Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH:11]1([CH:16]([CH2:19][CH:20]=[CH2:21])[CH2:17][OH:18])[CH2:15][CH2:14][CH2:13][CH2:12]1.C(N(CC)CC)C.Cl>ClCCl>[CH:11]1([CH:16]([CH2:19][CH:20]=[CH2:21])[CH:17]=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: C=CCC(CO)C1CCCC1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: C=CCC(C=O)C1CCCC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Dimethyl sulfoxide (4.82 mL, 67.9 mmol) was added dropwise over 15 minutes to a dichloromethane (75 mL) solution of oxalic acid chloride (4.47 g, 35.2 mmol) cooled to −78° C., and the mixture was then stirred at −78° C. for 30 minutes. Subsequently, a dichloromethane (20 mL) solution of 2-cyclopentylpent-4-en-1-ol (3.50 g, 22.7 mmol) was added dropwise thereto over 15 minutes, and the mixture was stirred at −78° C. for 45 minutes. Triethylamine (16.11 g, 159.3 mmol) was added dropwise thereto over 5 minutes, and the mixture was then stirred at room temperature for 2 hours. The mixture was neutralized with 1 N hydrochloric acid (160 mL). The organic layer was dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure to obtain a yellow oil substance as a mixture containing the compound of interest. This compound was used in the next reaction without being further purified.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][NH:5][C:6]1[C:7](=[O:23])[N:8]([C:19]([CH3:22])([CH3:21])[CH3:20])[S:9](=[O:18])(=[O:17])[C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH2:24]([O:27][C:28]1[CH:29]=[C:30]([OH:38])[CH:31]=[C:32]([O:34][CH2:35][CH2:36][CH3:37])[CH:33]=1)[CH2:25][CH3:26]>>[C:19]([N:8]1[C:7](=[O:23])[C:6]([NH:5][CH2:4][CH2:3][CH2:2][O:38][C:30]2[CH:31]=[C:32]([O:34][CH2:35][CH2:36][CH3:37])[CH:33]=[C:28]([O:27][CH2:24][CH2:25][CH3:26])[CH:29]=2)=[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[S:9]1(=[O:18])=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)N1C(=O)C(NCCCBr)=C(c2ccccc2)S1(=O)=O
Reactant: CCCOc1cc(O)cc(OCCC)c1
Product: CCCOc1cc(OCCC)cc(OCCCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)c1

Procedure:
The title compound was prepared from 4-[(3-bromopropyl)amino]-2-tert-butyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide and 3,5-dipropoxyphenol in a similar manner as described for Example 5. 1H NMR (500 MHz, CDCl3): δ 7.54-7.50 (m, 2H), 7.46-7.41 (m, 3H), 6.12-6.09 (m, 1H), 6.08-6.06 (m, 2H), 5.89-5.83 (m, 1H), 3.93-3.84 (m, 6H), 3.09-3.03 (m, 2H), 1.87-1.76 (m, 6H), 1.74 (s, 9H), 1.07-1.01 (m, 6H); 13C NMR (125 MHz, CDCl3): δ 161.2, 160.2, 159.9, 135.4, 131.8, 129.7, 128.8, 125.3, 107.1, 94.8, 94.6, 94.4, 94.0, 69.8, 66.4, 61.6, 42.7, 28.8, 27.8, 22.8, 10.8; Mass Spectrum: M+H+ 531.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH3:12])([CH3:11])[CH2:5][NH:6]2.Cl.CN(C)CCCN=C=NCC.[N:25]1([C:31]2[N:32]=[C:33]([CH2:38][C:39]([O-])=[O:40])[NH:34][C:35](=[O:37])[CH:36]=2)[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.[Na+].O>CN(C)C=O.N1C=CC=CC=1>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH3:12])([CH3:11])[CH2:5][N:6]2[C:39](=[O:40])[CH2:38][C:33]1[NH:34][C:35](=[O:37])[CH:36]=[C:31]([N:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)[N:32]=1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: CC1(C)CNc2cccc(F)c21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC1(C)CN(C(=O)Cc2nc(N3CCOCC3)cc(=O)[nH]2)c2cccc(F)c21
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.3 %

Procedure:
