reactant: C[C@H](Oc1cc(NS(=O)(=O)N2CCC2)nc(SCc2cccc(F)c2F)n1)[C@H]1COC2(CCCCC2)O1
Agent: Cl[Fe](Cl)Cl
Solvent: ClCCl
Solvent: O
Product: C[C@H](Oc1cc(NS(=O)(=O)N2CCC2)nc(SCc2cccc(F)c2F)n1)[C@H](O)CO
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of N-(2-[(2,3-difluorobenzyl)thio]-6-{(1S)-1-[(2R)-1,4-dioxaspiro[4.5]dec-2-yl]ethoxy}pyrimidin-4-yl)azetidine-1-sulfonamide (the product of step (43 mg) in DCM (4 ml) was added iron (III) chloride hexahydrate (73 mg). The reaction mixture was stirred at room temperature for 2 h after which time further iron (III) chloride hexahydrate (40 mg) was added. After 3 d at −18° C., H2O and DCM were added. The layers were separated and the aqueous material extracted with further DCM. The combined organic extracts were washed with saturated aqueous sodium chloride, dried with sodium sulfate, filtered and evaporated. TFA (1 ml) and DCM (4 ml) were added to the residue and the reaction mixture stirred at room temperature for 2 d. The mixture was partitioned between saturated aqueous sodium bicarbonate and DCM, then neutralised with 2 M aqueous hydrochloric acid, the layers separated and the aqueous material extracted with further DCM. The DCM extracts were allowed to slowly evaporate and the resulting solid washed with minimal cold DCM to afford the title compound as a white powder. Yield: 11 mg
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18]3[N:22]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[C:21]4[CH:31]=[CH:32][CH:33]=[CH:34][C:20]=4[N:19]=3)[CH2:13][CH2:12]2)[C:3]=1[NH2:35].N[C:37](N)=[O:38]>O>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[C:3]=1[N:35]=[C:37]([OH:38])[N:8]2[CH2:9][CH2:10][N:11]1[CH2:12][CH2:13][CH:14]([CH2:17][C:18]2[N:22]([CH2:23][C:24]3[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=3)[C:21]3[CH:31]=[CH:32][CH:33]=[CH:34][C:20]=3[N:19]=2)[CH2:15][CH2:16]1
Reactant: NC(N)=O
Reactant: Nc1c(Cl)ncnc1NCCN1CCC(Cc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Solvent: O
Product: Oc1nc2c(Cl)ncnc2n1CCN1CCC(Cc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Temperature: 220 °C
Yield: 32 %

Procedure:
A mixture of 7.5 parts of 6-chloro-N4 -[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]methyl]-1-piperidinyl]ethyl]-4,5-pyrimidinediamine and 3.6 parts of urea was stirred and heated for 20 minutes at 220° C. Water was added to the reaction mixture. The precipitated product was filtered off and crystallized from methanol. The product was filtered off and recrystallized from a mixture of N,N-dimethylformamide and methanol, yielding 2.5 parts (32%) of 6-chloro-9-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]methyl]-1-piperidinyl]ethyl]-9H-purin-8-ol; mp. 243.0° C. (494).
Reaction SMILES: Cl[CH2:2][C:3]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[F:20])([OH:12])[C:4]([F:11])([F:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6].N12CCCN=C1CCCCC2.O.Cl>C(Cl)Cl>[F:20][C:14]1[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=1[C:3]1([O:12][CH2:2]1)[C:4]([F:11])([F:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(F)(F)C(O)(CCl)c1ccc(F)cc1F
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)C(F)(F)C1(c2ccc(F)cc2F)CO1
Yield: 80 %

