Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([S:8]([NH2:11])(=[O:10])=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].[Cl:14][C:15]1[CH:20]=[C:19](Cl)[N:18]=[C:17]([S:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:25]=2[F:31])[N:16]=1>CN(C=O)C>[Cl:14][C:15]1[N:16]=[C:17]([S:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:25]=2[F:31])[N:18]=[C:19]([NH:11][S:8]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)(=[O:10])=[O:9])[CH:20]=1
Reactant: CN1CCN(S(N)(=O)=O)CC1
Reactant: Fc1c(Cl)cccc1CSc1nc(Cl)cc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCN(S(=O)(=O)Nc2cc(Cl)nc(SCc3cccc(Cl)c3F)n2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of the subtitle product of step i) (2.0 g) in dry DMF (20 ml) at 0° C. was added 60% sodium hydride (0.9 g) portionwise over 5 min. After further stirring at 0° C. for 30 min the subtitle product from step iii) (3.6 g) in DMF (10 ml) was added and the whole allowed to stir at room temperature for 24 h. The reaction mixture was carefully quenched with aqueous 2M hydrochloric acid until pH 7.4. The solvent was evaporated to dryness and the residue dissolved in a mixture of methanol/EtOAc and applied to an SCX column followed by further elution with EtOAc. This was then followed by elution with EtOAc/triethylamine mixtures and these fractions evaporated to dryness. The subtitle compound was obtained pure by trituration with Et2O and filtration, leaving a white solid. Yield: 1.5 g.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][N:28]=1>CN(C)C=O.C(OCC)(=O)C>[CH3:8][C:7]1[CH:6]=[CH:5][C:4]([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:3][C:2]=1[O:1][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][N:28]=1
Reactant: Cc1ccc(NC(=O)OCc2ccccc2)cc1O
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(NC(=O)OCc2ccccc2)cc1Oc1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.4 %

Procedure:
To a solution of benzyl (3-hydroxy-4-methylphenyl)carbamate (83.1 g, 321 mmol) in N,N-dimethylformamide (300 mL) were added cesium carbonate (157 g, 482 mmol) and 2-chloro-5-nitropyridine (50.9 g, 321 mmol), and the mixture was stirred at room temperature for 4 hr. The reaction mixture was diluted with ethyl acetate (500 mL) and washed with water (1 L), and the obtained aqueous layer was extracted with ethyl acetate (2×200 mL). The combined organic layer was washed with saturated brine (100 mL) and purified by basic silica gel (ethyl acetate). The obtained solution was concentrated under reduced pressure. The obtained residue was washed with ethyl acetate/hexane (1:1) to give the title compound (91.8 g, 75%) as a pale-yellow solid.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[N:16]([CH:17]([CH3:19])[CH3:18])[C:15]2[CH:20]=[CH:21][CH:22]=[CH:23][C:14]=2[N:13]=1)[CH2:9][C:10]#[CH:11]>>[CH:17]([N:16]1[C:15]2[CH:20]=[CH:21][CH:22]=[CH:23][C:14]=2[N:13]=[C:12]1[CH2:8][CH2:9][C:10]#[C:11][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)([CH3:19])[CH3:18]
Reactant: C#CCCc1nc2ccccc2n1C(C)C
Reactant: Ic1ccccn1
Product: CC(C)n1c(CCC#Cc2ccccn2)nc2ccccc21
Yield: 41.6 %

Procedure:
The title compound was prepared in accordance with the general method of Example 192(A), from 2-iodopyridine (81 mg, 0.39 mmol) and 2-(but-3-ynyl)-1-isopropyl-1H-benzo[d]imidazole (84 mg, 0.39 mmol). The crude residue was purified over silicagel chromatography (prepacked 5 g silicagel column, DCM/MeOH: from 100/0 to 96/4 as eluent) to afford 47 mg of 1-isopropyl-2-(4-(pyridin-2-yl)but-3-ynyl)-1H-benzo[d]imidazole as a light brown oil (Yield: 41%).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH2:16][CH3:17])[C:8]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=4)=[N:21][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.C[N:40](C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[Cl-].[NH4+]>CN(C)C=O.C(OCC)(=O)C.O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH2:16][CH3:17])[C:8]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH2:40])=[O:28])=[CH:25][CH:24]=4)=[N:21][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Reactant: CCN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3)ncc21
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(N)=O)cc3)ncc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 91 %

