Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=1)[C:9]([CH2:25][N:26]1[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]1)=[C:8]2[C:33]([NH:35][C@H:36]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:37]([F:40])([F:39])[F:38])=[O:34])(=[O:4])=[O:3].C(O)(=O)C.[CH3:51][C@H:52]1[CH2:56][CH2:55][CH2:54][NH:53]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH3:51][C@@H:52]1[CH2:56][CH2:55][CH2:54][N:53]1[CH:29]1[CH2:28][CH2:27][N:26]([CH2:25][C:9]2[C:10]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:24])[F:22])[CH:16]=3)=[N:11][C:12]3[C:7]([C:8]=2[C:33]([NH:35][C@H:36]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:37]([F:40])([F:39])[F:38])=[O:34])=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:14][CH:13]=3)[CH2:31][CH2:30]1
Reactant: C[C@H]1CCCN1
Reactant: CS(=O)(=O)c1ccc2nc(-c3cccc(C(F)(F)F)c3)c(CN3CCC(=O)CC3)c(C(=O)N[C@H](c3ccccc3)C(F)(F)F)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: C[C@@H]1CCCN1C1CCN(Cc2c(-c3cccc(C(F)(F)F)c3)nc3ccc(S(C)(=O)=O)cc3c2C(=O)N[C@H](c2ccccc2)C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 34.1 %

Procedure:
6-(Methylsulfonyl)-3-[(4-oxo-1-piperidinyl)methyl]-2-[3-(trifluoromethyl)phenyl]-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamide (0.093 g, 0.140 mmol) was dissolved in dichloromethane (1.4 mL) and acetic acid (0.012 mL, 0.210 mmol). (S)-2-Methylpyrrolidine (0.036 g, 0.420 mmol) was added followed by sodium triacetoxyborohydride (59.4 mg, 0.280 mmol). The mixture was stirred at room temperature for 2 d. The solvent was removed under reduced pressure, and the residue was purified via HPLC (Waters, Sunfire 30×100 mm, 26-60% CH3CN/H2O with 0.1% TFA) to afford 3-({4-[(2R)-2-methyl-1-pyrrolidinyl]-1-piperidinyl}methyl)-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamide (0.035 g, 32% yield). MS (m/z) 733.3 (M+H+).
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[N:19]=2)[CH:7]=1)=[O:5].[CH2:26]1[CH2:30][O:29][CH2:28][CH2:27]1>C1OC2C(=C[C-]=CC=2)OC1.[Mg+2].[Br-]>[O:5]1[C:4]2[CH:6]=[CH:15][C:14]([C:4]([C:6]3[C:15](=[O:16])[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[N:8]([CH2:17][C:18]4[CH:23]=[CH:22][CH:24]=[C:20]([CH3:21])[N:19]=4)[CH:7]=3)=[O:5])=[CH:27][C:28]=2[O:29][CH2:30][CH2:26]1
Reactant: C1CCOC1
Reactant: CON(C)C(=O)c1cn(Cc2cccc(C)n2)c2ccccc2c1=O
Agent: [Br-]
Agent: [Mg+2]
Agent: [c-]1ccc2c(c1)OCCO2
Product: Cc1cccc(Cn2cc(C(=O)c3ccc4c(c3)OCCO4)c(=O)c3ccccc32)n1

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60, from 161 mg (0.48 mmol) of 1-(6-methyl-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 2.5 mL THF and 2.4 mL 0.5M 3,4-(ethylenedioxy)phenylmagnesium bromide. Yield: 65 mg of a white solid. LC-MSD, m/z for C25H20N2O4 [M+H]+=413.1; HPLC retention time: 1.8 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11].C([O-])([O-])=O.[Na+].[Na+].[F:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>COCCOC>[F:31][C:32]1[CH:37]=[CH:36][C:35]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:11])=[CH:34][CH:33]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1ccccc1-c1ccc(F)cc1
Yield: 78 %