150 mg of 4-fluoro-3,3-dimethyl-2,3-dihydro-1H-indole [reference example 2c] and 279 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride are added to a solution of 261 mg of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate (obtained in step 2c of example 1c) in 5 ml of N,N-dimethylformamide and 5 ml of pyridine. The reaction mixture is stirred at ambient temperature for 16 hours and then 30 ml of water are added and the mixture is extracted with ethyl acetate. The organic phase is washed successively with water and a saturated sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by trituration from a mixture of ethyl acetate and diisopropyl ether, so as to give 194 mg of 2-[2-(4-fluoro-3,3-dimethyl-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one, the characteristics of which are the following:
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11]C)=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:31])[N:5]([C@@H:14]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH2:29][CH3:30])[CH:21]=1)[CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:6]2=[O:13].I[Si](C)(C)C>C(Cl)Cl.[Cl-].[Na+].O>[NH2:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:31])[N:5]([C@@H:14]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH2:29][CH3:30])[CH:21]=1)[CH2:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:6]2=[O:13]
Reactant: CCOc1cc([C@@H](CS(C)(=O)=O)N2C(=O)c3ccc(OC)c(N)c3C2=O)ccc1OC
Agent: C[Si](C)(C)I
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOc1cc([C@@H](CS(C)(=O)=O)N2C(=O)c3ccc(O)c(N)c3C2=O)ccc1OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3-Amino-4-methoxy-phthalic anhydride is prepared according to a procedure based on Rudolf Grewe (Berichte der Deutschen Chemischen Gesellschaft [Abteilung] B: Abhandlungen (1938), 71B 907-11). A stirred mixture of 3-amino-4-methoxy-phthalic anhydride (1 mmol) and (S)-1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethylamine (1 mmol) in acetic acid is heated to reflux overnight. The solvent is removed in vacuo. The residue is extracted with water and ethyl acetate. The organic layer is dried over MgSO4. The solvent is removed in vacuo to give the crude (S)-4-amino-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-5-methoxy-isoindole-1,3-dione. The product is purified by column chromatography or recrystallization. To a stirred solution of (S)-4-amino-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-5-methoxy-isoindole-1,3-dione (0.5 mmol) in anhydrous CH2Cl2, is added iodotrimethylsilane (3 mmol). The mixture is stirred at room temperature for 24 hours. The reaction mixture is diluted with brine and is extracted with CH2Cl2. The solvent is removed in vacuo to afford crude (S)-4-amino-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-5-hydroxy-isoindole-1,3-dione. The product is purified by column chromatography or recrystallization.
Reaction SMILES: C(OP([CH2:9][S:10]([N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][N:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])(OCC)=O)C.[H-].[Na+].[F:28][C:29]([F:38])([C:34]([F:37])([F:36])[F:35])[CH:30](OC)O>C1COCC1>[CH3:25][C:23]1[CH:22]=[CH:21][N:20]=[C:19]([N:16]2[CH2:15][CH2:14][N:13]([S:10](/[CH:9]=[CH:30]/[C:29]([F:38])([F:28])[C:34]([F:37])([F:36])[F:35])(=[O:11])=[O:12])[CH2:18][CH2:17]2)[CH:24]=1
Reactant: CCOP(=O)(CS(=O)(=O)N1CCN(c2cc(C)ccn2)CC1)OCC
Reactant: COC(O)C(F)(F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccnc(N2CCN(S(=O)(=O)/C=C/C(F)(F)C(F)(F)F)CC2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 55 %

Procedure:
To a solution of 1-(diethoxyphosphorylmethylsulfonyl)-4-(4-methyl-2-pyridyl)piperazine (242 mg, 0.618 mmol) in anhydrous THF (25 ml) were added molsieves 4A and sodium hydride (60%, 38 mg, 0.95 mmol) under nitrogen and the mixture was stirred at room temperature for 10 minutes. The mixture was cooled to 0° C. and 2,2,3,3,3-pentafluoro-1-methoxy-propan-1-ol (300 mg, 1.67 mmol) was added. The mixture was stirred at 0° C. for 30 minutes and then allowed to reach room temperature over one hour. The mixture was filtered through kieselguhr, concentrated under reduced pressure and the residue was purified by column chromatography (reveleris, gradient from 0 to 100% ethyl acetate in n-heptane) to yield 130 mg (0.337 mmol, yield 55%).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH:11]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)[CH2:10][CH2:9]2)=[O:5])C.[OH-].[Na+]>CO>[C:21]([N:18]1[CH2:19][CH2:20][N:15]([CH:11]2[C:12]3[C:8](=[CH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:14][CH:13]=3)[CH2:9][CH2:10]2)[CH2:16][CH2:17]1)([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]