Procedure:
To a mixture of 0.053 g (0.12 mmole) of 4-(9-cyclopentyl-5-ethyl-7,7-difluoro-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-benzoic acid (I-138) and 0.06 g (0.15 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate in 2 mL of dimethylformamide was added 0.03 mL (0.186 mmole) of diisopropylethylamine. After stirring at room temperature for 30 minutes 0.01 g (0.186 mmole) of ammonium chloride was added. The mixture was stirred at room temperature for 18 hours and then diluted with ethyl acetate and water. The aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed with water, brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with hexanes-ethyl acetate (30:70) to give 0.047 g of 4-(9-cyclopentyl-5-ethyl-7,7-difluoro-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-benzamide (I-139).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[C:12]([C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][CH:16]=1)(=[O:14])[CH3:13]>>[C:12]([C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][CH:6]=[CH:5]3)=[O:23])=[CH:17][CH:16]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)c1ccc(N=C=O)cc1
Reactant: Nc1ccc2ncccc2c1
Product: CC(=O)c1ccc(NC(=O)Nc2ccc3ncccc3c2)cc1

Procedure:
Prepared from 6-aminoquinoline and 4-acetylphenyl isocyanate. m/z (ES+) 306 (M+H)+.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.Cl.[C:17]1([CH:23]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35]([F:38])([F:37])[F:36])[CH:29]=2)[C:24]([OH:26])=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1C=CC2N(O)N=NC=2C=1.[N:49]12[CH2:56][CH2:55][CH:52]([CH2:53][CH2:54]1)[C@@H:51](O)[CH2:50]2>C1COCC1>[N:49]12[CH2:56][CH2:55][CH:52]([CH2:53][CH2:54]1)[C@@H:51]([O:25][C:24](=[O:26])[CH:23]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35]([F:36])([F:37])[F:38])[CH:29]=1)[CH2:50]2
Reactant: O[C@H]1CN2CCC1CC2
Reactant: O=C(O)C(Nc1cccc(OC(F)(F)F)c1)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(O[C@H]1CN2CCC1CC2)C(Nc1cccc(OC(F)(F)F)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86 %

Procedure:
PS-DCC (920 mg, 1.15 mmol, loading: 1.25 mmol/g) is suspended in THF (15 mL). Phenyl-(3-trifluoromethoxy-phenylamino)-acetic acid hydrochloride (I40) (200 mg, 0.57 mmol) and HOBT (176 mg, 1.15 mmol) are added, followed by (R)-quinuclidin-3-ol (219 mg, 1.73 mmol) and the mixture is shaken for 16 hours at RT. PS-DCC is filtered off and the filtrate is evaporated. The resulting residue is dissolved in EtOAc and washed with water, sat. NaHCO3, water and brine. The organic phase is dried over Na2SO4, filtered and evaporated to give the title compound as a colorless oil (206 mg, 85% yield, mixture of diastereoisomers).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C:11]1[C:12]([F:19])=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH:14]=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.[CH:27]([C:30]1[S:31][CH:32]=[C:33]([C:35]([N:37]2[CH2:42][C:41]3([CH2:47][CH2:46][NH:45][CH2:44][CH2:43]3)[O:40][CH2:39][CH2:38]2)=[O:36])[N:34]=1)([CH3:29])[CH3:28].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>CN1CCCC1=O.C(O)(=O)C.O>[Si:1]([O:8][CH2:9][CH2:10][C:11]1[C:12]([F:19])=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14][N:45]1[CH2:46][CH2:47][C:41]2([O:40][CH2:39][CH2:38][N:37]([C:35]([C:33]3[N:34]=[C:30]([CH:27]([CH3:28])[CH3:29])[S:31][CH:32]=3)=[O:36])[CH2:42]2)[CH2:43][CH2:44]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCc1cccc(C=O)c1F
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCO[Si](C)(C)C(C)(C)C)c4F)CC3)C2)cs1
Reaction time: 0.5 h