Procedure:
A solution of benzoic acid N′-[3-(2-bromo-phenyl)-propionyl]-N′-isopropyl-hydrazide (50 mg, 0.13 mmol) in DME (4 ml)/2M Na2CO3 (225 μL, 0.45 mmol) was treated with 4-fluoro-phenylboronic acid (29 mg, 0.19 mmol) and Pd[PPh3]4 (15 mg, 0.013 mmol) for 18 hours at 90° C. The reaction mixture was partitioned between water and dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-50% ethyl acetate/hexanes gradient to afford the product as a solid (41 mg, 79%). LC-MS m/e 405.25 (M+H+)
Reaction SMILES: C(O[C:4]([C:6]1[C:7]2[S:15][CH:14]=[C:13]([CH2:16][O:17][C:18]3[CH:23]=[C:22]([C:24]4[O:25][C:26]([CH2:29][C:30]5[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=5)=[N:27][N:28]=4)[CH:21]=[CH:20][C:19]=3[CH3:37])[C:8]=2[C:9]([NH2:12])=[N:10][CH:11]=1)=[O:5])C.[CH2:38]([CH2:40][NH2:41])[OH:39]>CS(C)=O>[OH:39][CH2:38][CH2:40][NH:41][C:4]([C:6]1[C:7]2[S:15][CH:14]=[C:13]([CH2:16][O:17][C:18]3[CH:23]=[C:22]([C:24]4[O:25][C:26]([CH2:29][C:30]5[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=5)=[N:27][N:28]=4)[CH:21]=[CH:20][C:19]=3[CH3:37])[C:8]=2[C:9]([NH2:12])=[N:10][CH:11]=1)=[O:5]
Reactant: NCCO
Reactant: CCOC(=O)c1cnc(N)c2c(COc3cc(-c4nnc(Cc5ccc(Cl)cc5)o4)ccc3C)csc12
Solvent: CS(C)=O
Product: Cc1ccc(-c2nnc(Cc3ccc(Cl)cc3)o2)cc1OCc1csc2c(C(=O)NCCO)cnc(N)c12
Temperature: 160 °C

Procedure:
A solution of 4-amino-3-{5-[5-(4-chloro-benzyl)-[1,3,4]oxadiazol-2-yl]-2-methyl-phenoxymethyl}-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.07 g, 0.13 mmol) (from Example 42 supra) in dimethylsulfoxide (0.5 mL) was treated with ethanolamine (1.5 mL) and heated at 160° C. for 2.8 hours in a microwave reactor. The reaction mixture was purified by C18 column chromatography and SFC column chromatography to give 4-amino-3-{5-[5-(4-chloro-benzyl)-[1,3,4]oxadiazol-2-yl]-2-methyl-phenoxymethyl}-thieno[3,2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide as a white powder. (Yield 8 mg, 11%).
Reaction SMILES: [CH3:1][S:2]([CH2:36][CH2:37][CH2:38][C:39]([O:41]C)=[O:40])(=[N:4][C:5]([C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[C:16]([O:18][C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[CH:30]=4)=[O:27])=[CH:21][CH:20]=3)[CH:15]=[CH:14][N:13]=2)[NH:9][CH:8]=1)=[O:6])=[O:3].[OH-].[Na+].O.Cl>CO>[CH3:1][S:2]([CH2:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40])(=[N:4][C:5]([C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[C:16]([O:18][C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[CH:30]=4)=[O:27])=[CH:21][CH:20]=3)[CH:15]=[CH:14][N:13]=2)[NH:9][CH:8]=1)=[O:6])=[O:3]
Reactant: COC(=O)CCCS(C)(=O)=NC(=O)c1c[nH]c(-c2cc(Oc3ccc(NC(=O)Nc4cccc(C)c4)cc3)ccn2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cccc(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)N=S(C)(=O)CCCC(=O)O)c[nH]4)c3)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of methyl 4-{S-methyl-N-[(5-{4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]sulfonimidoyl}butanoate (5 mg, 0.0087 mol) in MeOH (3 ml) was added 1M NaOH (0.5 ml, 0.5 mmol). The mixture was stirred at room temperature for 30 minutes, and poured into 30 ml of water. 2M HCl was added dropwise until pH=4. The precipitates were filtered, washed with water and dried to give 4-{S-methyl-N-[(5-{4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]sulfonimidoyl}butanoic acid as off-white solid. Yield: 5 mg, 100%.
Reaction SMILES: [C:1]1([CH:7]([OH:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(=O)CCCCC1>C1(C)C=CC=CC=1>[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])[CH3:8]
Reactant: CC(O)c1ccccc1
Solvent: O=C1CCCCC1
Solvent: Cc1ccccc1
Product: CC(=O)c1ccccc1