Reactant: CCOC(=O)c1ccc2c(c1)CCC2N1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(C2CCc3cc(C(=O)O)ccc32)CC1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
tert-Butyl 4-[5-(ethoxycarbonyl)-2,3-dihydro-1H-inden-1-yl)piperazin-1-carboxylate (8 g, 21.36 mmol) was dissolved in 20 mL of methanol, and 30 mL of sodium hydroxide (1 N) was added. The solution was stirred overnight at room temperature and at 50° C. for another 2 hours, and then concentrated. The residue was dissolved in water (50 mL) and the obtained solution was acidified to pH 5 with 1 N HCl and then extracted with ethyl acetate (3×100 mL). The extract liquor was pooled together, dried over magnesium sulfate, and concentrated to obtain the subtitle compound. MS (M+1)=347.19.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][C@H:11]2[N:21]3[C:22]4[N:13]([C:14](=[O:24])[CH:15]=[CH:16][C:17]=4[CH:18]=[CH:19][C:20]3=[O:23])[CH2:12]2)[CH2:6][CH2:5]1.[O:25]=[C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][C:30]([CH:36]=O)=[CH:31][CH:32]=2)[O:27]1.C([O-])(O)=O.[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CO>[O:25]=[C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][C:30]([CH2:36][NH:3][CH:4]3[CH2:5][CH2:6][N:7]([CH2:10][C@H:11]4[N:21]5[C:22]6[N:13]([C:14](=[O:24])[CH:15]=[CH:16][C:17]=6[CH:18]=[CH:19][C:20]5=[O:23])[CH2:12]4)[CH2:8][CH2:9]3)=[CH:31][CH:32]=2)[O:27]1
Reactant: O=Cc1ccc2ccc(=O)oc2c1
Reactant: NC1CCN(C[C@@H]2Cn3c(=O)ccc4ccc(=O)n2c43)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Solvent: ClCCl
Product: O=c1ccc2ccc(CNC3CCN(C[C@@H]4Cn5c(=O)ccc6ccc(=O)n4c65)CC3)cc2o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 10 mL round-bottomed flask were added (1R)-1-[(4-amino-1-piperidinyl)methyl]-1,2-dihydro-4H,9H-imidazo[1,2,3-ij]-1,8-naphthyridine-4,9-dione dihydrochloride (for a preparation see Example 5A(j)) (80 mg, 0.266 mmol), 2-oxo-2H-chromene-7-carbaldehyde (for a synthesis see WO2008009700 Example 224) (46.4 mg, 0.266 mmol), and NaHCO3 (100 mg, 1.190 mmol) in dichloromethane (DCM) (4 ml) and methanol (1 ml) to give a brown solution. Sodium sulfate (200 mg, 1.408 mmol) was added and the reaction was allowed to stir at rt overnight. After 15 h sodium triacetoxyborohydride (113 mg, 0.533 mmol) was added and the reaction was allowed to stir at 25° C. under nitrogen for 4 h. The reaction mixture was adsorbed onto silica and purified using 0-10% MeOH/DCM (1% NH4OH) to give the title compound as a free base (30 mg, 0.064 mmol, 24.07% yield) as a tan solid. LCMS & 1H NMR consistant with desired product.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][S:22]([F:25])(=[O:24])=[O:23])[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.B(F)(F)F.CCOCC>C(S)(S)C>[OH:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][S:22]([F:25])(=[O:24])=[O:23])[CH:12]=[CH:13][CH:14]=1
Reactant: O=S(=O)(F)CCCCCCCc1cccc(OCc2ccccc2)c1
Agent: CC(S)S
Agent: FB(F)F
Solvent: CCOCC
Product: O=S(=O)(F)CCCCCCCc1cccc(O)c1
Yield: 68.7 %

Procedure:
7-(3-Hydroxy-phenyl)-heptanesulfonyl fluoride (14.2) was synthesized as described in 14.1 using 13.2 (0.1 g, 0.26 mmol) in ethanedithiol (5 mL) and BF3.Et2O (0.14 g, 1.0 mmol). Purification by flash column chromatography on silica gel gave 14.2 (0.049 g, 69% yield) as a viscous liquid.