Procedure:
3-(2-(tert-Butyldimethylsilyloxy)ethyl)-2-fluorobenzaldehyde [Aromatic Intermediate 5] (4.07 g) was added to (2-isopropylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate [Example 1, step b] (6.10 g) in a mixture of N-methyl-2-pyrrolidinone (50 mL) and acetic acid (0.83 mL) and stirred for 30 min. Sodium triacetoxyborohydride (4.58 g) was then added and the mixture stirred overnight. The reaction mixture was poured into water (100 mL), the pH was adjusted to 8 using saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic phases were washed with water (3×100 mL) and brine (100 mL), dried over sodium sulphate, filtered and evaporated. The residue was purified by flash silica chromatography using 77.5:17.5:5 isohexane:ethyl acetate:triethylamine as solvent to give the subtitled compound as a clear oil. Yield 5.35 g.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[N:12]=[C:13]1[NH:17][CH2:16][C:15]2([CH2:21][CH2:20][CH2:19][CH2:18]2)[S:14]1)[CH3:2].[CH:22]1(Br)[CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH:22]1([N:17]2[CH2:16][C:15]3([CH2:21][CH2:20][CH2:19][CH2:18]3)[S:14][C:13]2=[N:12][C:4]2[CH:5]=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:3]=2[CH2:1][CH3:2])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CCc1cc([N+](=O)[O-])ccc1N=C1NCC2(CCCC2)S1
Reactant: BrC1CCCC1
Product: CCc1cc([N+](=O)[O-])ccc1N=C1SC2(CCCC2)CN1C1CCCC1

Procedure:
2- Ethylaniline was converted to 2-ethylacetanilide according to Method A2a, Step 1. The acetanilide was converted to 2-ethyl-4-nitroacetanilide according to Method A2a, Step 2. The acetanilide was deprotected according to Method A2a, Step 3 to give 2-ethyl-4-nitroaniline. The aniline was converted to 2-ethyl-4-nitrophenyl isothiocyanate according to Method A2a, Step 3. 1-Amino-1-(hydroxymethyl)cyclopentane was synthesized as described in Method B1c. The 2-hydroxyethylamine was reacted with with SOCl2 according to Method B7a to give 1-amino-1-(chloromethyl)cyclopentane HCl salt. The 2-chloroethylamine was reacted with 2-ethyl-4-nitrophenyl isothiocyanate according to Method C1a to give 2-(2-ethyl-4-nitrophenylimino)-1-thia-3-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to afford 3-cyclopentyl-2-(2-ethyl-4-nitrophenylimino)-1-thia-3-azaspiro[4.4]nonane.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:17]=[C:16]([NH:18][CH2:19][CH2:20][CH3:21])[C:12]([C:13]([OH:15])=O)=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:22][C:23]1[CH:24]=[C:25]([NH:29][C:30](=[O:42])[C@@H:31]([N:33]([CH3:41])[C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH3:32])[CH:26]=[CH:27][CH:28]=1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.C(=O)([O-])O.[Na+]>CN(C)C=O.C(N(CC)C(C)C)(C)C>[F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:17]=[C:16]([NH:18][CH2:19][CH2:20][CH3:21])[C:12]([C:13]([NH:22][C:23]3[CH:24]=[C:25]([NH:29][C:30](=[O:42])[C@@H:31]([N:33]([CH3:41])[C:34](=[O:40])[O:35][C:36]([CH3:37])([CH3:39])[CH3:38])[CH3:32])[CH:26]=[CH:27][CH:28]=3)=[O:15])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCCNc1cc(Nc2cccc(F)c2)ncc1C(=O)O
Reactant: C[C@@H](C(=O)Nc1cccc(N)c1)N(C)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCCNc1cc(Nc2cccc(F)c2)ncc1C(=O)Nc1cccc(NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)c1
Temperature: 40 °C
Reaction time: 15 h
Yield: 72.4 %