Procedure:
5.0 g (40.9 mmol) of 1-phenylethanol, 15.0 g (153 mmol) of cyclohexanone and 1.0 g of catalyst from Example 9 in 30 g of toluene were heated at 70° C. under argon. After a reaction time of 10 hours, the reaction mixture was analyzed by gas chromatography. The yield of product was 94.2 percent.
Reaction SMILES: [ClH:1].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.C(N(CC)CC)C.[O:32]1[C:41]2[C:36](=[CH:37][C:38]([CH:42]=O)=[CH:39][CH:40]=2)[CH2:35][CH2:34][CH2:33]1.NC1CCN(C[C@H]2N3C4N(C(=O)C=CC=4C=CC3=O)C2)CC1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CO.C(=O)(O)[O-].[Na+]>[ClH:1].[O:32]1[C:41]2[C:36](=[CH:37][C:38]([CH2:42][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:39][CH:40]=2)[CH2:35][CH2:34][CH2:33]1
Reactant: NC1CCN(C[C@@H]2Cn3c(=O)ccc4ccc(=O)n2c43)CC1
Reactant: O=Cc1ccc2c(c1)CCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=c1ccc2ccc(=O)n3c2n1C[C@H]3CN1CCC(NCc2ccc3c(c2)CCCO3)CC1
Reaction time: 0.08 h
Yield: 22 %

Procedure:
A solution of (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)) (12 mg, 0.032 mmol) and triethylamine (0.139 ml, 0.999 mmol) in DCM (4.5 ml) and methanol (0.5 ml) at rt was stirred for 5 min. 3,4-Dihydro-2H-chromene-6-carbaldehyde (commercially available) (45 mg, 0.277 mmol) was added and the resulting solution was stirred overnight for 18 h. LCMS showed that aldehyde remained and no amine remained. Additional (1R)-1-[(4-amino-1-piperidinyl)methyl]-1,2-dihydro-4H,9H-imidazo[1,2,3-ij]-1,8-naphthyridine-4,9-dione (120 mg, 0.321 mmol) and additional triethylamine (0.138 ml, 0.999 mmol) were added and the resulting mixture stirred for 1 h. Additional sodium triacetoxyborohydride (294 mg, 1.387 mmol) was added and resulting solution was stirred for 60 h. The reaction was diluted with DCM (10 ml) and sodium bicarbonate solution (10 ml) and stirred at rt for 10 mins and extracted with methanol:DCM (20%, 3×150 ml). The combined organic extracts were dried (MgSO4), filtered, evaporated and chromatographed (0-50% methanol:DCM). The column waste was concentrated to afford a brown oil that was re-chromatographed (0-50% methanol:DCM). The relevant fractions were combined to afford the free base of the title compound as a white solid (27 mg, 0.06 mmol, 22%).
Reaction SMILES: [C:1]1([C:7]2[C:8]([CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])=[CH:9][N:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]5[CH:32]=[N:31][CH:30]=[CH:29][N:28]=5)[CH:22]=4)=[CH:15][CH:14]=3)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[C:1]1([C:7]2[C:8]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[CH:9][N:10]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]5[CH:32]=[N:31][CH:30]=[CH:29][N:28]=5)[CH:22]=4)=[CH:17][CH:18]=3)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3cccc(-c4cnccn4)c3)cc2)cc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)CCc1cn(Cc2ccc(OCc3cccc(-c4cnccn4)c3)cc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.8 %

