Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[C:4]#[N:5].CN(C1C=CC=CN=1)C.[C:20](Cl)(=[O:28])[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>CC(N(C)C)=O>[Cl:10][C:7]1[CH:8]=[CH:9][C:2]([NH:1][C:20](=[O:28])[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:3]([C:4]#[N:5])[CH:6]=1
Reactant: N#Cc1cc(Cl)ccc1N
Reactant: O=C(Cl)Oc1ccccc1
Agent: CN(C)c1ccccn1
Solvent: CC(=O)N(C)C
Solvent: O
Product: N#Cc1cc(Cl)ccc1NC(=O)Oc1ccccc1
Reaction time: 8 h

Procedure:
(Step 1) To a solution of 2-amino-5-chlorobenzonitrile (5.0 g) and dimethylaminopyridine (0.12 g) in dimethylacetamide (25 ml) was added dropwise phenyl chlorocarbonate (6.2 ml) at room temperature, and the mixture was stirred overnight. The reaction mixture was poured into water, and extracted twice with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:5-*3:7) to give phenyl (4-chloro-2-cyanophenyl)carbamate (7.04 g).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH2:15][C@@H:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH2:19][C@@H:20]2[CH2:28][OH:29])[CH2:12][C@@H:11]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[K+].C1OCCOCCOCCOCCOCCOC1.Br[CH2:59][CH2:60][CH2:61][C:62]([CH2:73][CH3:74])([O:65][Si:66]([CH2:71][CH3:72])([CH2:69][CH3:70])[CH2:67][CH3:68])[CH2:63][CH3:64].[Cl-].[NH4+]>O1CCCC1>[Si:1]([O:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH2:15][C@@H:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH2:19][C@@H:20]2[CH2:28][O:29][CH2:59][CH2:60][CH2:61][C:62]([CH2:73][CH3:74])([O:65][Si:66]([CH2:71][CH3:72])([CH2:67][CH3:68])[CH2:69][CH3:70])[CH2:63][CH3:64])[CH2:12][C@@H:11]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:32])[CH3:33])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC2=CC[C@H]3[C@@H]4CC[C@H](CO)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](O[Si](C)(C)C(C)(C)C)C1
Reactant: CCC(CC)(CCCBr)O[Si](CC)(CC)CC
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: CCC(CC)(CCCOC[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C)O[Si](CC)(CC)CC
Reaction time: 0.08 h
Yield: 99.6 %

Procedure:
1α,3β-Bis(tert-butyldimethylsilyloxy)-17β-(hydroxymethyl)androst-5-ene (11.0 g) was dissolved in tetrahydrofuran. Under cooling with ice, potassium hydride (30% in oil, 200.3 g) and 18-crown-6 (2.64 g) were added to the solution, which was then stirred for 5 min. 1-Bromo-4-ethyl-4-(triethylsilyloxy)hexane (25.91 g) was then added to the mixture and reacted for 3.5 hours. After stopping the reaction by adding a saturated aqueous ammonium chloride solution, the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated under reduced pressure to remove the solvent. The resulting residue was purified by column chromatography (hexane:ethyl acetate=50:1) to give the titled compound (15.8 g).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=2[CH3:18])[N:5]=[N:6][C:7]=1[NH2:8].[CH2:19]([S-:21])[CH3:20].[Na+].CO.C(Cl)Cl>CN(C=O)C.C(OCC)(=O)C>[CH2:19]([S:21][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=2[CH3:18])[N:5]=[N:6][C:7]=1[NH2:8])[CH3:20]
Reactant: Cc1c(-c2nnc(N)c(Cl)n2)cccc1[N+](=O)[O-]
Reactant: CC[S-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CO
