Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[S:2]1(=[O:20])[CH2:6][CH2:5][CH:4]([N:7]2[CH2:12][CH2:11][N:10]([C:13]3[N:18]=[CH:17][N:16]=[C:15]([NH2:19])[CH:14]=3)[CH2:9][CH2:8]2)[CH2:3]1.[H-].[Na+].Cl[C:24]1[S:25][C:26]([C:29]#[N:30])=[CH:27][N:28]=1>>[O:20]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH:4]([N:7]2[CH2:8][CH2:9][N:10]([C:13]3[N:18]=[CH:17][N:16]=[C:15]([NH:19][C:24]4[S:25][C:26]([C:29]#[N:30])=[CH:27][N:28]=4)[CH:14]=3)[CH2:11][CH2:12]2)[CH2:3]1
Reactant: Nc1cc(N2CCN(C3CCS(=O)(=O)C3)CC2)ncn1
Reactant: N#Cc1cnc(Cl)s1
Agent: [H-]
Agent: [Na+]
Product: N#Cc1cnc(Nc2cc(N3CCN(C4CCS(=O)(=O)C4)CC3)ncn2)s1

Procedure:
6-[4-(1,1-Dioxidotetrahydrothien-3-yl)piperazin-1-yl]pyrimidin-4-amine 39-2 (0.30 g, 1.01 mmol), sodium hydride (0.081 g, 2.02 mmol) and 2-chloro-1,3-thiazole-5-carbonitrile 2-2 (0.14 g, 1.01 mmol) were treated as in Scheme 4 above. The product was purified on a C18 column. Hi-Res MS: calc: 406.1114 found: 406.1105. 1H-NMR: 8.46(s, 1H); 8.01(s, 1H); 6.24(s, 1H); 3.86(br s, 6H); 3.59(m, 1H); 3.39(m, 1H); 3.27(m, 1H); 3.17(complex, 4H); 2.70(m, 1H); 2.29(m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:9][C:10]2[CH:20]=[CH:19][C:13]([O:14][CH:15]([CH3:18])[CH:16]=[O:17])=[CH:12][CH:11]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[S:21](=[O:24])([OH:23])[O-:22].[Na+:25]>CO.O>[Cl:1][C:2]1[C:3]([O:9][C:10]2[CH:20]=[CH:19][C:13]([O:14][CH:15]([CH3:18])[CH:16]([OH:17])[S:21]([O-:24])(=[O:23])=[O:22])=[CH:12][CH:11]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[Na+:25]
Reactant: O=S([O-])O
Reactant: CC(C=O)Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1)C(O)S(=O)(=O)[O-]
Temperature: 25 °C
Reaction time: 96 h
Yield: 72.7 %

Procedure:
A solution of 2-{p-[(3,5-dichloro-2-pyridyl)oxy]phenoxy}propionaldehyde (25.38 g, 0.0813 mol) in methanol (300 mL) is added dropwise to a solution of sodium bisulfite (10.2 g, 0.0976 mol) in water (100 mL). The reaction mixture is stirred for 4 days at room temperature and filtered. The filter cake is dried in a vacuum oven overnight to obtain the title product as a white solid (24.6 g, mp 172°-173° C.).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[C:11]([C:12](OCC)=O)=[CH:10][N:9]=[C:8]2[CH:17]=[N:18][NH:19][C:7]=12)[CH2:2][CH2:3][CH3:4].[H-].[Al+3].[Li+].[H-].[H-].[H-].CCOCC.[OH-].[Na+]>C1COCC1.O>[CH2:1]([NH:5][C:6]1[C:11]([CH3:12])=[CH:10][N:9]=[C:8]2[CH:17]=[N:18][NH:19][C:7]=12)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1c(C(=O)OCC)cnc2cn[nH]c12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CCCCNc1c(C)cnc2cn[nH]c12

