Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([C:20]2[S:21][C:22]([Cl:25])=[CH:23][CH:24]=2)=[N:4][C:5]([NH:8][CH2:9][CH2:10][N:11]2[C:15]([CH3:17])([CH3:16])[C:14](=[O:18])[NH:13][C:12]2=[O:19])=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:34]2[CH:42]=[CH:41][CH:40]=[C:39]3[C:35]=2[CH:36]=[CH:37][N:38]3[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])O1>>[Cl:25][C:22]1[S:21][C:20]([C:3]2[C:2]([C:34]3[CH:42]=[CH:41][CH:40]=[C:39]4[C:35]=3[CH:36]=[CH:37][N:38]4[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[CH:7][N:6]=[C:5]([NH:8][CH2:9][CH2:10][N:11]3[C:15]([CH3:17])([CH3:16])[C:14](=[O:18])[NH:13][C:12]3=[O:19])[N:4]=2)=[CH:24][CH:23]=1
Reactant: CC1(C)C(=O)NC(=O)N1CCNc1ncc(Br)c(-c2ccc(Cl)s2)n1
Reactant: CC(C)(C)OC(=O)n1ccc2c(B3OC(C)(C)C(C)(C)O3)cccc21
Product: CC(C)(C)OC(=O)n1ccc2c(-c3cnc(NCCN4C(=O)NC(=O)C4(C)C)nc3-c3ccc(Cl)s3)cccc21

Procedure:
The title compounds were prepared from 1-{2-[5-bromo-4-(5-chlorothiophen-2-yl)pyrim-idin-2-ylamino]ethyl}-5,5-dimethylimidazolidine-2,4-dione and tert-butyl 4-(4,4,5,5-tetra-methyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate in a manner analogous to Example 269, then purified and separated by C-8 prep HPLC to give tert-butyl 4-{4-(5-chlorothiophen-2-yl)-2-[2-(5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)ethylamino]pyrimidin-5-yl}-1H-indole-1-carboxylate: MS (M+H)+ 581; and 1-{2-[4-(5-chlorothiophen-2-yl)-5-(1H-indol-4-yl)pyrimidin-2-ylamino]ethyl}-5,5-dimethylimidazolidine-2,4-dione: MS (M+H)+ 481.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C@@H:11]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:12]([N:14]1[CH2:19][CH2:18][C:17]2[C:20](=[O:33])[O:21][C:22]([CH2:29][CH:30]([CH3:32])[CH3:31])([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:16]=2[CH2:15]1)=[O:13]>>[CH2:29]([C:22]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:16]2[CH2:15][N:14]([C:12](=[O:13])[C@@H:11]([NH:10][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:34][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH2:19][CH2:18][C:17]=2[C:20](=[O:33])[O:21]1)[CH:30]([CH3:32])[CH3:31]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)CC1(c2ccccc2)OC(=O)C2=C1CN(C(=O)[C@@H](N)Cc1ccccc1)CC2
Product: CC(C)CC1(c2ccccc2)OC(=O)C2=C1CN(C(=O)[C@H](Cc1ccccc1)NC(=O)c1ccccc1)CC2