Procedure:
In 150 ml of methylene chloride was dissolved 15.7 g of ethyl 4-chloro-3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxybutyrate. To the solution was dropwise added 8.4 g of 1,8-diazabicyclo[5.4.0]undec-7-ene at 5°-10° C. The mixture was subjected to reaction at the same temperature for 2 hours. The resulting reaction mixture was introduced into 150 ml of water and adjusted to p 1.0 with 6N hydrochloric acid. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by a column chromatography (eluant: n-hexane/toluene=2/1) to obtain 11.1 g of oily ethyl 3-(2,4-difluorophenyl)-3,4-epoxy-2,2-difluorobutyrate.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][C:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:32][CH2:33][CH3:34])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:35]1([CH2:41][CH2:42][C:43](Cl)=[O:44])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([C:43](=[O:44])[CH2:42][CH2:41][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[N:12]=2)=[C:7]([O:32][CH2:33][CH3:34])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1
Reactant: O=C(Cl)CCc1ccccc1
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)CCc1ccccc1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was reacted with 3-phenyl-propionyl chloride (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C38H41N2O2Cl2 [(M+H)+] 627.2540, observed 627.2541.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[N:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][CH:20]([CH2:23][NH2:24])[CH2:19][CH2:18]2)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:24][CH2:23][CH:20]1[CH2:19][CH2:18][N:17]([C:14]2[CH:15]=[CH:16][N:11]=[CH:12][CH:13]=2)[CH2:22][CH2:21]1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: NCC1CCN(c2ccncc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1NCC1CCN(c2ccncc2)CC1
Reaction time: 16 h
Yield: 50.4 %

Procedure:
A solution of 2-fluoronitrobenzene (0.13 mL, 1.3 mmol) and 1-(4-pyridyl)piperidine-4-methylamine (242 mg, 1.27 mmol) in DMF (5 mL) was treated with potassium carbonate (175 mg, 1.3 mmol). After 16 h, the mixture was diluted with EtOAc, the organic layer was washed with water (3×), brine, dried with K2CO3, and concentrated. The residue was dissolved in 5% HOAc in MeOH and loaded onto an SCX ion exchange column. Elution with MeOH followed by 2 M NH3 in MeOH yielded 200 mg of the title compound; which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9]N)[CH:5]=[C:6]([F:8])[CH:7]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH:22]2[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]2)(=[O:20])=[O:19])=[CH:14][CH:13]=1>C(O)C.S(=O)(=O)(O)O.O>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH:22]2[CH2:23][C:24]3[C:3]4[C:4](=[CH:5][C:6]([F:8])=[CH:7][C:2]=4[F:1])[NH:9][C:25]=3[CH2:26][CH2:27]2)(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: O=C1CCC(NS(=O)(=O)c2ccc(Cl)cc2)CC1
Reactant: NNc1cc(F)cc(F)c1
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: O
Product: O=S(=O)(NC1CCc2[nH]c3cc(F)cc(F)c3c2C1)c1ccc(Cl)cc1

Procedure:
14.0 g (97 mmol) of the compound of Example I and 27.95 g (97 mmol) of 4-chloro-N-(4-oxo-cyclohexyl)benzenesulphonamide are refluxed for 5 hours in 190 ml of ethanol and 36 ml of concentrated sulphuric acid, then the mixture is cooled and diluted with 300 ml of water. The mixture is extracted 4 times using 250 ml of ethyl acetate each time, and the organic phase is dried using sodium sulphate, filtered with suction over kieselguhr and evaporated. The residue is stirred with methylene chloride and dried in a high vacuum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[NH:10][C:11]2[CH2:12][S:13][CH2:14][C@:15]([C:18]3[CH:23]=[C:22](Br)[CH:21]=[CH:20][C:19]=3[F:25])([CH3:17])[N:16]=2)=[CH:5][CH:4]=1.CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.[C:76](=[NH:89])([C:83]1[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=1)[C:77]1[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[NH:10][C:11]2[CH2:12][S:13][CH2:14][C@:15]([C:18]3[CH:23]=[C:22]([N:89]=[C:76]([C:77]4[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=4)[C:83]4[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=4)[CH:21]=[CH:20][C:19]=3[F:25])([CH3:17])[N:16]=2)=[CH:5][CH:4]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)CSC2)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1ccc(C(NC2=N[C@](C)(c3cc(N=C(c4ccccc4)c4ccccc4)ccc3F)CSC2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 105 °C
Reaction time: 5 h
Yield: 81.5 %