Reaction SMILES: C(OC([N:8]1[C@H:12]([C:13](O)=O)[C@@H:11]([CH3:16])[O:10]C1(C)C)=O)(C)(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C.[NH2:47][C:48]1[CH:49]=[C:50]([C:55]2[CH:60]=[CH:59][C:58]([C:61]#[N:62])=[CH:57][C:56]=2[F:63])[CH:51]=[CH:52][C:53]=1[NH2:54]>CN(C=O)C.CCOC(C)=O>[NH2:8][C@H:12]([C:13]1[NH:54][C:53]2[CH:52]=[CH:51][C:50]([C:55]3[CH:60]=[CH:59][C:58]([C:61]#[N:62])=[CH:57][C:56]=3[F:63])=[CH:49][C:48]=2[N:47]=1)[C@H:11]([OH:10])[CH3:16]
Reactant: C[C@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@@H]1C(=O)O
Reactant: N#Cc1ccc(-c2ccc(N)c(N)c2)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H](O)[C@H](N)c1nc2cc(-c3ccc(C#N)cc3F)ccc2[nH]1
Temperature: -5 °C
Reaction time: 1.5 h
Yield: 13.4 %

Procedure:
To a solution of (4S,5R)-3-(tert-butoxycarbonyl)-2,2,5-trimethyl-1,3-oxazolidine-4-carboxylic acid (Preparation 57, 778 mg, 3 mmol) and HOBt (551 mg, 3.60 mmol) in DMF (23 mL) was added NMM (0.33 mL, 3 mmol) and the mixture cooled to −5° C. EDCI (690 mg, 3.60 mmol) was added and the reaction stirred at −5° C. for 90 minutes. A solution of 3′,4′-diamino-2-fluorobiphenyl-4-carbonitrile (Preparation 79, 750 mg, 3.30 mmol) in DMF (7 mL) was added and the reaction was allowed to warm to room temperature for 3 days. The reaction was poured in EtOAc (120 mL), washed with 3% aqueous NaHCO3 solution (4×120 mL), brine (30 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with EtOAc:Heptane 1:1. The residue was dissolved in AcOH (7 mL) and stirred at 40° C. for 18 hours. The reaction was concentrated in vacuo and treated with saturated aqueous NaHCO3 solution (15 mL), extracted into EtOAc (2×15 mL), the organic layers combined, dried over Na2SO4 and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with acetone:heptanes 1:3. The residue was dissolved in 4M HCl in dioxane with 1 drop of water and stirred at room temperature for 2 hours. The reaction was eluted through an SCX column washing through with MeOH followed by 3N NH3 in MeOH and the filtrate concentrated in vacuo. The residue was treated with water (1 mL) and MeOH (0.5 mL) and freeze dried to afford the title compound (125 mg, 75%).
Reaction SMILES: C([O:8][C:9](=[O:28])[C@@H:10]([NH:14][C:15](=[O:27])[C@@H:16]([N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH3:19])[CH3:17])[CH:11]([CH3:13])[CH3:12])C1C=CC=CC=1.[OH-].[Li+]>C1COCC1.CO.O>[C:23]([O:22][C:20]([N:18]([CH3:19])[C@@H:16]([CH3:17])[C:15]([NH:14][C@@H:10]([CH:11]([CH3:12])[CH3:13])[C:9]([OH:28])=[O:8])=[O:27])=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 104.7 %

Procedure:
(S)-2-[(S)-2-(tert-Butoxycarbonyl-methyl-amino)-propionylamino]-3-methyl-butyric acid benzyl ester (7 g, 18 mmol) and 1 M aqueous lithium hydroxide (40 mL, 40 mmol) was added to THF/MeOH/H2O (3:1:1; 200 mL) to give a yellow solution. The reaction mixture was stirred at rt overnight and then concentrated in vacuo. The residue was dissolved in water and then acidified to pH 2 using first 6 M and then 1 M aqueous HCl. The mixture was extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacuo to give crude (S)-2-[(S)-2-(tert-butoxycarbonyl-methyl-amino)-propionylamino]-3-methyl-butyric acid (5.7 g) which was used directly in the next step without further purification, m/z=303 (M+H).