Procedure:
The procedure described for R06039-427 was employed to convert benzoyl chloride (6 mg, 0.041 mmol) to 5-((S)-2-amino-3-phenylpropanoyl)-3-isobutyl-3-phenyl-4,5,6,7-tetrahydrofuro[3,4-c]pyridin-1(3H)-one (16 mg, 0.037 mmol) to provide N-((2S)-1-(3-isobutyl-1-oxo-3-phenyl-6,7-dihydrofuro[3,4-c]pyridin-5 (1H,3H,4H)-yl)-1-oxo-3-phenylpropan-2-yl)benzamide. The desired product was purified by column chromatography (4 g, SiO2, 0 to 100% dichloromethane/diethylether in hexanes) and isolated as a colorless oil (13 mg, 69%): 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.76-0.95 (m, 6H), 1.46-1.92 (m, 4H), 2.06-2.39 (m, 2H), 2.99-3.37 (m, 2H), 3.40-3.62 (m, 1H), 3.82-4.07 (m, 1H), 4.60 (d, J=19.59 Hz, 1H), 5.15-5.30 (m, 1H), 5.31-5.50 (m, 1H), 6.94-7.57 (m, 13H), 7.70-7.85 (m, 2H); MS m/z 523 (M+H)+, 521 (M−H)−.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13](/[CH:15]=[CH:16]/[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][S:25]([CH2:28][CH2:29][CH2:30][CH3:31])(=[O:27])=[O:26])=[C:20]([O:32][CH3:33])[CH:19]=2)[CH:12]=[CH:11][C:10]=1/[CH:34]=[CH:35]/[C:36]([O:38][CH3:39])=[O:37])C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH2:28]([S:25]([O:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][CH2:16][CH2:15][C:13]2[CH:12]=[CH:11][C:10]([CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])=[C:9]([OH:8])[CH:14]=2)=[CH:19][C:20]=1[O:32][CH3:33])(=[O:27])=[O:26])[CH2:29][CH2:30][CH3:31]
Reactant: CCCCS(=O)(=O)Oc1ccc(C/C=C/c2ccc(/C=C/C(=O)OC)c(OCc3ccccc3)c2)cc1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCCCS(=O)(=O)Oc1ccc(CCCc2ccc(CCC(=O)OC)c(O)c2)cc1OC
Yield: 93.8 %

Procedure:
78 mg (10% mass equivalent) of 10% palladium-on-charcoal are added to a solution of 780 mg (1.4 mmol) of methyl(E)-3-(2-benzyloxy-4-{(E)-3-[4-(butane-1-sulfonyloxy)-3-methoxyphenyl]propenyl}phenyl)acrylate in 8 ml of methanol. The reaction mixture is placed under an atmospheric pressure of hydrogen at room temperature for 16 hours and then filtered through Celite and rinsed with dichloromethane. The solvents are evaporated off and the residue is then purified by chromatography on a column of silica eluted with a 60/40 heptane/ethyl acetate mixture. 610 mg (94%) of methyl 3-(4-{3-[4-(butane-1-sulfonyloxy)-3-methoxyphenyl]propyl}-2-hydroxyphenyl)propanoate are obtained in the form of a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[Br:13]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCOCC1>[NH2:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([Br:13])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1N
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1COCCO1
Product: N#Cc1cc(Br)c([N+](=O)[O-])cc1N
Temperature: 60 °C
Reaction time: 6 h
Yield: 36 %

Procedure:
2-Amino-4-nitrobenzonitrile (1.6 g, 9.81 mmol) is presented as an initial charge in 30 mL of dioxane and is mixed at 10° C. with bromine (0.56 mL, 11 mmol). This is followed by stirring at 60° C. for 6 hours. After cooling to room temperature, the batch is added to dilute sodium thiosulphate solution. After extraction of dichloromethane, the combined organic phases are dried over sodium sulphate to leave, after removal of the solvent and chromatographic purification (silica gel, n-hexane/ethyl acetate: 0→100% ethyl acetate), the product in 36% yield (820 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1.N1C=CC=CC=1.[Cl:26][C:27]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:28]=1[S:37](Cl)(=[O:39])=[O:38]>C1COCC1>[Cl:26][C:27]1[CH:32]=[C:31]([C:33]([F:35])([F:34])[F:36])[CH:30]=[CH:29][C:28]=1[S:37]([NH:19][C:4]1[CH:5]=[CH:6][C:7]([S:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=2)=[C:2]([Cl:1])[CH:3]=1)(=[O:39])=[O:38]
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1Cl
Reactant: Nc1ccc(Sc2ccc3ccccc3c2)c(Cl)c1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc(Sc2ccc3ccccc3c2)c(Cl)c1)c1ccc(C(F)(F)F)cc1Cl
Yield: 89.3 %