Procedure:
To a mixture of (R)—N-(bis(4-methoxyphenyl)(phenyl)methyl)-5-(5-bromo-2-fluorophenyl)-5-methyl-5,6-dihydro-2H-1,4-thiazin-3-amine (1.67 g, 2.76 mmol, Eq: 1.00), sodium tert-butoxide (795 mg, 8.27 mmol, Eq: 3), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (85.6 mg, 82.7 μmol, Eq: 0.03) and 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (117 mg, 276 μmol, Eq: 0.1) in toluene (22.0 ml) at 23° C. was added benzophenone imine (1.00 g, 926 μl, 5.52 mmol, Eq: 2) this reaction mixture was stirred under argon atmosphere at 105° C. for 5 hours. Extracted with water and ethyl acetate, dried the organic layer over Na2SO4, filtered off and evaporated totally. The crude material was purified by silica gel flash chromatography with n-heptane and ethyl acetate to give the (R)—N-(bis(4-methoxyphenyl)(phenyl)methyl)-5-(5-(diphenylmethyleneamino)-2-fluorophenyl)-5-methyl-5,6-dihydro-2H-1,4-thiazin-3-amine (1.59 g, 2.25 mmol, 81.7% yield) as a yellow oil. MS (ISP): m/z=706.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][CH3:10])[CH:5]=[C:4]([NH2:11])[N:3]=1.[N:12]([O-])=[O:13].[Na+]>C(O)(=O)C.O>[N:12]([C:5]1[C:6]([O:8][CH2:9][CH3:10])=[N:7][C:2]([NH2:1])=[N:3][C:4]=1[NH2:11])=[O:13]
Reactant: O=N[O-]
Reactant: CCOc1cc(N)nc(N)n1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOc1nc(N)nc(N)c1N=O
Temperature: 80 °C
Reaction time: 2 h
Yield: 68.3 %

Procedure:
To a solution of the compound of example 54 (6.13 g, 39.8 mmoles) in 20% aqueous acetic acid (57 ml) was added dropwise a solution of NaNO2 (3.29 g) in water (13 ml) at 80° C. A pink precipitate was formed which was stirred at 80° C. for an additional 2 hours. The reaction mixture was cooled down in the refrigerator overnight and the resulting precipitate was filtered off, yielding the title compound as a pink powder (4.98 g, yield 68%). Spectral data are identical with those described e.g. by W. Pfleiderer et al. in Chem. Ber. (1961) 94, 12.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH2:13][CH2:14][OH:15])[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5]1.[O:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23]Cl)[CH2:18][CH2:17]1.Cl>O.C1C=CC=CC=1>[CH3:3][C:4]1([CH2:13][CH2:14][O:15][CH2:23][CH2:22][N:19]2[CH2:20][CH2:21][O:16][CH2:17][CH2:18]2)[O:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[O:8]1
Reactant: CC1(CCO)Oc2ccccc2O1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CC1(CCOCCN2CCOCC2)Oc2ccccc2O1

Procedure:
3.2 g. of 80% NaH are added a little at a time, with cooling, to 10 g. of 2-methyl-2-(β-hydroxyethyl)-1,3-benzodioxole dissolved in 180 cc. of anhydrous benzene. The mixture is refluxed for one hour and cooled. 15 g. of morpholino-ethyl chloride are added drop by drop, and the mixture is refluxed for three hours. The solvent is eliminated under vacuum, and the residue is dissolved in water, acidified with dilute HCl and extracted with ether. The aqueous phase is made alkaline, and again extracted with ether. The organic phase is separated, dried over Na2SO4, and evaporated.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([O:15][CH3:16])=[C:11](Br)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:18][S:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.N>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([O:15][CH3:16])=[C:11]([C:23]3[CH:24]=[CH:25][C:20]([S:19][CH3:18])=[CH:21][CH:22]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(Br)cnn(-c2cccc(Cl)c2)c1=O
Reactant: CSc1ccc(B(O)O)cc1
Agent: N
Product: COc1c(-c2ccc(SC)cc2)cnn(-c2cccc(Cl)c2)c1=O