Procedure:
To a solution of 6-((3-fluorophenyl)amino)-4-(propylamino)nicotinic acid (S16, 87 mg), (S)-tert-butyl (1-((3-aminophenyl)amino)-1-oxopropan-2-yl)(methyl)carbamate (B9, 115 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (115 mg) and 1-hydroxybenzotriazole monohydrate (81 mg) in N,N-dimethylformamide (2 mL), N,N-diisopropylethylamine (157 μL) was added at room temperature, and the mixture was stirred at 40° C. for 15 hours. The reaction mixture was cooled to room temperature, and then saturated aqueous sodium hydrogencarbonate was added to the reaction mixture. The solid matter was taken by filtration, washed with water, and then purified by silica gel column chromatography (eluent, 75 to 35% hexane in ethyl acetate) to obtain (S)-tert-butyl (1-((3-(6-((3-fluorophenyl)amino)-4-(propylamino)nicotinamido)phenyl)amino)-1-oxopropan-2-yl)(methyl)carbamate (S17, 123 mg).
Reaction SMILES: C([O:9][C@@H:10]1[C@H:14]([O:15]C(=O)C2C=CC=CC=2)[C@@H:13]([C:24]([NH:26][CH2:27][CH3:28])=[O:25])[O:12][C@H:11]1[N:29]1[CH:37]=[N:36][C:35]2[C:30]1=[N:31][C:32]([C:55]#[N:56])=[N:33][C:34]=2[NH:38][CH2:39][CH:40]([C:48]1[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][CH:49]=1)[C:41]1[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=1)(=O)C1C=CC=CC=1.N.[CH:58]([N:61]([CH:72]([CH3:74])[CH3:73])[CH2:62][CH2:63][NH:64][C:65](N1C=CN=C1)=[O:66])([CH3:60])[CH3:59].N1C=CN=C1>C(O)C.[Pd].ClCCl.C(O)(C)C>[Cl:47][C:44]1[CH:43]=[CH:42][C:41]([CH:40]([C:48]2[CH:49]=[CH:50][C:51]([Cl:54])=[CH:52][CH:53]=2)[CH2:39][NH:38][C:34]2[N:33]=[C:32]([CH2:55][NH:56][C:65]([NH:64][CH2:63][CH2:62][N:61]([CH:72]([CH3:74])[CH3:73])[CH:58]([CH3:59])[CH3:60])=[O:66])[N:31]=[C:30]3[C:35]=2[N:36]=[CH:37][N:29]3[C@@H:11]2[O:12][C@H:13]([C:24]([NH:26][CH2:27][CH3:28])=[O:25])[C@@H:14]([OH:15])[C@H:10]2[OH:9])=[CH:46][CH:45]=1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccc(Cl)cc4)c4ccc(Cl)cc4)nc(C#N)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Reactant: CC(C)N(CCNC(=O)n1ccnc1)C(C)C
Agent: [Pd]
Agent: N
Agent: c1c[nH]cn1
Solvent: CCO
Solvent: CC(C)O
Solvent: ClCCl
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccc(Cl)cc4)c4ccc(Cl)cc4)nc(CNC(=O)NCCN(C(C)C)C(C)C)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 33.4 %