Reaction SMILES: C([NH:4][CH:5]([CH3:21])[CH2:6][NH:7][S:8]([C:11]1[C:12]2[CH:13]=[CH:14][N:15]=[CH:16][C:17]=2[CH:18]=[CH:19][CH:20]=1)(=[O:10])=[O:9])(=O)C.C(Cl)(Cl)Cl>Cl>[NH2:4][CH:5]([CH3:21])[CH2:6][NH:7][S:8]([C:11]1[C:12]2[CH:13]=[CH:14][N:15]=[CH:16][C:17]=2[CH:18]=[CH:19][CH:20]=1)(=[O:10])=[O:9]
Reactant: CC(=O)NC(C)CNS(=O)(=O)c1cccc2cnccc12
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CC(N)CNS(=O)(=O)c1cccc2cnccc12
Reaction time: 36 h
Yield: 55.6 %

Procedure:
In 50 ml of 10% hydrochloride was dissolved 3.0 g of N-(2-acetylaminopropyl)-5-isoquinolinesulfonamide as obtained above, and the mixture was stirred at a temperature of 90° C. to 100° C. for 36 hours. The reaction solution was washed with chloroform, rendered alkaline with 1N sodium hydroxide and extracted with chloroform. The chloroform layer was washed with water, dried with anhydrous magnesium sulfate, and the chloroform was distilled threfrom under reduced pressure. The residue thus obtained was subjected to an alumina column chromatography (alumina: 70 g; solvent: chloroform) to give 1.44 g of N-(2-aminopropyl)-5-isoquinolinesulfonamide in a yield of 56%.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:13]([N:15]1[CH2:20][CH2:19][CH:18]([F:21])[CH2:17][CH2:16]1)=[O:14])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:21][CH:18]1[CH2:17][CH2:16][N:15]([C:13]([C@H:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)=[O:14])[CH2:20][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)N1CCC(F)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C([C@H]1CCCN1)N1CCC(F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
A mixture of (R)-2-(4-fluoro-piperidine-1-carbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (1.5 g, 5 mmol) and TFA (3 mL) in DCM (4 mL) was stirred at rt for one hour to give 1 g of (4-fluoro-piperidin-1-yl)-(R)-pyrrolidin-2-yl-methanone.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[CH:17]=[C:18]([NH:25][C:26]2[N:31]=[C:30]([CH3:32])[C:29]([C:33]([OH:35])=[O:34])=[CH:28][CH:27]=2)[C:19]([C:22](=[O:24])[NH2:23])=[N:20][CH:21]=1)=O)(C)(C)C.[C:36]([OH:42])([C:38]([F:41])([F:40])[F:39])=[O:37]>ClCCl>[OH:42][C:36]([C:38]([F:41])([F:40])[F:39])=[O:37].[NH2:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[CH:17]=[C:18]([NH:25][C:26]2[N:31]=[C:30]([CH3:32])[C:29]([C:33]([OH:35])=[O:34])=[CH:28][CH:27]=2)[C:19]([C:22](=[O:24])[NH2:23])=[N:20][CH:21]=1
Reactant: Cc1nc(Nc2cc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)cnc2C(N)=O)ccc1C(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(Nc2cc(N[C@@H]3CCCC[C@@H]3N)cnc2C(N)=O)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-{[5-({(1R,2S)-2-[(tert-butoxycarbonyl)amino]cyclohexyl}amino)-2-carbamoylpyridin-3-yl]amino}-2-methylpyridine-3-carboxylic acid (49 mg, 0.10 mmol) in dichloromethane (1 mL) was added TFA (0.12 mL, 1.5 mmol), and the reaction mixture was stirred for 1 hour at room temperature. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase HPLC (acetonitrile/water with 0.1% TFA, linear gradient) to afford 6-[(5-{[(1R,2S)-2-aminocyclohexyl]amino}-2-carbamoylpyridin-3-yl)amino]-2-methylpyridine-3-carboxylic acid TFA salt. MS ESI calc'd. for C19H25N6O3 [M+H]+ 385. found 385. 1H NMR (500 MHz, DMSO-d6) δ 12.73 (s, 1H), 12.22 (s, 1H), 8.67 (s, 1H), 8.05 (d, J=8.6 Hz, 1H), 8.01 (s, 1H), 7.85 (s, 3H), 7.76 (s, 1H), 7.48 (s, 1H), 6.73 (d, J=8.6 Hz, 1H), 6.45 (d, J=7.8 Hz, 1H), 3.93-3.77 (m, 1H), 3.64-3.49 (m, 1H), 2.72 (s, 3H), 1.94-1.79 (m, 2H), 1.79-1.70 (m, 1H), 1.71-1.50 (m, 3H), 1.51-1.36 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.[Cl:22][C:23]1[CH:24]=[C:25]([CH2:29][C:30](O)=[O:31])[CH:26]=[CH:27][CH:28]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O.CO.CCCCCC.C(OCC)(=O)C>[Cl:22][C:23]1[CH:24]=[C:25]([CH2:29][C:30]([NH:1][C:2]2[CH:3]=[C:4]3[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]4=[C:7]([C:11]5[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=5)[NH:8][C:9]([CH:10]=2)=[C:5]34)=[O:31])[CH:26]=[CH:27][CH:28]=1