Procedure:
The title compound was prepared according to the method of Example 6 starting with 2-(3-chlorophenyl)-4-methoxy-5-bromo-3(2H)-pyridazinone in place of 2-benzyl-4-bromo-5-methoxy-3(2H)-pyridazinone and substituting 4-(methylthio)benzeneboronic acid in place of 4-fluorobenzeneboronic acid (yield: 3.3 g, 68%). 1H NMR (300 MHz, DMSO-d6) δ 2.54 (s, 3H), 4.03 (s, 3H), 7.40 (d, J=9.0 Hz, 2H), 7.50-7.64 (m, 5H), 7.73-7.77 (m, 1H), 8.18 (s, 1H). MS (DCI/NH3) m/z 359 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[C:5]([CH3:21])[C:6]=1[NH:7][C:8]([NH:10][CH:11]1[CH2:20][CH2:19][CH2:18][CH2:17][C:12]21OCCO2)=[NH:9]>Cl.O>[ClH:1].[Cl:1][C:2]1[S:3][CH:4]=[C:5]([CH3:21])[C:6]=1[N:7]1[C:12]2[CH2:17][CH2:18][CH2:19][CH2:20][C:11]=2[N:10]=[C:8]1[NH2:9]
Reactant: Cc1csc(Cl)c1NC(=N)NC1CCCCC12OCCO2
Agent: Cl
Solvent: O
Product: Cc1csc(Cl)c1-n1c(N)nc2c1CCCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 198.8 %

Procedure:
N-(2-Chloro-4-methylthiophen-3-yl)-N′-(1,4-dioxaspiro[4.5]dec-6-yl)guanidine (24 mg) was dissolved in 2N hydrochloric acid (1 ml) and stirred at room temperature for 30 min. Concentrated hydrochloric acid (1 ml) was then added, and the mixture was stirred for another two hours. The mixture was then diluted with a little water and freeze-dried. Toluene was added to the residue and then distilled off under reduced pressure. This step was repeated twice, giving 22 mg of the desired product as a solid.
Reaction SMILES: [C:1]1([CH:6]([N:28]2[CH2:33][CH2:32][CH:31]([O:34][CH3:35])[CH2:30][CH2:29]2)[C:7]([NH:9][C:10]2[CH:11]=[C:12]([CH:24]=[CH:25][C:26]=2[F:27])[CH2:13][C:14]2([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15]2)=[O:8])[CH2:5][CH2:4][CH2:3][CH:2]=1>CO.[Pt](=O)=O>[CH:1]1([CH:6]([N:28]2[CH2:33][CH2:32][CH:31]([O:34][CH3:35])[CH2:30][CH2:29]2)[C:7]([NH:9][C:10]2[CH:11]=[C:12]([CH:24]=[CH:25][C:26]=2[F:27])[CH2:13][C:14]2([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:15][CH2:16]2)=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC1CCN(C(C(=O)Nc2cc(CC3(C(=O)OC(C)(C)C)CC3)ccc2F)C2=CCCC2)CC1
Agent: O=[Pt]=O
Solvent: CO
Product: COC1CCN(C(C(=O)Nc2cc(CC3(C(=O)OC(C)(C)C)CC3)ccc2F)C2CCCC2)CC1
Reaction time: 5 h