Procedure:
A mixture of ethyl 3-[4-phenyl-1-[4-[3-(2-pyrazinyl)benzyloxy]benzyl]-3-pyrrolyl]propionate (647 mg), 1N aqueous sodium hydroxide solution (2.5 ml), tetrahydrofuran (5 ml), and ethanol (5 ml) was stirred at room temperature overnight, and 1N hydrochloric acid (2.5 ml) was added to the mixture, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The colorless crystals obtained were collected by filtration to yield 3-[4-phenyl-1-[4-[3-(2-pyrazinyl)benzyloxy]benzyl]-3-pyrrolyl]propionic acid (470 mg, yield: 77%). This was recrystallized from ethyl acetate-hexane. Melting point: 91–92° C.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][C:10](Cl)=[O:11])[CH:5]=[N:4][N:3]=[N:2]1.N1C=CC=CC=1.S.O[S:21](O)(=O)=O>C(Cl)Cl.C(Cl)(Cl)Cl>[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:11])=[S:21])[CH:5]=[N:4][N:3]=[N:2]1
Reactant: O=C(Cl)CCCCn1cnnn1
Reactant: O=S(=O)(O)O
Agent: S
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: OC(=S)CCCCn1cnnn1
Reaction time: 1 h

Procedure:
5 g of 5-(tetrazol-1-yl)-valeric acid chloride are dissolved in 4.5 ml of absolute methylene chloride and, at 0°, this solution is added dropwise to 35.5 ml of a solution of pyridine and H2S in methylene chloride (30 ml of pyridine and 6 g of H2S in 100 ml of methylene chloride). The mixture is then stirred at 0° under a nitrogen atmosphere for 1 hour. The reaction mixture is taken up in chloroform, and the aqueous phase is acidified to pH 2 with 2N H2SO4 and extracted twice with chloroform. The combined organic phases are washed twice with 25 ml of 10% NaHCO3 solution. The pH is then adjusted to 3 with 2N H2SO4 and the title compound is obtained by repeated extraction with chloroform. It is dried over sodium sulphate and concentrated.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[CH:13][C:6]2[CH2:7][C:8](=[O:12])[NH:9][CH:10]=[CH:11][C:5]=2[CH:4]=1.Br[CH2:18][CH2:19][CH2:20][Cl:21]>>[CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[CH:13][C:6]2[CH2:7][C:8](=[O:12])[N:9]([CH2:18][CH2:19][CH2:20][Cl:21])[CH:10]=[CH:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)CC(=O)NC=C2
Reactant: ClCCCBr
Product: COc1cc2c(cc1OC)CC(=O)N(CCCCl)C=C2

Procedure:
This compound was prepared analogous to Example 111(a) by reacting 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one with 1-bromo-3-chloro-propane.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:23]([O:25]C)=O)[CH:5]=[CH:6][CH:7]=1.Cl.[OH-].[NH4+:29]>C1COCC1.C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:23](=[O:25])[NH2:29])[CH:5]=[CH:6][CH:7]=1
Reactant: [NH4+]
Reactant: COC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc(C)c1
Agent: Cl
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cccc(Cn2c3cccc(O)c3c3c(C(N)=O)cccc32)c1
Yield: 40 %