Procedure:
(2R,3R,4S,5S)-4-(Benzoyloxy)-2-(6-{[2,2-bis(4-chlorophenyl)ethyl]amino}-2-cyano-9H-purin-9-yl)-5-[(ethylamino)carbonyl]tetrahydro-3-furanyl benzoate (220 mg, 0.28 mmol) (Preparation 68) was added to a saturated solution of ammonia in ethanol (15 ml). 10% Palladium on carbon (40 mg) was added and the suspension was stirred under an atmosphere of hydrogen gas (413.7 kPa, 60 psi) at room temperature for 16 hours. The reaction temperature was then stirred at 60° C. under an atmosphere of hydrogen gas (413.7 kPa, 60 psi) for a further 48 hours. The reaction mixture was filtered through Arbocel (Trade Mark) and the solvent was removed under reduced pressure. The crude residue was dissolved in toluene (8 ml) and isopropyl alcohol (2 ml) and N-[2-(diisopropylamino)ethyl]-1H-imidazole-1-carboxamide (50 mg, 0.21 mmol) (Preparation 27) were added. The solution was heated under reflux for 3 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel eluting with dichloromethane methanol:0.88 concentrated aqueous ammonia (90:10:2 by volume). The solvent was removed under reduced pressure give a product that was contaminated with imidazole. The product was dissolved in dichloromethane (60 ml) and the resulting solution was washed three times with water (10 ml) and dried over anhydrous magnesium sulphate. The solvent was removed under reduced pressure to give the title compound (53 mg) as a foam.
Reaction SMILES: [C:1](OC(N1CC[C@H](NC2C=CC(N)=CN=2)C1)=O)(C)(C)C.[CH3:21][O:22][C:23]([C@@H:25]1[CH2:29][CH2:28][C@H:27]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][N:32]=2)[CH2:26]1)=[O:24].COC([C@@H]1CC[C@H](NC2C=CC([N+]([O-])=O)=CN=2)C1)=O>>[CH2:21]([O:22][C:23]([C@@H:25]1[CH2:29][CH2:28][C@H:27]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][N:32]=2)[CH2:26]1)=[O:24])[CH3:1]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2ccc(N)cn2)C1
Reactant: COC(=O)[C@@H]1CC[C@H](Nc2ccc(N)cn2)C1
Agent: COC(=O)[C@@H]1CC[C@H](Nc2ccc([N+](=O)[O-])cn2)C1
Product: CCOC(=O)[C@@H]1CC[C@H](Nc2ccc(N)cn2)C1

Procedure:
With a method similar to that used for the preparation of (S)-3-(5-amino-pyridin-2-ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester above, (1R,3S)-3-(5-amino-pyridin-2-ylamino)-cyclopentanecarboxylic acid methyl ester was prepared by the hydrogenation of (1R,3S)-3-(5-nitro-pyridin-2-ylamino)-cyclopentanecarboxylic acid methyl ester. This material was directly used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:3]=1[C:4](=[O:26])[C:5]([C:21]([O:23]CC)=[O:22])=[CH:6][N:7]2[CH2:13][C:14]1[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=1.N1C2C=CC=CC=2NC=1.O[C:37]1[CH:38]=[CH:39][CH:40]=[C:41]2[C:46]=1[N:45]=[CH:44][CH:43]=C2.C(=O)([O-])[O-].[Cs+].[Cs+].[Al].Cl>CS(C)=O.[OH-].[Li+].[Cu]I>[F:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:3]=1[C:4](=[O:26])[C:5]([C:21]([OH:23])=[O:22])=[CH:6][N:7]2[CH2:13][C:14]1[CH:15]=[CH:16][C:17]([N:45]2[C:46]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:43]=[CH:44]2)=[CH:18][CH:19]=1
Reactant: CCOC(=O)c1cn(Cc2ccc(I)cc2)c2c(F)ccc(F)c2c1=O
Reactant: Oc1cccc2cccnc12
Agent: [Cu]I
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: O=C(O)c1cn(Cc2ccc(-n3ccc4ccccc43)cc2)c2c(F)ccc(F)c2c1=O
Temperature: 95 °C
Reaction time: 10 h