Procedure:
20.7 mg (0.04 mmol) of rac-tert-Butyl 1-(3-{[cyclopent-1-en-1-yl(4-methoxypiperidin-1-yl)acetyl]amino}-4-fluorobenzyl)cyclopropanecarboxylate were initially charged in 3 ml of methanol, 3 mg (0.01 mmol) of platinum(IV) oxide were added and the mixture was hydrogenated at RT and standard pressure for 5 h. The mixture was then filtered through kieselguhr, the residue was washed thoroughly with methanol and the filtrate was concentrated under reduced pressure. 19.5 mg (100% purity, 94% of theory) of the title compound were obtained.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[C:7]1(=O)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[O:8]1>O1CCOCC1>[N:4]1[N:3]=[C:2]([N:1]2[C:7](=[O:8])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:16])[NH:6][CH:5]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Nc1nc[nH]n1
Solvent: C1COCCO1
Product: O=C1c2ccccc2C(=O)N1c1nnc[nH]1
Temperature: 120 °C

Procedure:
3-Amino-[1,2,4]triazole (8.40 g, 100 mmol) and isobenzofuran-1,3-dione (14.8 g, 100 mmol) were suspended in 1,4-dioxane (200 ml) and heated at 120° C. for 2 days. After the reaction mixture was cooled down at room temperature, the resulting precipitate was filtered, and the cake was washed with H2O then EtOAc to obtain the intended compound as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]2[NH:7][C:8](=[O:19])[N:9]([CH:12]3[CH2:17][CH2:16][NH:15][CH:14]([CH3:18])[CH2:13]3)[CH2:10][CH2:11][C:5]=2[CH:4]=1.Cl[C:23]1[N:28]=[CH:27][N:26]=[C:25]([C:29]([C:31]2[CH:41]=[C:40]([CH3:42])[C:34]3[N:35]([CH3:39])[C:36](=[O:38])[O:37][C:33]=3[CH:32]=2)=[O:30])[CH:24]=1>CN(C=O)C>[CH3:39][N:35]1[C:34]2[C:40]([CH3:42])=[CH:41][C:31]([C:29]([C:25]3[N:26]=[CH:27][N:28]=[C:23]([N:15]4[CH2:16][CH2:17][CH:12]([N:9]5[CH2:10][CH2:11][C:5]6[CH:4]=[C:3]([O:2][CH3:1])[CH:21]=[CH:20][C:6]=6[NH:7][C:8]5=[O:19])[CH2:13][CH:14]4[CH3:18])[CH:24]=3)=[O:30])=[CH:32][C:33]=2[O:37][C:36]1=[O:38]
Reactant: COc1ccc2c(c1)CCN(C1CCNC(C)C1)C(=O)N2
Reactant: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2oc(=O)n(C)c12
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c5c(c4)oc(=O)n5C)ncn3)C(C)C1)C(=O)N2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
60 mg (0.21 mmol) 7-methoxy-3-(2-methyl-piperidin-4-yl)-1,3,4,5-tetrahydro-benzo[d]-[1,3]diazepin-2-one, 60 mg (0.20 mmol) 6-(6-chloropyrimidine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one and 0.040 mL (0.29 mmol) TEA were combined in 1 mL DMF and stirred for three days at RT. Then 7-methoxy-3-(2-methyl-piperidin-4-yl)-1,3,4,5-tetrahydrobenzo[d][1,3]diazepin-2-one was added again and the mixture was stirred for 3 h at 80° C. The reaction mixture was purified by preparative HPLC. The fractions containing the product were combined and the solvent was evaporated down by half. The aqueous residue was extracted with DCM, the combined organic phases were dried on sodium sulphate, filtered and the filtrate was evaporated down.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:6]2[CH:16]=[CH:17][CH:18]=[C:19]([CH3:20])[C:5]=2[N:4]([CH2:21][C:22]([N:24]2[CH2:30][CH:29]3[CH2:31][CH2:32][CH:26]([CH2:27][CH2:28]3)[CH2:25]2)=[O:23])[C:3]1=[O:33].[C:34](N1C=CN=C1)([N:36]1[CH:40]=[CH:39][N:38]=[CH:37]1)=[O:35].C(OCC)(=O)C.O>O1CCCC1>[CH:26]12[CH2:32][CH2:31][CH:29]([CH2:28][CH2:27]1)[CH2:30][N:24]([C:22]([CH2:21][N:4]1[C:5]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:6]=3[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[F:15])=[N:8][CH:2]([NH:1][C:34]([N:36]3[CH:40]=[CH:39][N:38]=[CH:37]3)=[O:35])[C:3]1=[O:33])=[O:23])[CH2:25]2
Reactant: Cc1cccc2c1N(CC(=O)N1CC3CCC(CC3)C1)C(=O)C(N)N=C2c1ccccc1F
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cccc2c1N(CC(=O)N1CC3CCC(CC3)C1)C(=O)C(NC(=O)n1ccnc1)N=C2c1ccccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 105 %