Procedure:
The title compound was prepared using the method of example 94, starting with 3-chloro-4-(naphthalen-2-ylsulfanyl)-phenylamine (150 mg, 0.53 mmol), pyridine (Aldrich, 0.21 mL, 2.63 mmol) and 2-chloro-4-trifluoromethylbenzenesulfonyl chloride (Maybridge, 162 mg, 0.58 mmol) in THF. 250 mg (90%) of title compound (95) was obtained as a pale yellow solid.
Reaction SMILES: [C:1]([N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[C:18](O)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:10]1=[O:26])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:28]>C1(C)C=CC=CC=1>[C:1]([N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[C:18]([Cl:28])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:10]1=[O:26])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C1C(=C(O)c2ccccc2)c2ccccc2N1C(=O)c1ccccc1
Solvent: Cc1ccccc1
Product: O=C1C(=C(Cl)c2ccccc2)c2ccccc2N1C(=O)c1ccccc1

Procedure:
Prepared analogously to Example 2b from 1-benzoyl-3-(1-hydroxy-1-phenyl-methylidene)-2-indolinone and phosphorus pentachloride in toluene.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]([C:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([OH:22])=[CH:16][C:15]=1[C:23]1[CH:28]=[CH:27][C:26]([C:29]([OH:31])=O)=[CH:25][CH:24]=1)[CH:8]1[CH2:32][C:33]3[C:38]([CH:7]21)=[CH:37][CH:36]=[CH:35][CH:34]=3)(=[NH:3])[NH2:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH2:72]([NH2:76])[CH:73]([CH3:75])[CH3:74]>CN(C=O)C>[CH2:72]([NH:76][C:29]([C:26]1[CH:25]=[CH:24][C:23]([C:15]2[CH:16]=[C:17]([OH:22])[C:18]([O:20][CH3:21])=[CH:19][C:14]=2[CH:9]2[CH:8]3[CH2:32][C:33]4[C:38]([CH:7]3[C:6]3[C:11](=[CH:12][CH:13]=[C:4]([C:1](=[NH:3])[NH2:2])[CH:5]=3)[NH:10]2)=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:28][CH:27]=1)=[O:31])[CH:73]([CH3:75])[CH3:74]
Reactant: CC(C)CN
Reactant: COc1cc(C2Nc3ccc(C(=N)N)cc3C3c4ccccc4CC23)c(-c2ccc(C(=O)O)cc2)cc1O
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: CN(C)C=O
Product: COc1cc(C2Nc3ccc(C(=N)N)cc3C3c4ccccc4CC23)c(-c2ccc(C(=O)NCC(C)C)cc2)cc1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
(0.1 mmol; 50.5 mg) of 2′-(2-Carbamimidoyl-5,6a,7,11b-tetrahydro-6H-indeno[2,1-c]quinolin-6-yl)-5′-hydroxy-4′-methoxy-biphenyl-4-carboxylic acid was dissolved in 4 mL of DMF followed by the addition of HATU (0.3 mmol; 114 mg), N,N-diisoproplyethylamine (0.6 mmol; 0.1 mL) and isobutylamine (0.6 mmol; 0.6 ml). The reaction was stirred at room temperature for 18 hours, filtered and purified by LC/MS prep system to give 2′-(2-Carbamimidoyl-5,6a,7,11b-tetrahydro-6H-indeno[2,1-c]quinolin-6-yl)-5′-hydroxy-4′-methoxy-biphenyl-4-carboxylic acid isobutyl-amide. Mass spectrum: 561 (M+1).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][C:5](=O)[CH:4]([CH2:9][C:10](=O)[C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH2:3]1.[NH2:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1>>[CH3:1][CH:2]1[CH2:7][CH2:6][C:5]2[N:18]([C:19]3[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=3)[C:10]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)=[CH:9][C:4]=2[CH2:3]1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: CC1CCC(=O)C(CC(=O)c2cccnc2)C1
Product: CC1CCc2c(cc(-c3cccnc3)n2-c2ccc(C(=O)O)cc2)C1
Yield: 63 %