Product: CCSc1nc(-c2cccc([N+](=O)[O-])c2C)nnc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To a solution of 5-chloro-3-(2-methyl-3-nitrophenyl)-1,2,4-triazin-6-amine (Ex. 1, A) (1.34 g, 5.04 mmol) in DMF (30 mL) at 0° C. was added sodium ethanethiolate (0.509 g, 6.05 mmol) in one portion. The resulting mixture was stirred at rt for 1 hr before it was diluted with ethyl acetate (300 mL) and washed sequentially with 5% NaHCO3 (50 mL), water (2×50 mL), and brine (50 mL). The organic layer was dried over anhydrous MgSO4 and concentrated under vacuum. The product, 5-(ethylthio)-3-(2-methyl-3-nitrophenyl)-1,2,4-triazin-6-amine (1.333 g, 4.58 mmol, 91% yield), was isolated as a yellow solid by ISCO (120 g silica gel, solid loading, 2-5% MeOH/CH2Cl2).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:13]3([CH2:17][O:16][C:15]([N:18](C(OC(C)(C)C)=O)[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[N:14]3)[C:10]3([CH2:12][CH2:11]3)[CH2:9][O:8][C:5]2=[CH:6][CH:7]=1.F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.C[Si]([N-:55][Si](C)(C)C)(C)C.[Li+].Cl>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].CO>[NH2:55][C:2]1[CH:3]=[C:4]2[C:13]3([CH2:17][O:16][C:15]([NH:18][C:19](=[O:20])[O:21][C:22]([CH3:25])([CH3:23])[CH3:24])=[N:14]3)[C:10]3([CH2:12][CH2:11]3)[CH2:9][O:8][C:5]2=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=NC2(CO1)c1cc(Br)ccc1OCC21CC1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Pd]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: Cl
Solvent: CO
Product: CC(C)(C)OC(=O)NC1=NC2(CO1)c1cc(N)ccc1OCC21CC1
Temperature: 100 °C
Reaction time: 1 h
Yield: 75.9 %

Procedure:
To a mixture of di-tert-butyl (6′-bromodispiro[cyclopropane-1,3′-chromene-4′,4″-[1,3]oxazol]-2″-yl)imidodicarbonate (200 mg, 0.393 mmol), bis(dibenzylideneacetone)palladium (0) (22.6 mg, 0.039 mmol), and tri-tert-butylphosphonium tetrafluoroborate (11.6 mg, 0.039 mmol) was added lithium bis(trimethylsilyl)amide (1 M in toluene, 1.96 mL, 1.96 mmol) at ambient temperature. After stirring for 1 hour at 100° C., the mixture was cooled down to ambient temperature. To the mixture were added 1M aqueous HCl (1.96 mL) and MeOH (1.96 mL) at ambient temperature, and the mixture was stirred for 30 minutes at the same temperature. The mixture was extracted with CHCl3, and the organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated at reduced pressure and purified with column chromatography on silica gel (hexane-EtOAc, a linear gradient of EtOAc from 0 to 90%) to afford tert-butyl (6′-aminodispiro[cyclopropane-1,3′-chromene-4′,4″-[1,3]oxazol]-2″-yl)carbamate (103 mg).
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][C:6]1[CH:7]=[N:8][N:9]([CH2:12][C:13]2[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][C:14]=2[O:20][CH2:21][CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[C:10]=1[CH3:11])C.[Li+].[OH-].O>C1COCC1.CO>[Br:19][C:17]1[CH:16]=[CH:15][C:14]([O:20][CH2:21][CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[C:13]([CH:18]=1)[CH2:12][N:9]1[C:10]([CH3:11])=[C:6]([CH2:5][C:4]([OH:27])=[O:3])[CH:7]=[N:8]1
Reactant: CCOC(=O)Cc1cnn(Cc2cc(Br)ccc2OCC(CC)CC)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCC(CC)COc1ccc(Br)cc1Cn1ncc(CC(=O)O)c1C
Temperature: 100 °C
Yield: 10 %

Procedure:
To a solution of {1-[5-bromo-2-(2-ethyl-butoxy)-benzyl]-5-methyl-1H-pyrazol-4-yl}-acetic acid ethyl ester, 3, 0.1 g (0.22 mmol) in a mixture of THF (1 mL) and methanol (0.5 ml) was added a solution of LiOH (0.12 g in 1 ml H2O). The resulting mixture was heated at 100° C. on microwave for 20 minutes. The mixture was poured into water (20 mL) and extracted with EtOAc (3×15 mL). The organic layers were combined, washed with brine (30 mL), dried (MgSO4) and the volatiles removed in vacuo. The crude product was purified on silica to yield 7.4 mg (10%) of {1-[5-Bromo-2-(2-ethyl-butoxy)-benzyl]-5-methyl-1H-pyrazol-4-yl}-acetic acid, 4 as a white solid.