Procedure:
To a solution of ethyl 5,8-difluoro-1-(4-iodobenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (0.200 g, 0.426 mmol) and benzimidazole (0.252 g, 2.13 mmol) in 3 mL of dimethylsulfoxide under nitrogen was added 8-hydroxyquinoline (0.013 g, 0.085 mmol), 1 N cesium carbonate (0.852 mL, 0.852 mmol), and copper(I)iodide (0.041 g, 0.21 mmol). The reaction vessel was covered with aluminum foil and heated to 95° C. for 24 hours. The reaction mixture was cooled to room temperature, and saturated aqueous lithium hydroxide (20 drops) was added. After 10 hours, 6 N HCl was added to pH ˜4. The reaction mixture was filtered and purified via reverse phase HPLC to provide the title compound which gave a proton NMR consistent with theory and a mass ion (ES+) of 432.1 for M+H+. 1H NMR (400 MHz, d6-DMSO) δ 9.21 (s, 1H), 7.84-7.70 (m, 2H), 7.67 (d, J=8.2 Hz, 2H), 7.62 (bs, 1H), 7.43 (m, 3H), 7.32-7.26 (m, 3H), 5.99 (d, J=3.5 Hz, 2H).
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[C:10]1([CH2:16][CH2:17][CH2:18]O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>ClCCl>[F:7][CH2:18][CH2:17][CH2:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: OCCCc1ccccc1
Solvent: ClCCl
Product: FCCCc1ccccc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 60.8 %

Procedure:
15.6 g of diethylaminosulfurtrifluoride (DAST, 96.91 mmol) were dissolved in 18 ml of dichloromethane. At 0-5° C., 12 g of 3-phenyl-1-propanol (88.1 mmol) dissolved in 30 ml of dichloromethane, were added dropwise. The reaction mixture was stirred for 18 h, and, after addition of 30 ml of dichloromethane, poured onto 100 ml of ice water. The organic layer was separated, dried over magnesium sulfate, filtered, and the solvent evaporated. The crude product was purified by distillation at a bath temperature of 106° C. at 20 mm to yield 7.4 g of the title compound.
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[NH2:16][C@@H:17]([C:33]1[CH:38]=[CH:37][C:36]([F:39])=[C:35]([C:40]([F:43])([F:42])[F:41])[CH:34]=1)[CH2:18][N:19]([CH3:32])S(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O>>[F:39][C:36]1[CH:37]=[CH:38][C:33]([C@H:17]([NH:16][C:2]2[C:3]3[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:18][NH:19][CH3:32])=[CH:34][C:35]=1[C:40]([F:41])([F:42])[F:43]
Reactant: CN(C[C@@H](N)c1ccc(F)c(C(F)(F)F)c1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Agent: Cl
Product: CNC[C@@H](Nc1ncnc2c(C(N)=O)ccnc12)c1ccc(F)c(C(F)(F)F)c1