Procedure:
A solution of ethyl 7-n-butylamino-1H-pyrazolo[4,3-b]-pyridine-6-carboxylate (524 mg, 2 mmol) in dry THF (15 ml) was added dropwise to a stirred suspension of lithium aluminium hydride (152 mg, 4 mmol) in THF (15 ml). The mixture was heated under reflux under nitrogen for 90 min then cooled. Ether (30 ml), water (0.15 ml), 10% sodium hydroxide solution (0.15 ml) and water (0.45 ml) were added sequentially, with stirring, and the mixture was filtered, then evaporated in vacuo. The glassy residue (300 mg) was recrystallised from ethyl acetate/ether, to give a white solid, m.p. 86°-95° C.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:5]([CH2:10][NH2:11])=[N:6][CH:7]=[CH:8][N:9]=1.C(N=C=NCCCN(C)C)C.C(N(C(C)C)CC)(C)C.[CH2:32]=[C:33]1[CH2:36][CH:35]([C:37](O)=[O:38])[CH2:34]1>C(Cl)Cl>[Cl:3][C:4]1[C:5]([CH2:10][NH:11][C:37]([CH:35]2[CH2:36][C:33](=[CH2:32])[CH2:34]2)=[O:38])=[N:6][CH:7]=[CH:8][N:9]=1
Reactant: C=C1CC(C(=O)O)C1
Reactant: NCc1nccnc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=C1CC(C(=O)NCc2nccnc2Cl)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
C-(3-Chloropyrazin-2-yl)-methylamine bis-HCl (1.0 g, 4.62 mmol), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide (EDC) (1.31 g, 6.47 mmol, 1.4 eq.), 4-dimethylamino pyridine DMAP) (0.141 g, 1.15 mmol, 0.25 eq.), and diisopropylethylamine (DIPEA) (2.42 mL, 1.79 g, 13.9 mmol, 3.0 eq.) were dissolved in anhydrous CH2Cl2 (25 mL). To this solution, a solution of 3-methylenecyclobutanecarboxylic acid (0.622 g, 5.54 mmol, 1.2 eq.) in anhydrous CH2Cl2 (25 mL) was added under N2 and the reaction was allowed to stir overnight at rt. Reaction mixture was concentrated in vacuo and the resulting residue was dissolved in EtOAc, washed with water (2×), NaHCO3 (1×), water (1×), and brine (1×), dried over Na2SO4, filtered, and concentrated in vacuo, giving crude title compound, as a brown oil. The crude material was purified by chromatography on silica gel [Jones Flashmaster, 20 g/70 mL cartridge, eluting with EtOAc:Hex 10%→20%→40%→70%], affording the title compound as a pale yellow solid. Additionally, the title compound could be prepared by the following route: 1,1′—Carbonyldiimidazole (CDT) (0.824 g, 5.08 mmol, 1.1 eq.) and 3-methylenecyclobutanecarboxylic acid (0-570 g, 5.08 mmol, 1.1 eq.) were dissolved in anhydrous THF (12 mL) and allowed to stir at 60° C. for 2 h. A solution of C-(3-chloropyrazin-2-yl)-methylamine bis-HCl (1.0 g, 4.62 mmol) and diisopropylethylamine (DIPEA) (2.42 mL, 1.79 g, 13.9 mmol, 3.0 eq.) in anhydrous CH2Cl2 (13 mL) was added to the acid mixture and the reaction was allowed to stir at 60° C., under N2, overnight. The reaction mixture was concentrated in vacuo and the resulting residue was dissolved in EtOAc, washed with NaHCO3 (2×) and brine (1×), dried over Na2SO4, filtered, and concentrated in vacuo, giving crude title compound, as a brown oil. The crude material was purified by chromatography on silica gel [Jones Flashmaster, 20 g/70 mL cartridge, eluting with EtOAc:Hex 10%→20%→40%→70%], affording the title compound as a pale yellow solid; 1H NMR (CDCl3, 400 MHz) δ 2.86-2.96 (m, 2H), 3.03-3.19 (m, 3H), 4.72 (dd, J=4.4, 0.8 Hz, 2H), 4.79-4.84 (m, 2H), 6.78 (s, —NH), 8.32-8.34 (m, 1H), 8.46 (d, J=2.8 Hz, IRS); MS (ES+): m/z 238.19 (90) [MH+]; HPLC: tR=2.67 min (OpenLynx, polar—7 min).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6](=[NH:8])[NH2:7])[CH3:2].[CH2:10]([O:12][C:13](=[O:18])[C:14]([CH2:16]Br)=O)[CH3:11]>CN1C(=O)N(C)CCC1>[NH2:8][C:6]1[NH:7][C:14]([C:13]([O:12][CH2:10][CH3:11])=[O:18])=[CH:16][C:5]=1[C:4]([O:3][CH2:1][CH3:2])=[O:9]
Reactant: CCOC(=O)C(=O)CBr
Reactant: CCOC(=O)CC(=N)N
Solvent: CN1CCCN(C)C1=O
Product: CCOC(=O)c1cc(C(=O)OCC)c(N)[nH]1
Temperature: 60 °C