Reaction SMILES: [CH:1]1([C:4]2[N:8]=[C:7]([CH:9]3[CH2:14][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=4)[CH2:12][N:11]([C:26]([N:28]4[CH2:33][CH2:32][S:31][CH2:30][CH2:29]4)=[O:27])[CH2:10]3)[O:6][N:5]=2)[CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:42])C=1>>[CH:1]1([C:4]2[N:8]=[C:7]([CH:9]3[CH2:14][CH:13]([C:15]4[CH:16]=[CH:17][C:18]([CH2:21][C:22]([F:25])([F:23])[F:24])=[CH:19][CH:20]=4)[CH2:12][N:11]([C:26]([N:28]4[CH2:33][CH2:32][S:31](=[O:42])[CH2:30][CH2:29]4)=[O:27])[CH2:10]3)[O:6][N:5]=2)[CH2:3][CH2:2]1
Reactant: O=C(N1CCSCC1)N1CC(c2ccc(CC(F)(F)F)cc2)CC(c2nc(C3CC3)no2)C1
Reactant: O=C(OO)c1cccc(Cl)c1
Product: O=C(N1CCS(=O)CC1)N1CC(c2ccc(CC(F)(F)F)cc2)CC(c2nc(C3CC3)no2)C1

Procedure:
78.0 mg (0.162 mmol) of the compound from Example 46A were reacted according to General Method 1 with 50.4 mg (0.146 mmol) of meta-chloroperbenzoic acid. Yield: 76.2 mg (88% of theory)
Reaction SMILES: [C:1]([CH2:6][N:7]1[N:11]=[N:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=3)[CH:13]=2)=[N:8]1)([O:3]CC)=[O:2].C(O)(=[O:32])C>C(O)C.[OH-].[Na+].O>[C:1]([CH2:6][N:7]1[N:11]=[N:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=3)=[O:32])[CH:13]=2)=[N:8]1)([OH:3])=[O:2]
Reactant: CC(=O)O
Reactant: CCOC(=O)Cn1nnc(-c2cccc(OCc3ccc4ccccc4n3)c2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)Cn1nnc(-c2cccc(OC(=O)c3ccc4ccccc4n3)c2)n1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
A mixture of 1.3 g of 2-carbethoxymethyl-5-[3-(2-quinolylmethyloxy)phenyl]tetrazole in 5 ml ethanol and 40 ml of 1N NaOH was stirred at 70° C. for 4 hours. It was cooled, diluted with water, acidified with acetic acid, filtered, washed with water, and then ethyl acetate to give 1.0 g product.