Procedure:
A mixture of (3RS)-3-amino-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-2,3-dihydro-9-methyl-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one (1.0 g) and 1,1′-carbonyldiimidazole (723 mg) in tetrahydrofuran (20 ml) was stirred at room temperature overnight. Ethyl acetate and water were added to the reaction mixture. The separated organic layer was washed with water twice, brine and dried over magnesium sulfate. The solvent was evaporated in vacuo to afford (3RS)-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-2,3-dihydro-5-(2-fluorophenyl)-9-methyl-3-(imidazol-1-yl)carbonylamino-1H-1,4-benzodiazepin-2-one (1.27 g) as a crystalline powder.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([S:13]([NH2:16])(=[O:15])=[O:14])[CH2:9][CH2:8]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:58]1[CH:63]=[C:62]([O:64][CH3:65])[N:61]=[C:60]([S:66][CH2:67][C:68]2[CH:73]=[CH:72][CH:71]=[C:70]([F:74])[C:69]=2[F:75])[N:59]=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:75][C:69]1[C:70]([F:74])=[CH:71][CH:72]=[CH:73][C:68]=1[CH2:67][S:66][C:60]1[N:59]=[C:58]([NH:16][S:13]([N:10]2[CH2:9][CH2:8][N:7]([C:2]3[N:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH2:12][CH2:11]2)(=[O:15])=[O:14])[CH:63]=[C:62]([O:64][CH3:65])[N:61]=1
Reactant: NS(=O)(=O)N1CCN(c2ncccn2)CC1
Reactant: COc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COc1cc(NS(=O)(=O)N2CCN(c3ncccn3)CC2)nc(SCc2cccc(F)c2F)n1

Procedure:
The title compound was prepared according to the procedure outlined in example 1 step (iv) using a mixture of 4-pyrimidin-2-ylpiperazine-1-sulfonamide (0.24 g), tris(dibenzylideneacetone)dipalladium (0) (60 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (31 mg), cesium carbonate (0.32 g) and 4-Chloro-2-[[(2,3-difluorophenyl)methyl]thio]-6-methoxypyrimidine (the product of Example 35, step i) (0.20 g) in dioxane (6 ml). The crude material was purified by column chromatography using EtOAc/isohexane (2:8 to 1:1 gradient) as eluent to give the title compound as a pale yellow foam. Yield: 0.19 g.
Reaction SMILES: [NH2:1][C:2]1[C:20]([C:21]#[CH:22])=[CH:19][C:5]([O:6][C:7]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:8]=2[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:4]([Cl:23])[CH:3]=1>C(O)C.C(OCC)(=O)C>[Cl:23][C:4]1[CH:3]=[C:2]2[C:20]([CH:21]=[CH:22][NH:1]2)=[CH:19][C:5]=1[O:6][C:7]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: C#Cc1cc(Oc2cc(F)ccc2C(=O)OCC)c(Cl)cc1N
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(F)cc1Oc1cc2cc[nH]c2cc1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of EXAMPLE 242D (1.0 g) in ethanol (20 mL) was added NaAuCl4.2H2O (60 mg). The mixture was stirred at room temperature for 4 hours. The mixture was diluted with ethyl acetate (200 mL) and washed with water, brine and dried over Na2SO4. The mixture was filtered, and the solvent was evaporated and the residue was loaded on a column and eluted with 10% ethyl acetate in hexane to give the pure product.