Procedure:
Following the general methods as outlined under Intermediate 13, starting from 4-methyl-2-(2-oxo-2-pyridin-3-ylethyl)cyclohexanone and 4-aminobenzoic acid, the title compound was isolated in 63% yield (98% purity by HPLC). MS(ESI+): 333.5; MS(ESI−): 331.4.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([Cl:28])[C:26]=1Cl.CCN(C(C)C)C(C)C>O1CCOCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([CH:14]2[CH2:15][CH2:16][N:17]([C:26]3[C:25]([Cl:28])=[CH:24][N:23]=[CH:22][C:21]=3[Cl:20])[CH2:18][CH2:19]2)(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)C2CCNCC2)cc1
Reactant: Clc1cncc(Cl)c1Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(S(=O)(=O)C2CCN(c3c(Cl)cncc3Cl)CC2)cc1
Yield: 10.4 %

Procedure:
Using the procedure from Example 7A, 4-[(4-tert-butylphenyl)sulfonyl]piperidine (100 mg, 0.36 mmol) was reacted with 3,4,5-trichloropyridine (134 mg, 0.72 mmol), DIEA (0.25 ml, 1.44) and 1,4-dioxane (0.3 ml) at 185° C. to afford the title compound (16 mg), a white solid, in 10% yield.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH3:10])[N:8]([CH2:11][C@H:12]2[CH2:16][CH2:15][CH2:14][O:13]2)/[C:7](=[N:17]/[C:18](=[O:36])[C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:20]=2[O:29][CH2:30][CH2:31][C:32](O)([CH3:34])[CH3:33])/[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CCN(S(F)(F)[F:43])CC>C(Cl)Cl>[C:1]([C:5]1[N:9]([CH3:10])[N:8]([CH2:11][C@H:12]2[CH2:16][CH2:15][CH2:14][O:13]2)/[C:7](=[N:17]/[C:18](=[O:36])[C:19]2[CH:24]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:22]=[CH:21][C:20]=2[O:29][CH2:30][CH2:31][C:32]([F:43])([CH3:33])[CH3:34])/[CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCN(CC)S(F)(F)F
Reactant: Cn1c(C(C)(C)C)c/c(=N\C(=O)c2cc(C(F)(F)F)ccc2OCCC(C)(C)O)n1C[C@H]1CCCO1
Solvent: ClCCl
Product: Cn1c(C(C)(C)C)c/c(=N\C(=O)c2cc(C(F)(F)F)ccc2OCCC(C)(C)F)n1C[C@H]1CCCO1
Temperature: 25 °C
Yield: 22.3 %