Reaction SMILES: [C:1]([C:4]1[CH:34]=[CH:33][C:7]2[NH:8][C:9]([C:11]3[CH:12]=[C:13]([CH2:29][C:30](O)=[O:31])[CH:14]=[C:15]([C:18]4[CH:23]=[C:22]([S:24](=[O:27])(=[O:26])[NH2:25])[CH:21]=[CH:20][C:19]=4[OH:28])[C:16]=3[OH:17])=[N:10][C:6]=2[CH:5]=1)(=[NH:3])[NH2:2].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CC1C(C)=C(C)C=CN=1.[NH2:68][CH2:69][CH2:70][N:71]1[CH2:76][CH2:75][O:74][CH2:73][CH2:72]1.Cl.C(#N)C>CN(C)C=O>[C:1]([C:4]1[CH:34]=[CH:33][C:7]2[NH:8][C:9]([C:11]3[CH:12]=[C:13]([CH2:29][C:30]([NH:68][CH2:69][CH2:70][N:71]4[CH2:76][CH2:75][O:74][CH2:73][CH2:72]4)=[O:31])[CH:14]=[C:15]([C:18]4[CH:23]=[C:22]([S:24](=[O:27])(=[O:26])[NH2:25])[CH:21]=[CH:20][C:19]=4[OH:28])[C:16]=3[OH:17])=[N:10][C:6]=2[CH:5]=1)(=[NH:3])[NH2:2]
Reactant: N=C(N)c1ccc2[nH]c(-c3cc(CC(=O)O)cc(-c4cc(S(N)(=O)=O)ccc4O)c3O)nc2c1
Reactant: NCCN1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cc1ccnc(C)c1C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC#N
Product: N=C(N)c1ccc2[nH]c(-c3cc(CC(=O)NCCN4CCOCC4)cc(-c4cc(S(N)(=O)=O)ccc4O)c3O)nc2c1
Reaction time: 1 h
Yield: 53.1 %

Procedure:
[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-acetic acid (96 mg, 0.20 mmol), prepared as in Reference 9, was dissolved in dry N,N-dimethylformamide (20 mL) and the solution was treated with O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (84 mg, 0.22 mmol) and 2,3,4-trimethyl-pyridine (0.106 mL, 0.80 mmol). The mixture was stirred for one hour and then 4-(2-aminoethyl)-morpholine (29 uL, 0.22 mmol) was added. The mixture was stirred until the reaction was complete (½ to 1 hours) and then neutralizated with 1N hydrochloric acid to pH ˜3. The solvents were evaporated at 30° C. to give an oily residue. The crude amide then was prepped at 2:30 (acetonitrile/20 mmol HCl) and the solvents were lyophilized to give 2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-N-(2-morpholin-4-yl-ethyl)-acetamide (63.0 mg, 53%). LCMS: (MH+)=594.3; (MH−)=592.2. NMR (DMSO-d6) δ 2.78 (m, 4H), 3.12 (m, 2H), 3.26 (t, J=3 Hz, 2H), 3.57 (m, 4H), 3.59 (s, 2H), 7.17 (d, J=5 Hz, 1H), 7.23 (br s, 1H), 7.37 (d, J=1.5 Hz, 1H), 7.70 (m, 2H), 7.79 (d of d, J=1.5 Hz, 1H), 7.88 (d, J=5 Hz, 1H), 8.22 (d, J=1 Hz, 1H), 8.24 (s, 1H), 8.59 (t, J=3 Hz, 1H), 9.18, 9.43 (2s, 4H).
Reaction SMILES: O[C@@H]1CCN(C(C2C=CC(OC(F)(F)F)=CC=2)=O)[C@H]1C(NOCC1C=CC=CC=1)=O.COC(=O)C([NH:44][C:45](=[O:63])[C:46]1[CH:51]=[CH:50][C:49]([C:52]#[C:53][C:54]#[C:55][C:56]2[CH:61]=[CH:60][C:59]([NH2:62])=C[CH:57]=2)=[CH:48][CH:47]=1)CNC(OC(C)(C)C)=O.CCN(CC)CC>C(Cl)Cl.CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[N:62]1[CH:59]=[CH:60][CH:61]=[C:56]([C:55]#[C:54][C:53]#[C:52][C:49]2[CH:50]=[CH:51][C:46]([C:45]([NH2:44])=[O:63])=[CH:47][CH:48]=2)[CH:57]=1