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Reactant: O=C(O)Cc1cccc(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Cc1cccc(Cl)c1)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Yield: 13.6 %

Procedure:
Preparation of example 46 from the title compound of Example 7 (30 mg, 0.11 mmol), (3-chlorophenyl)acetic acid (28 mg, 0.16 mmol), triethylamine (0.076 mL, 0.55 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (62 mg, 0.16 mmol) in N,N-dimethylformamide (1.5 mL) was carried out analogously to Example 11. Silica gel chromatography (1:1 ethyl acetate:hexane), also in an analogous manner, followed by methanol trituration afforded the title compound (6.5 mg, 0.015 mmol) as a yellow powder in 14% yield.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[C:13]2([CH2:16][CH2:15][CH2:14]2)[CH2:12][N:11]([C@@H](C2C=CC=CC=2)C)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6]([NH:8][CH:9]1[C:13]2([CH2:14][CH2:15][CH2:16]2)[CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H](c1ccccc1)N1CC(NC(=O)OC(C)(C)C)C2(CCC2)C1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CNCC12CCC2
Reaction time: 1 h
Yield: 102.6 %

Procedure:
To a solution of 4.1 g of 8-tert-butoxycarbonylamino-6-[1-(R)-phenylethyl]-6-azaspiro[3.4]octane in 60 ml of ethanol there was added 4.5 g of 5% palladium on charcoal (50% wet) and reduction was carried out under a hydrogen atmosphere (H2 pressure: 4 atm.) for 5 hrs. During the reduction, the reaction vessel was warmed by irradiation with a tungsten lamp. At 1 hr. from the beginning of the reduction, 2 g of the same catalyst was further added and the reduction continued for an additional 4 hours at the same condition to total 5 hours. The catalyst was removed by filtration and the solvent was removed under reduced pressure to yield 2.88 g of the titled compound.
Reaction SMILES: [CH3:1][CH:2]([CH3:30])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22](=O)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].Cl.[CH3:32][C:33]1[CH:38]=[CH:37][C:36]([NH:39]N)=[CH:35][CH:34]=1>>[CH3:1][CH:2]([CH3:30])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][C:21]3[C:37]4[C:36](=[CH:35][CH:34]=[C:33]([CH3:32])[CH:38]=4)[NH:39][C:22]=3[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccccc3)CC2)c1
Reactant: Cc1ccc(NN)cc1
Agent: Cl
Product: Cc1ccc2[nH]c(-c3ccccc3)c(CCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c2c1

Procedure:
Prepared by Procedure E and Scheme M using 2-methyl-N-{3-[1-(5-oxo-5-phenylpentyl)-4-piperidinyl]phenyl}propanamide and 1-(4-methylphenyl)hydrazine hydrochloride: ESMS m/e: 494.3 (M+H)+.
Reaction SMILES: [CH2:1]([C@@H:8]1[C@@H:16]([OH:17])[C@H:15]([CH3:18])[O:14][C:13](=[O:19])[C@@H](NC(=O)C2C(O)=C(OC)C=CN=2)COC1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>Cl>[CH2:1]([C@@H:8]1[C@@H:16]([OH:17])[C@H:15]([CH3:18])[O:14][C:13]1=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccnc(C(=O)N[C@H]2COC(=O)[C@H](Cc3ccccc3)[C@@H](O)[C@H](C)OC2=O)c1O
Agent: Cl
Product: C[C@@H]1OC(=O)[C@H](Cc2ccccc2)[C@H]1O
Temperature: 23 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
A suspension of N-((3S,7R,8R,9S)-7-benzyl-8-hydroxy-9-methyl-2,6-dioxo-1,5-dioxonan-3-yl)-3-hydroxy-4-methoxypicolinamide, prepared as described by Ricks, Michael J. et al. in U.S. Pat. No. 6,706,740 2004, (20.0 grams (g), 38.7 millimole (mmol), 1.00 equivalent (equiv)) in 6M HCl (200 milliliters (mL)) was heated to 100° C. with rapid stirring. After 1 hour (h), the resulting brown solution was cooled to 23° C. and extracted with diethyl ether (Et2O; 2×200 mL). The organic extracts were combined, washed with saturated (sat'd) aqueous sodium bicarbonate (NaHCO3) solution (100 mL), dried over magnesium sulfate (MgSO4), filtered, and concentrated to provide (3R,4R,5S)-3-benzyl-4-hydroxy-5-methyldihydrofuran-2(3H)-one (5.62 g, 70%) as a tan solid.