Procedure:
The product from Example 43A (215 mg, 0.42 mmol) in CH2Cl2 (10 mL) was treated dropwise with DAST (66 μL, 0.504 mmol) at −78° C. The reaction mixture was allowed to warm up to room temperature for 4 hrs. The mixture was quenched with saturated NaHCO3 and extracted with EtOAc (2×). The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 50% hexanes/EtOAc to 100% EtOAc to 9:1:0.1 EtOAc:MeOH:Et3N) to afford 48 mg (22%) of the title compound. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.45 (d, J=21.48 Hz, 6H) 1.50 (s, 9H) 1.82-1.99 (m, 3H) 2.19-2.37 (m, 3H) 3.67-3.83 (m, 2H) 4.14-4.23 (m, 1H) 4.24 (s, 3H) 4.48 (t, J=7.36 Hz, 2H) 4.80-4.97 (m, 1H) 5.48 (d, J=17.18 Hz, 1H) 6.97 (s, 1H) 7.13 (d, J=8.59 Hz, 1H) 7.74 (dd, J=7.98, 1.84 Hz, 1H) 8.08 (d, J=2.15 Hz, 1H); MS (DCI/NH3) m/z 514 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]2[N:7]([C:14]3[N:15]=[CH:16][C:17]([NH2:20])=[N:18][CH:19]=3)[C:8]([C:10]([F:13])([F:12])[F:11])=[N:9][C:5]=2[CH:4]=1.[F:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:25]=1[C:26](O)=[O:27].C(N=C=NCCCN(C)C)C.CCOC(C)=O>C(Cl)(Cl)Cl>[F:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:25]=1[C:26]([NH:20][C:17]1[CH:16]=[N:15][C:14]([N:7]2[C:6]3[CH:21]=[CH:22][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[N:9]=[C:8]2[C:10]([F:12])([F:13])[F:11])=[CH:19][N:18]=1)=[O:27]
Reactant: O=C(O)c1c(F)cccc1F
Reactant: COc1ccc2c(c1)nc(C(F)(F)F)n2-c1cnc(N)cn1
Agent: CCN=C=NCCCN(C)C
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)nc(C(F)(F)F)n2-c1cnc(NC(=O)c2c(F)cccc2F)cn1
Temperature: 55 °C
Reaction time: 8 h

Procedure:
Into a 50 mL round bottom flask, was placed 5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-ylamine (v) (30 mg, 0.10 mmol). To this was added 2,6-difluorobenzoic acid (30 mg, 0.19 mmol), 1-ethyl-3-[3-dimethylaminopropyl]-carbodiimide (EDC) (100 mg, 0.52 mmol) and N,N-dimethylamino-pyridine (DMAP) (70 mg, 0.57 mmol) followed by CHCl3 (10 mL). The resulting solution was stirred at 55° C. overnight. The reaction progress was monitored by TLC (EtOAc/PE=1:2). After completion, the resultant solution was diluted with 20 mL of CHCl3, washed with 20 mL of H2O and dried over Na2SO4. After removal of the solvent and volatile components under reduced pressure, the residue was purified by eluting through a silica gel column with a 1:5 EtOAc/PE solvent system. This resulted in 20 mg (46%) of 2,6-difluoro-N-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-benzamide (Compound 1) as a white solid.
Reaction SMILES: [CH3:1][N:2]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[C:24]([CH3:32])[CH:23]=2)=[CH:16][CH:15]=1)(=[O:13])=[O:12])[C@H:3]1[CH2:7][CH2:6][CH2:5][C@H:4]1[C:8]([OH:10])=O.[NH2:33][OH:34]>>[OH:34][NH:33][C:8]([C@@H:4]1[CH2:5][CH2:6][CH2:7][C@@H:3]1[N:2]([CH3:1])[S:11]([C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[C:24]([CH3:32])[CH:23]=2)=[CH:18][CH:19]=1)(=[O:13])=[O:12])=[O:10]
Reactant: Cc1cc(COc2ccc(S(=O)(=O)N(C)[C@H]3CCC[C@H]3C(=O)O)cc2)c2ccccc2n1
Reactant: NO
Product: Cc1cc(COc2ccc(S(=O)(=O)N(C)[C@H]3CCC[C@H]3C(=O)NO)cc2)c2ccccc2n1
Yield: 97 %