Reactant: COC(=O)C(CNC(=O)OC(C)(C)C)NC(=O)c1ccc(C#CC#Cc2ccc(N)cc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=C(NOCc1ccccc1)[C@H]1[C@H](O)CCN1C(=O)c1ccc(OC(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(C#CC#Cc2cccnc2)cc1
Reaction time: 0.08 h

Procedure:
Resin 1 (142 mg, 0.109 mmol) was swelled in DCM (2 mL) for 1 h and drained. A solution of 3-ethynylpyridine 2 (38 mg, 0.368 mmol) and Et3N (200 μL 1.4 mmol) in DMF (2 mL) was added and the resin agitated for 5 min. A mixture of PdCl2(PPh3)2 (22 mg, 0.031 mmol) and CuI (25 mg, 0.131 mmol) was added and the resin was agitated for 72 h. The resin was drained, washed with DMF (3×2 mL), DCM (3×2 mL) and cleaved with 10% TFA/DCM (1.5 mL) for 20 min. The solution was collected and the resin was rinsed with additional 10% TFA/DCM (1.0 mL). The cleavage fractions were combined, treated with neat TFA (2.0 mL), stirred for 1 h at rt and concentrated by rotary evaporation to give a crude brown residue. Purification by RP-HPLC (C18 column, CH3CN gradient 5-65%, 0.1% TFA, UV analysis 300 nm, 24 min) and lyophilization of the collected fractions afforded 4.4 mg (11% yield) of N-(2R)-hydroxy-(1S)-hydroxycarbamoyl-propyl)-4-(4-pyridin-3-yl-buta-1,3-diynyl)-benzamide. LRMS (ES+) m/z 364.0 (C20H17N3O4+H requires 364.13); RP-HPLC (300 nm, 24 min run) 11.2 min.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:23])=[CH:4][N:3]=1.[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:26]=1[OH:32]>>[Cl:23][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:32][C:26]2[C:25]([F:24])=[CH:30][CH:29]=[CH:28][C:27]=2[F:31])=[N:3][CH:4]=1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Cl)cc1
Reactant: Oc1c(F)cccc1F
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Oc2c(F)cccc2F)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 48 from methyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 48) and 2,6-difluorophenol: 1H-NMR (CDCl3) δ 8.54 (1H, d, J=2.7 Hz), 8.11 (1H, d, J=2.7 Hz), 8.05–7.94 (3H, m), 7.48–7.42 (2H, m), 7.33–7.23 (1H, m), 7.12–7.02 (2H, m), 5.45–5.33 (1H, m), 3.90 (3H, s), 1.61 (3H, d, J=7.0 Hz); MS (ESI) m/z 447 (M+H)+, 445 (M−H)−.
Reaction SMILES: [C:1]1([NH:7][C@@H:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]2[NH:14]C(OC(C)(C)C)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]1([NH:7][C@@H:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]2[NH2:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CCCC[C@H]1Nc1ccccc1
Reaction time: 8 h

Procedure:
The cis-N-phenyl-N′-(t-butyloxycarbonyl)-cyclohexane-1,2-diamine isomer from above (0.095 g, 0.33 mmol) was dissolved in CH2Cl2 (2 mL) and treated with trifluoroacetic acid (2 mL) and the mixture stirred overnight. The reaction was worked up to afford the title compound (0.069 g) as a pale yellow solid. 1H NMR (CDCl3) 1.28–1.37 (m, 5H), 1.50–1.63 (m, 6H), 3.18 (br s, 1H), 3.42–3.45 (m, 1H), 6.63–6.70 (m, 3H), 7.16 (br t, 2H, J=7.5 Hz).