Procedure:
A solution of the 9-[(3-methylphenyl)methyl]-4-hydroxy-5-carbomethoxy carbazole (300 mg, 0.87 mM) in 10 mL THF and 30 mL concentrated aqueous ammonium hydroxide was sonicated for 5 hours at 40-50° C. The mixture was diluted with ethyl acetate and acidified to pH 1 with 5 N HCl. The aqueous layer was extracted three times with ethyl acetate. The combined organic extracts were washed with H2O and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient hexanes/ethyl acetate) to afford 114 mg (40%) of the 9-[(3-methylphenyl)methyl]-4-hydroxy-5-carbamoyl carbazole as an off-white solid. 1H NMR (DMSO-d6) δ10.5 (s, 1H), 8.8 (br s, 1H), 8.4 (br s, 1H), 7.8 (dd, 1H, J=1 and 8 Hz), 7.4 (m, 2H), 7.3 (t, 1H, J=8 Hz), 7.15-7.0 (m, 3H), 6.85 (d, 1H, J=8 Hz), 6.6 (d, 1H, J=8 Hz), 5.95 (d, 1H, J=8 Hz), 5.65 (s, 2H), and 2.25 (s, 3H). IR (KBr, cm−1) 3434, 3203, 1629, 1599, 1579, 1552, 1443, 1330, 1262, 1214, and 776. MS (ES) m/e 329, 331.
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:31][CH3:32])[C:4]([N:6]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]2[NH:24][N:23]=[N:22][N:21]=2)=[CH:10][CH:9]=1)=[O:5].[C:33]([O:37][C:38]([NH:40][C:41]([CH3:47])([CH3:46])[CH2:42][C:43](O)=[O:44])=[O:39])([CH3:36])([CH3:35])[CH3:34]>>[C:33]([O:37][C:38]([NH:40][C:41]([CH3:47])([CH3:46])[CH2:42][C:43]([NH:2][C@H:3]([CH2:31][CH3:32])[C:4]([N:6]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]2[NH:24][N:23]=[N:22][N:21]=2)=[CH:12][CH:13]=1)=[O:5])=[O:44])=[O:39])([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(CC(=O)O)NC(=O)OC(C)(C)C
Reactant: CC[C@@H](N)C(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)c1ccccc1
Agent: Cl
Product: CC[C@@H](NC(=O)CC(C)(C)NC(=O)OC(C)(C)C)C(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)c1ccccc1

Procedure:
Prepared as in Example 1, Step N from (R)-2-amino-N-phenyl-N-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]butanamide, hydrochloride and 3-t-butoxycarbonylamino-3-methylbutanoic acid, N-hydroxysuccinimide ester.
Reaction SMILES: [CH2:1]1[O:13][C:12]2[C:3](=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH2:8][C:7](=[O:14])[CH2:6][CH2:5]3)[O:2]1.[N+:15]([C:18]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[CH:22][C:19]=1[CH:20]=O)([O-:17])=[O:16]>>[N+:15]([C:18]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[CH:22][C:19]=1[CH:20]=[C:8]1[C:9]2[C:4](=[C:3]3[O:2][CH2:1][O:13][C:12]3=[CH:11][CH:10]=2)[CH2:5][CH2:6][C:7]1=[O:14])([O-:17])=[O:16]
Reactant: O=C1CCc2c(ccc3c2OCO3)C1
Reactant: COc1cc(C=O)c([N+](=O)[O-])cc1OC
Product: COc1cc(C=C2C(=O)CCc3c2ccc2c3OCO2)c([N+](=O)[O-])cc1OC

Procedure:
Prepared from 5,6-methylendioxy-2-tetralone and 2-nitro-4,5-dimethoxybenzaldehyde; mp 66-68° C.: IR (Nujol): 1710, 1553; 1H NMR: δ2.98 (2H, t), 3.19 (2H, t), 4.02 (3H, s), 4.03 (3H, s), 6.03 (2H, s), 6.82 (1H, d, J=8.1), 7.07 (1H, s), 7.29 (1H, d, J=8.1), 7.49 (1H, s), 8.20 (1H, s); 13C NMR: δ21.8, 30.8, 56.5, 56.7, 101.8, 105.7, 107.6, 117.9, 119.1, 123.9, 125.9, 126.9, 128.7, 143.4, 145.4, 147.7, 150.1, 152.9, 156.1, 176.4; Anal. (C20H17NO7) C, H, N.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:4]([CH2:15][CH2:16]Cl)[CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[CH2:6][N:7]=1.[Na]>CO>[ClH:14].[Cl:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[CH:5]1[N:4]2[CH2:15][CH2:16][NH:2][C:3]2=[N:7][CH2:6]1
Reactant: NC1=NCC(c2ccccc2Cl)N1CCCl
Agent: Cl
Agent: [Na]
Solvent: CO
Product: Clc1ccccc1C1CN=C2NCCN21