Procedure:
At 0-5° C., 56.0 g (0.43 mol) of 2-amidino-acetic acid ethyl ester [for preparation see: Liebigs Ann. Chem., 1561 (1981)] are introduced into 172 ml of DMPU. 56.0 ml (0.45 mol) of bromopyruvic acid ethyl ester are added dropwise thereto within the course of 30 min and the reaction mixture is then heated at 60° C. for 3 hours. The dark-brown reaction solution is poured into 1 liter of ice-water and extracted with 1 liter of ethyl acetate and twice with a 0.5 liter of ethyl acetate each time. The organic phases are washed three times with a 0.5 liter of water and a 0.5 liter of brine, dried (Na2SO4) and concentrated by evaporation. Column chromatography (SiO2, hexane/ethyl acetate [1:1]) and crystallization from diethyl ether/hexane yield the title compound; m.p. 147-149° C.; MS: (M)+ =226.
Reaction SMILES: [CH:1]1([CH2:4][C:5](=O)/[C:6](/[C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[N:12]=2)=[CH:7]\N(C)C)[CH2:3][CH2:2]1.Cl.[NH2:26][C:27]([NH2:29])=[NH:28].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:1]1([CH2:4][C:5]2[C:6]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)[N:12]=3)=[CH:7][N:26]=[C:27]([NH2:29])[N:28]=2)[CH2:3][CH2:2]1
Reactant: N=C(N)N
Reactant: CN(C)/C=C(\C(=O)CC1CC1)c1ccnc(Nc2ccncc2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ncc(-c2ccnc(Nc3ccncc3)n2)c(CC2CC2)n1
Temperature: 60 °C
Yield: 31.3 %

Procedure:
To a solution of (3Z)-1-cyclopropyl-4-(dimethylamino)-3-[2-(pyridin-4-ylamino)pyrimidin-4-yl]but-3-en-2-one (9) (80 mg, 0.247 mmol) in DMF (2061 μl), Guanidine HCl (35.3 mg, 0.371 mmol) and potassium carbonate (103 mg, 0.742 mmol) were added and the reaction was heated at 60° C. for 4 hours. The crude product was purified by reverse-phase HPLC [30-90% organic phase over 15 minutes] followed by Biotage™ silica gel chromatography [10 g SNAP column, 100% DCM to 12% MeOH/DCM] to obtain the desired product as a white solid (24.72 mg, 31.3% yield). 1H NMR (400 MHz, MeOD) δ ppm 0.01-0.14 (m, 2 H) 0.39 (q, J=6.06 Hz, 2 H) 0.94-1.10 (m, 1 H) 2.87 (d, J=7.07 Hz, 2 H) 7.10 (d, J=5.05 Hz, 1 H) 7.83 (d, J=6.57 Hz, 2 H) 8.30 (d, J=6.57 Hz, 2 H) 8.41 (s, 1 H) 8.57 (d, J=5.05 Hz, 1 H). HRMS (ES+) for C17 H17N7.H+ [MH+]: calcd, 320.1624. found, 320.1636. UV-LC: 100% UV purity at 254/214 nm; tR=4.67 minute over 7.75 minutes.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[C:23](O)(=[O:30])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C1(N=C=NC2CCCCC2)CCCCC1.N1(C2C=CN=CC=2)CCCC1>O1CCCC1.C(Cl)Cl>[CH2:24]([C:23]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:6][CH:7]=1)=[O:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCC(=O)O
Reactant: CCCCCCc1ccc2nc(-c3ccc(O)cc3)sc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCCCCC(=O)Oc1ccc(-c2nc3ccc(CCCCCC)cc3s2)cc1
Temperature: 25 °C
Yield: 92.2 %