Reaction SMILES: OCC1C=CC(C[NH:8][C:9]([C:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)=[O:10])=CC=1.S(Cl)(Cl)=O.O>CN(C=O)C.[Cl-].[Na+].O>[O:21]=[C:20]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=[C:11]1[C:9]([NH2:8])=[O:10]
Reactant: O=C(NCc1ccc(CO)cc1)c1c[nH]c2ccccc2c1=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1c[nH]c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-[4-(hydroxymethyl)benzyl] 4-oxo-1,4-dihydro-quinoline-3-carboxamide (279 mg; 0.79 mmol) in anhydrous DMF (8 mL) at 0° is added thionyl chloride (61 μL; 0.83 mmol) and the solution is stirred at room temperature for 1 h. Water (10 mL) and brine (10 mL) are added, and the precipitate is collected, rinsed with a small quantity of methanol and ether, and dried to give 214 mg of N-[4-chloromethyl)benzyl] 4-oxo-1,4-dihydro-quinoline-3-carboxamide.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:25]([CH3:27])[CH3:26])[C:7]([N:9]1[CH2:13][C:12](=[O:14])[CH2:11][C@H:10]1[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])=[O:8])=[O:4].C1(C)C=CC(S(=O)=O)=CC=1.[CH2:38](O)[CH2:39][OH:40]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:25]([CH3:27])[CH3:26])[C:7]([N:9]1[C@H:10]([C:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])[CH2:11][C:12]2([O:40][CH2:39][CH2:38][O:14]2)[CH2:13]1)=[O:8])=[O:4]
Reactant: OCCO
Reactant: COC(=O)N[C@H](C(=O)N1CC(=O)C[C@H]1C(=O)OCc1ccccc1)C(C)C
Agent: Cc1ccc([SH](=O)=O)cc1
Solvent: Cc1ccccc1
Product: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1C(=O)OCc1ccccc1)OCCO2)C(C)C

Procedure:
(S)-benzyl 1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-4-oxopyrrolidine-2-carboxylate (2.45 g, 6.51 mmol) in a round bottom flask was dissolved in anhydrous toluene (200 mL) and p-toluene sulfonic acid monohydride (124 mg, 0.1 mmol) and ethylene glycol (808 mg, 13.02 mmol) were added and the mixture was refluxed for 18 hours, removing the generated byproduct water with a Dean-Stark apparatus. The crude mixture was then diluted with ethyl acetate and washed, respectively, with 10% citric acid, saturated ammonium chloride, 10% sodium carbonate and finally with brine. The organic layers were combined and dried over sodium sulfate and concentrated down on rotovap. The crude residue was then purified on normal phase column chromatography with 5% MeOH/DCM. (2.3 g, 84%)
Reaction SMILES: O.C(O)(=O)C.[N+:6]([C:9]1[C:10]([NH:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[N:11][CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)([O-])=O>[Fe].C(O)C>[F:24][C:21]([F:22])([F:23])[CH2:20][NH:19][C:10]1[C:9]([NH2:6])=[CH:14][C:13]([C:15]([F:16])([F:17])[F:18])=[CH:12][N:11]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cnc1NCC(F)(F)F
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1cc(C(F)(F)F)cnc1NCC(F)(F)F
Temperature: 70 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
A mixture of an iron powder (2.12 g), ethanol 6 ml), water 4 ml) and acetic acid 0.1 ml) was added dropwise a mixture of (3-nitro-5-trifluoromethylpyridin-2-yl)-(2,2,2-trifluoroethyl)amine (1.83 g) and ethanol (10 ml) at 70° C., and then the mixture was stirred at 70° C. for 1 hour. After allowing to cool, the cooled reaction mixture was filtrated. To the filtrate was added water, and then the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressure to give N2-(2,2,2-trifluoroethyl)-5-trifluoromethylpyridin-2,3-diamine (1.59 g).