Procedure:
To a stirred solution of 4.6 parts of 2-amino-1-(2-chloroethyl)-5-(o-chlorophenyl)-2-imidazoline hydrochloride in 12 parts of methanol is added a solution of 0.725 parts of sodium in 12 parts of methanol. The whole is stirred and refluxed for 1 hr. 30 minutes. The reaction mixture is evaporated and to the residue is added 50 parts of water and a small amount of a 10N sodium hydroxide solution. The product is extracted twice with 40 parts of methylene chloride. The combined extracts are dried, filtered and evaporated. The residue is converted into the hydrochloride salt in 2-propanol and diisopropylether. The salt is filtered off, washed with acetone and dried, yielding 5-(o-chlorophenyl)-2,3,5,6-tetrahydro-1H-imidazo[1,2-a]imidazole hydrochloride; m.p. 215°-222°C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[CH2:7][CH2:8][CH2:9][C:10](=[O:33])[CH2:11][S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[N:26]=[CH:25][C:24]([O:27][CH2:28][C:29]([F:32])([F:31])[F:30])=[CH:23][N:22]=2)[CH2:17][CH2:16]1)(=[O:14])=[O:13].[BH4-].[Na+]>C(Cl)Cl.CO>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[CH2:7][CH2:8][CH2:9][CH:10]([OH:33])[CH2:11][S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[N:22]=[CH:23][C:24]([O:27][CH2:28][C:29]([F:30])([F:32])[F:31])=[CH:25][N:26]=2)[CH2:17][CH2:16]1)(=[O:13])=[O:14]
Reactant: O=C(CCCc1ncccn1)CS(=O)(=O)N1CCN(c2ncc(OCC(F)(F)F)cn2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: O=S(=O)(CC(O)CCCc1ncccn1)N1CCN(c2ncc(OCC(F)(F)F)cn2)CC1
Temperature: 25 °C
Yield: 95.9 %

Procedure:
To a stirred solution of 5-pyrimidin-2-yl-1-({4-[5-(2,2,2-trifluoroethoxy)pyrimidin-2-yl]piperazin-1-yl}sulfonyl)pentan-2-one (9.47 g, 19.4 mmol) in DCM/MeOH (100 mL/100 mL) was added NaBH4 (807 mg, 21.3 mmol) portionwise and the reaction stirred at room temperature. The reaction was then quenched by addition of a saturated solution of NH4Cl (250 mL) and the organics removed in vacuo. The aqueous residue was then extracted with EtOAc (2×250 mL), combined organics washed with brine (250 mL), dried (MgSO4), filtered and concentrated in vacuo to give 5-pyrimidin-2-yl-1-({4-[5-(2,2,2-trifluoroethoxy)pyrimidin-2-yl]piperazin-1-yl}sulfonyl)pentan-2-ol as a white solid (9.10 g, 18.6 mmol, 96%).
Reaction SMILES: C(=O)([O-])O.[Na+].[CH3:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:14]=2)[C:9]([NH2:24])=[N:8]1.Cl[C:26]([O:28][CH2:29][CH3:30])=[O:27]>O1CCCC1.O>[CH3:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:14]=2)[C:9]([NH:24][C:26](=[O:27])[O:28][CH2:29][CH3:30])=[N:8]1
Reactant: Cn1nc(N)c2ccc(OCc3ccccc3)cc21
Reactant: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)Nc1nn(C)c2cc(OCc3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.2 %