Procedure:
According to the procedure of Example 10, Step 2, the reaction of 222 mg (0.39 mmol) of cis-2-[methyl({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclopentanecarboxylic acid with hydroxylamine provided 183 mg of cis-N-hydroxy-2-[methyl({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclopentanecarboxamide in 97% yield. MS: 470.1 (M+H)+
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH3:8].[C:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CCOCC>[C:17]1([C:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)([OH:16])[CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH3:8])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: COCCCCBr
Agent: [Mg]
Solvent: CCOCC
Product: COCCCCC(O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of 3.9 g. (0.16 mole) of magnesium turnings in 300 ml. of dry ether was added dropwise 26.7 g. (0.16 mole) of 1-bromo-4-methoxybutane in 80 ml. of ether and the mixture refluxed for four hours. The reaction mixture was cooled and 14.6 g. (0.008 mole) of benzophenone in 100 ml. of dry ether was added dropwise. The mixture was stirred at ambient temperature for 18 hours, cautiously quenched with water and the ether layer separated. The aqueous layer was extracted with ether and the combined ether extract was dried and concentrated to give 1,1-diphenyl-5-methoxy-1-pentanol, m.p. 112°-115° C.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH2:7][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])[NH:5][CH:6]=1.[C:16](O)(=[O:19])[C:17]#[CH:18].N1(C(N2C=CN=C2)=O)C=CN=C1>>[C:8]([C:7]1[CH:18]=[CH:17][C:16](=[O:19])[N:5]2[CH:6]=[C:2]([Br:1])[NH:3][C:4]=12)(=[O:9])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cc1nc(Br)c[nH]1)c1ccccc1
Reactant: C#CC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Product: O=C(c1ccccc1)c1ccc(=O)n2cc(Br)[nH]c12

Procedure:
The compound is prepared as described in example 6 with 96.50 mg (0.36 mmol) of 2-(4-bromo-1H-imidazol-2-yl)-1-phenylethanone (example XXXXIII), 39.84 mg (0.55 mmol) of propiolic acid and 106.24 mg (0.66 mmol) of 1-(1H-imidazol-1-ylcarbonyl)-1H-imidazole.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3]([NH:5][C:6]1[S:7][C:8](=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[C:9](=[O:11])[N:10]=1)=[NH:4].[NH2:27][CH2:28][C@H:29]([OH:44])[CH2:30][O:31][C:32]1[CH:41]=[CH:40][C:39]([OH:42])=[C:38]2[C:33]=1[CH2:34][CH2:35][C:36](=[O:43])[NH:37]2>>[OH:44][C@H:29]([CH2:30][O:31][C:32]1[CH:41]=[CH:40][C:39]([OH:42])=[C:38]2[C:33]=1[CH2:34][CH2:35][C:36](=[O:43])[NH:37]2)[CH2:28][NH:27][CH:22]1[CH2:23][CH2:24][N:19]([C:16]2[CH:15]=[CH:14][C:13]([CH:12]=[C:8]3[S:7][C:6]([NH:5][C:3](=[NH:4])[N:2]([CH3:26])[CH3:1])=[N:10][C:9]3=[O:11])=[CH:18][CH:17]=2)[CH2:20][CH2:21]1
Reactant: CN(C)C(=N)NC1=NC(=O)C(=Cc2ccc(N3CCC(=O)CC3)cc2)S1
Reactant: NC[C@H](O)COc1ccc(O)c2c1CCC(=O)N2
Product: CN(C)C(=N)NC1=NC(=O)C(=Cc2ccc(N3CCC(NC[C@H](O)COc4ccc(O)c5c4CCC(=O)N5)CC3)cc2)S1