Reaction SMILES: [Cl-].[K+].[C:3]([O-:15])(=[O:14])[CH2:4][C:5]([CH2:10][C:11]([O-:13])=[O:12])([C:7]([O-:9])=[O:8])[OH:6].[K+].[K+].[K+].C([O-])(=O)CC(CC([O-])=O)(C([O-])=O)O.[Mg+2:32].C([O-])(=O)CC(CC([O-])=O)(C([O-])=O)O.[Mg+2].[Mg+2].C([O-])(=O)CC(CC([O-])=O)(C([O-])=O)O.[Mg+2].[K+].[K]>>[Mg:32].[C:3]([O-:15])(=[O:14])[CH2:4][C:5]([CH2:10][C:11]([O-:13])=[O:12])([C:7]([O-:9])=[O:8])[OH:6]
Reactant: [Mg+2]
Agent: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Agent: [Cl-]
Agent: [K+]
Product: [Mg]

Procedure:
Each patient underwent five phases of study: placebo, potassium chloride, potassium citrate, magnesium citrate, and potassium-magnesium citrate. The results (mean values for the two patients) are outlined in Table 1. Compared to potassium chlorlde, potassium magnesium citrate gave a higher urinary pH, magnesium, and citrate. Compared to potassium citrate, potassium magnesium citrate produced a greater citrate excretion as magnesium citrate, potassium magnesium citrate gave higher values for urinary pH and citrate. Finally, compared to the placebo, potassium magnesium citrate produced higher values for urinary pH, magnesium, potassium and citrate, and lower values for urinary calcium and oxalate.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:16])[N:4]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[N:5]=[CH:6][C:7]=1[OH:8].[Cl:17][C:18]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:19]=1[CH2:20]Cl.C(N(CC)CC)C.O>CN(C)C=O>[Cl:1][C:2]1[C:3](=[O:16])[N:4]([C:9]2[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=2)[N:5]=[CH:6][C:7]=1[O:8][CH2:20][C:19]1[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:18]=1[Cl:17]
Reactant: O=c1c(Cl)c(O)cnn1-c1ccc(Cl)cc1
Reactant: ClCc1ccc(Cl)cc1Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=c1c(Cl)c(OCc2ccc(Cl)cc2Cl)cnn1-c1ccc(Cl)cc1
Reaction time: 7 h
Yield: 70 %

Procedure:
In 50 ml of N,N-dimethylformamide were dissolved 1.5 g (5.9 m mol) of 4-chloro-2-(4-chlorophenyl)-5-hydroxy-3(2H)-pyridazinone and 1.3 g (6.6 m mol) of 2,4-dichlorobenzyl chloride, and thereto was added 0.7 g of triethylamine. The reaction mixture was heated under stirring on an oil bath at 100° to 120° C. for 7 hours. After allowing to cool, the reaction mixture was poured into 200 ml of water and the precipitated solid was taken out by filtration, washed with water, dried and then recrystallized from benzene to give 1.7 g of the intended compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:32])([CH3:31])[CH2:12][C:13]([OH:30])([C:26]([F:29])([F:28])[F:27])[CH2:14][C:15]2[NH:23][C:22]3[C:17](=[N:18][C:19]([C:24]#[N:25])=[CH:20][CH:21]=3)[CH:16]=2)[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.B.CSC.Cl>C1COCC1.C(OCC)(=O)C>[NH2:25][CH2:24][C:19]1[N:18]=[C:17]2[CH:16]=[C:15]([CH2:14][C:13]([OH:30])([CH2:12][C:11]([C:4]3[C:5]4[O:9][CH2:8][CH2:7][C:6]=4[CH:10]=[C:2]([Cl:1])[CH:3]=3)([CH3:32])[CH3:31])[C:26]([F:29])([F:27])[F:28])[NH:23][C:22]2=[CH:21][CH:20]=1
Reactant: CC(C)(CC(O)(Cc1cc2nc(C#N)ccc2[nH]1)C(F)(F)F)c1cc(Cl)cc2c1OCC2
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CSC
Product: CC(C)(CC(O)(Cc1cc2nc(CN)ccc2[nH]1)C(F)(F)F)c1cc(Cl)cc2c1OCC2
Temperature: 25 °C
Yield: 47.6 %

Procedure:
2-[4-(5-Chloro-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-pyrrolo[3,2-b]pyridine-5-carbonitrile (100 mg, 0.22 mmol) was dissolved in 3 mL of THF and borane-methyl sulfide (10 M, 0.065 mL, 0.648 mmol) was added. The reaction was heated at reflux for 1 hour and then cooled to room temperature. 1 mL of a 6 N HCl solution was then added. The reaction was heated at reflux overnight. The reaction was cooled to room temperature, diluted with 50 mL of ethyl acetate, and then quenched with saturated sodium carbonate solution until the pH was 12. The organic layer was separated and aqueous layer was extracted with three 50 mL portions of ethyl acetate. The combined organic fractions were dried over sodium sulfate and the solvent was removed in vacuo. The residue was purified by preparative HPLC (polar condition) to give the title compound (49 mg, 49% yield).