Procedure:
9.8 g of sodium hydrogen carbonate (0.117 mol) are added to a solution of 19.7 g (0.078 mol) of 1-methyl-6-(phenylmethoxy)-1H-indazol-3-amine in 200 ml of a 9:1 mixture of tetrahydrofuran/water, and then 8.9 ml (0.093 mol) of ethyl chloroformate are added dropwise while maintaining the temperature at 25° C. A milky suspension is obtained which is left with stirring for 30 minutes, and then the solvent is evaporated off under reduced pressure. The residue is treated with dichloromethane and water. The organic phase is decanted off, dried over sodium sulphate and concentrated under reduced pressure. The product is crystallized from diisopropyl ether. 20.1 g of product are obtained.
Reaction SMILES: [N:1]1[C:10]2[CH:9]=[CH:8][NH:7][C:6](=O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.O=P(Cl)(Cl)[Cl:14]>>[Cl:14][C:6]1[N:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH:4]=[CH:3][CH:2]=[N:1]2
Reactant: O=c1[nH]ccc2ncccc12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1nccc2ncccc12
Temperature: 0 °C
Yield: 95 %

Procedure:
A solution of 1,6-naphthyridin-5(6H)-one (500 mg, 3.42 mmol) in POCl3 (10 mL) was stirred at 100° C. for 14 h. POCl3 was removed under reduced pressure. The residue was dissolved with DCM (40 mL), and the solution was stirred at 0° C. Then aqueous Na2CO3 was added cautiously to adjust pH to 6-7. Then the organic phase was separated from the aqueous phase, and the aqueous phase was extracted with EtOAc (4×15 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 5-chloro-1,6-naphthyridine as a yellow solid (533 mg, yield 95%). ESI MS: m/z 165 [M+H]+.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:11]([O:13][C:14]1[C:19]([C:20]2[NH:21][C:22](=[O:39])[C:23]3[C:24](=[C:26]([CH2:36][CH2:37][CH3:38])[N:27]([CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)[N:28]=3)[N:25]=2)=[CH:18][C:17]([S:40]([N:43]2[CH2:48][CH2:47][N:46]([CH2:49][CH3:50])[CH2:45][CH2:44]2)(=[O:42])=[O:41])=[CH:16][N:15]=1)[CH3:12]>OCC1C=COC=1>[CH2:49]([N:46]1[CH2:47][CH2:48][N:43]([S:40]([C:17]2[CH:18]=[C:19]([C:20]3[NH:21][C:22](=[O:39])[C:23]4[C:24](=[C:26]([CH2:36][CH2:37][CH3:38])[N:27]([CH2:29][C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=5)[N:28]=4)[N:25]=3)[C:14]([O:13][CH2:11][C:12]3[CH:12]=[CH:11][O:13][CH:14]=3)=[N:15][CH:16]=2)(=[O:41])=[O:42])[CH2:44][CH2:45]1)[CH3:50]
Reactant: CCCc1c2nc(-c3cc(S(=O)(=O)N4CCN(CC)CC4)cnc3OCC)[nH]c(=O)c2nn1Cc1ccccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: OCc1ccoc1
Agent: [K+]
Product: CCCc1c2nc(-c3cc(S(=O)(=O)N4CCN(CC)CC4)cnc3OCc3ccoc3)[nH]c(=O)c2nn1Cc1ccccn1
Yield: 62.7 %

Procedure:
Potassium bis(trimethylsilyl)amide (176 mg, 0.88 mmol) was added to a stirred suspension of the title compound of Example 26 (100 mg, 0.17 mmol) in 3-hydroxymethylfuran (4 ml) and the reaction mixture heated under reflux for 24 hours then allowed to cool. The resulting mixture was evaporated under reduced pressure and the residue purified by column chromatography on silica gel, using dichloromethane: methanol (95:5) as eluant, to furnish the title compound (33 mg, 31%) as a pale yellow foam. δ (CDCl3): 0.93 (3H,t), 1.04 (3H,t), 1.72 (2H,m), 2.41 (2H,q), 2.55 (4H,m), 2.99 (2H,t), 3.14 (4H,m), 5.63 (2H,s), 5.68 (2H,s), 6.60 (1H,s), 7.09 (1H,d), 7.22 (1H,m), 7.44 (1H,s), 7.64 (2H,m), 8.57 (1H,d), 8.68 (1H,s), 9.02 (1H,s), 10.53 (1H,s). LRMS: m/z 619 (M+1)+.