Procedure:
The title compound was prepared from N,N-dimethyl-N′-{4-oxo-5-[4-(4-oxo-piperidin-1-yl)-benzylidene]-4,5-dihydro-thiazol-2-yl}-guanidine(which was obtained in Intermediate 23) and 5-((2S)-3-amino-2-hydroxy-propoxy)-8-hydroxy-3,4-dihydro-1 H-quinolin-2-one (which was obtained in Intermediate 12) according to the procedure of Example 1 as a yellowish solid; mp >140° C. (dec.); 1H NMR (300 MHz, DMSO-d6) δ 1.20-1.40 (m, 2 H), 1.80-1.95 (m, 6 H), 2.40 (t, J=7.9 Hz, 2 H), 2.55-3.20 (m, 12 H), 3.70-3.95 (m, 6 H), 6.44 (d, J=8.7 Hz, 1 H), 6.60 (d, J=8.7 Hz, 1 H), 7.00 (d, J=8.9 Hz, 2 H), 7.41 (d, J=8.9 Hz, 2 H), 7.47 (s, 1 H), 8.82 (brs, 1 H); MS (ES) m/z: 304.6 ((M+2 H)2+, 100%); 608.1 (MH+, 10%); HRMS Calcd. for C30H38N7O5S (MH+): 608.2655. Found: 608.2655.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:8](Cl)=[O:9])=[N:6][CH:7]=1.C(N(CC)CC)C.[NH2:18][C@@H:19]([CH3:35])[CH2:20][N:21]1[CH:25]=[CH:24][C:23]([C:26]2[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[C:28]([Cl:34])[CH:27]=2)=[N:22]1>C1COCC1>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([NH:18][C@@H:19]([CH3:35])[CH2:20][N:21]2[CH:25]=[CH:24][C:23]([C:26]3[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[C:28]([Cl:34])[CH:27]=3)=[N:22]2)=[O:9])=[N:6][CH:7]=1
Reactant: O=C(Cl)c1cnc(Cl)cn1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cnc(Cl)cn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 68.4 %

Procedure:
5-Chloropyrazine-2-carbonyl chloride (3.28 mmol, 580 mg) was dissolved in dry THF (40 ml). Triethylamine (9.83 mmol, 995 mg) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (3.28 mmol, 854 mg) were added and the resulting mixture was stirred for one day at RT. The crude product was purified by recrystallization from DCM. 900 mg of the title compound was obtained. 1H-NMR (400 MHz, CDCl3): δ 1.25 (d, 3H), 4.29 (dd, 1H), 4.47 (dd, 1H), 4.59-4.71 (m, 1H), 6.66 (d, 1H), 7.51 (d, 1H), 7.68-7.73 (m, 1H), 7.75-7.80 (m, 1H), 8.12 (d, 1H), 8.64 (d, 1H), 8.77 (d, 1H), 9.17 (d, 1H).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:4]=[C:5]([B:9]([OH:11])[OH:10])[CH:6]=[CH:7][CH:8]=1.O[C:13]([C:16](O)([CH3:18])[CH3:17])([CH3:15])[CH3:14].S([O-])([O-])(=O)=O.[Mg+2]>C(OCC)(=O)C>[Br:1][CH2:2][C:3]1[CH:4]=[C:5]([B:9]2[O:11][C:16]([CH3:18])([CH3:17])[C:13]([CH3:15])([CH3:14])[O:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(O)C(C)(C)O
Reactant: OB(O)c1cccc(CBr)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCOC(C)=O
Product: CC1(C)OB(c2cccc(CBr)c2)OC1(C)C
Reaction time: 8 h
Yield: 102.5 %

Procedure:
To a solution of 3-(bromomethyl)phenyl boronic acid (3.13 g) in ethyl acetate (45 ml) were sequentially added pinacol (1.72 g) and anhydrous magnesium sulfate (15 g) at room temperature, and the mixture was stirred for 8 hours. The insoluble substance was filtered off, and the filtrate was concentrated under reduced pressure to give the titled compound (4.43 g).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)[S:6][CH:7]=1.[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([O-:27])=[O:26])=[CH:21][CH:20]=1.[Na+]>CN(C=O)C>[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH2:2][C:3]2[N:4]=[C:5]([C:8]3[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=3)[S:6][CH:7]=2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: Cc1ccc(S(=O)[O-])cc1
Reactant: COC(=O)c1ccc(-c2nc(CCl)cs2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2nc(CS(=O)(=O)c3ccc(C)cc3)cs2)cc1
Yield: 76.7 %