Procedure:
Compound 49 was prepared following general synthesis scheme 7 wherein 4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with N—[(S)-2-Amino-2-(4-fluoro-3-trifluoromethyl-phenyl)-ethyl]-N-methyl-4-nitro-benzenesulfonamide hydrochloride to give the title compound as a white solid. LC/MS [409 (M+H)]; 1H NMR (400 MHz, Acetonitrile-d3) δ 10.30 (s, 1H), 8.94 (d, 1H), 8.47 (d, 3H), 7.72 (dd, 2H), 7.28 (t, 1H), 6.59 (s, 1H), 5.41 (d, 1H), 3.13 (dd, 1H), 3.03 (dd, 1H), 2.38 (s, 3H).
Reaction SMILES: C([O:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17]CC2C=CC=CC=2)[C:10]=1[CH:11]=[O:12])C1C=CC=CC=1.B(Br)(Br)Br.O>C(Cl)Cl>[OH:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[C:10]=1[CH:11]=[O:12]
Reactant: O=Cc1c(OCc2ccccc2)cccc1OCc1ccccc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: O=Cc1c(O)cccc1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2,6-bis-benzyloxybenzaldehyde (1.9 g, 6 mmol) in methylene chloride (15 mL) is added BBr3 (18 mL, 18 mmol, 1M in methylene chloride) and the mixture is stirred at RT for 18 h. Water is added to the mixture and the methylene chloride is removed under reduced pressure. The aqueous is extracted with EtOAc and the organic phase is washed with water and brine then is dried over sodium sulfate. The solvent is removed under reduced pressure and the residue is purified by flash chromatography using hexane/EtOAc (5:1) as eluent to give the title compound as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:39]=[CH:40][CH:41]=1)[CH2:6][N:7]([CH:18]1[CH2:23][CH2:22][N:21]([CH:24]([CH3:38])[CH2:25][CH2:26][NH:27][C:28]([C:30]2[C:31]([CH3:37])=[N:32][CH:33]=[N:34][C:35]=2[CH3:36])=[O:29])[CH2:20][CH2:19]1)[C:8]1[CH:13]=[CH:12][C:11]([O:14]C(=O)C)=[CH:10][CH:9]=1)#[N:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:49][C:50]([O:52][CH3:53])=[O:51]>CN(C=O)C>[CH3:53][O:52][C:50](=[O:51])[CH2:49][O:14][C:11]1[CH:10]=[CH:9][C:8]([N:7]([CH2:6][C:5]2[CH:39]=[CH:40][CH:41]=[C:3]([C:1]#[N:2])[CH:4]=2)[CH:18]2[CH2:23][CH2:22][N:21]([CH:24]([CH3:38])[CH2:25][CH2:26][NH:27][C:28]([C:30]3[C:31]([CH3:37])=[N:32][CH:33]=[N:34][C:35]=3[CH3:36])=[O:29])[CH2:20][CH2:19]2)=[CH:13][CH:12]=1
Reactant: CC(=O)Oc1ccc(N(Cc2cccc(C#N)c2)C2CCN(C(C)CCNC(=O)c3c(C)ncnc3C)CC2)cc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(N(Cc2cccc(C#N)c2)C2CCN(C(C)CCNC(=O)c3c(C)ncnc3C)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.6 %

Procedure:
To a solution of COMPOUND 138 (105 mg, 0.205 mmol) in DMF (1 mL) were added K2CO3 (87 mg, 0.63 mmol) followed by methyl bromoacetate (40 μL, 0.42 mmol) and the mixture was stirred at room temperature overnight to afford COMPOUND 148 as a tan solid (81 mg, 66%) following work-up and purification. 1H NMR (CDCl3) δ 0.86-1.03 (m, 5H), 1.52-1.60 (m, 1H), 1.74-1.78 (m, 3H), 2.14 (t, 1H, J=11.4 Hz), 2.51 (s, 6H), 2.51-2.59 (m, 1H), 2.72-2.88 (m, 3H), 3.29-3.48 (m, 2H), 3.78-3.83 (m, 6H), 4.53 (s, 2H), 6.53 (d, 2H, J=8.4 Hz), 6.75 (d, 2H, J=8.1 Hz), 7.40-7.44 (m, 1H), 7.49-7.54 (m, 3H), 8.71 (br s, 1H), 8.84 (s, 1H). 13C NMR (CDCl3) δ 11.37, 19.90, 27.17, 28.32, 28.69, 37.93, 41.60, 46.92, 49.93, 50.15, 55.37, 58.15, 64.12, 110.38, 113.84, 114.32, 116.98, 127.17, 128.17, 128.50, 128.83, 129.20, 139.97, 141.27, 148.72, 155.46, 161.02, 164.27, 167.71. ES-MS m/z 585 (M+H). Anal. Calcd. for C33H40N6O4.0.7H2O: C, 66.36; H, 6.99; N, 14.07. Found. C, 66.32; H, 6.83; N, 13.71.