Procedure:
Reaction of chloride 51 (402 mg, 1.5 mmol) and sodium 4-methylbenzenesulfinate (294 mg, 1.7 mmol) in dry DMF (10 mL) gave benzoate 52 (446 mg, 77%) as a white powder: mp (EtOAc) 160-161° C.; 1H NMR (CDCl3) δ 8.05 (ddd, J=8.6, 1.9, 1.7 Hz, 2H, H-2, H-6), 7.77 (ddd, J=8.6, 1.9, 1.7 Hz, 2H, H-3, H-5), 7.64 (ddd, J=8.3, 1.9, 1.7 Hz, 2H, H-2″, H-6″), 7.42 (s, 1H, H-5′), 7.27 (br d, J=8.3 Hz, 2H, H-3″, H-5″), 4.60 (s, 2H, CH2SO2), 3.94 (s, 3H, OCH3), 2.41 (s, 3H, CH3); MS m/z 388.6 (MH+, 100%). Anal. calcd for C19H17NO4S2: C, 58.90; H, 4.42; N, 3.61. Found: C, 58.83; H, 4.33; N, 3.55%.
Reaction SMILES: [F:1][CH:2]([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[C:12]3[CH2:20][CH2:19][NH:18][CH2:17][C:13]=3[N:14]=[CH:15][N:16]=2)=[CH:6][CH:5]=1.Cl[C:23]1[C:28]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][CH:26]=[CH:25][N:24]=1.C(N(CC)C(C)C)(C)C>>[F:21][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[C:12]3[CH2:20][CH2:19][N:18]([C:23]4[C:28]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][CH:26]=[CH:25][N:24]=4)[CH2:17][C:13]=3[N:14]=[CH:15][N:16]=2)=[CH:6][CH:5]=1
Reactant: FC(F)Oc1ccc(Nc2ncnc3c2CCNC3)cc1
Reactant: CS(=O)(=O)c1cccnc1Cl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1cccnc1N1CCc2c(ncnc2Nc2ccc(OC(F)F)cc2)C1
Yield: 63.3 %

Procedure:
The title compound was prepared according to the procedure given for Example 9 using N-(4-(difluoromethoxy)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine (0.088 g, 0.30 mmol), 2-chloro-3-(methylsulfonyl)pyridine (Ponticello et al, J. Org. Chem., 44(17), 1979) (0.115 mg, 0.60 mmol) and N,N-diisopropylethylamine (0.079 mL, 0.45 mmol) to obtain 0.085 g of title compound as a light yellow solid.
Reaction SMILES: N.[NH2:2][C:3]1([C:8]([NH2:10])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4]1.[CH:11](=O)[CH2:12][CH2:13][CH2:14][CH3:15].CC(CC(C)=O)C>O>[CH2:12]([CH:11]1[NH:10][C:8](=[O:9])[C:3]2([CH2:7][CH2:6][CH2:5][CH2:4]2)[NH:2]1)[CH2:13][CH2:14][CH3:15]
Reactant: NC(=O)C1(N)CCCC1
Reactant: CCCCC=O
Agent: N
Solvent: O
Solvent: CC(=O)CC(C)C
Product: CCCCC1NC(=O)C2(CCCC2)N1
Temperature: 70 °C
Reaction time: 7 h

Procedure:
Ammonia solution (20%; 20 g, 0.30 mol.) is added to a solution of 126 g of 1-aminocyclopentanecarboxamide (>98%, 0.98 mol.) in 150 g of water. 86 g of valeraldehyde (0.99 mol.) are then added at 15° C., during which the temperature rises to 32° C. The reaction mixture is heated to 70° C. and stirred for 7 hours at that temperature. 350 ml of MIBK are added to the emulsion, and the mixture is cooled, with stirring, and the organic phase is separated off. The extract is extensively concentrated by evaporation (200 g), and 200 g of n-hexane are added, and the crystals are filtered off. After drying there remain 125 g of 2-butyl-1,3-diaza-spiro [4.4]nonan4-one (HPLC: 98.6%).