Procedure:
To 0.32 g (1.03 mM) of 2-(p-hydroxyphenyl)-6-hexylbenzothiazole, 0.13 g (1.03 mM) of heptanoic acid, 15 ml of methylene chloride and 5 ml of tetrahydrofuran were added, followed by addition of 0.21 g of N,N'-dicyclohexylcarbodiimide (DCC) and 0.02 g of 4-pyrrolidinopyridine under stirring at room temperature and further stirring for 6 hours at room temperature. After the reaction, the resultant N,N'-dicyclohexylurea was recovered by filtration, followed by washing with methylene chloride to be added to the filtrate. The solvent of the resultant filtrate was distilled-off under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (eluent: toluene), followed by two times of recrystallization from a mixture solvent of toluene/methanol to obtain 0.39 g of 2-(p-hexylcarbonyloxyphenyl)-6-hexylbenzothiazole (Yield: 88.6%). ##STR203##
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][CH2:19][CH3:20])[C:13]([C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1)=[C:12]2[CH3:30])C1C=CC=CC=1.Br>C(O)(=O)C>[CH3:30][C:12]1[C:11]2[C:15](=[CH:16][CH:17]=[C:9]([OH:8])[CH:10]=2)[N:14]([CH2:18][CH2:19][CH3:20])[C:13]=1[C:21]1[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=1
Reactant: CCCn1c(-c2ccc([N+](=O)[O-])cc2)c(C)c2cc(OCc3ccccc3)ccc21
Agent: Br
Solvent: CC(=O)O
Product: CCCn1c(-c2ccc([N+](=O)[O-])cc2)c(C)c2cc(O)ccc21

Procedure:
Four grams (10 m mole) of 5-benzyloxy-3-methyl-2-(4-nitro-phenyl)-1-propyl-1H-indole and 40 ml of a saturated solution of hydrogen bromide in glacial acetic acid were refluxed for 20 minutes. After evaporation, the residue was purified by chromatography on silicagel (solvent: toluene/acetone (20:1)).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[N:9]([O-])=O.[Na+].O.O.[Sn](Cl)Cl.[OH-].[Na+]>Cl.O>[Cl:8][C:3]1[C:2]([NH:1][NH2:9])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: Nc1cccnc1Cl
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: NNc1cccnc1Cl
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 35.8 %

Procedure:
A solution of 3-amino-2-chloropyridine (5 g, 38.9 mmol) in concentrated hydrochloric acid (50 ml) was cooled to −5° C. and a solution of sodium nitrite (2.7 g, 38.9 mmol) in water (25 ml) was added thereto. The reaction mixture was stirred for 15 minutes at 0° C. and a solution of tin(II) chloride dihydrate (17.6 g, 77.8 mmol) in concentrated hydrochloric acid (17.5 ml) was slowly added thereto. The reaction mixture was stirred for 1 hour at room temperature, basified with 2N sodium hydroxide solution, and then extracted with dichloromethane. The organic layer was dried on anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The resulting residue was crystallized with ethyl ether to give 2 g of the titled compound as a pale yellow solid. (Yield: 36%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([Li])CCC.C1COCC1.Br[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Br:25])[N:20]=1>C1(C)C=CC=CC=1.CN(C)CCN(C)C.[Cl-].[Zn+2].[Cl-].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:25][C:21]1[N:20]=[C:19]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: Brc1cccnc1
Reactant: Brc1cccc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CN(C)CCN(C)C
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Brc1cccc(-c2cccnc2)n1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 44.7 %

Procedure:
Under nitrogen atmosphere, 6.32 g of 3-bromopyridine was dissolved in 400 ml of dehydrated toluene. The solution was cooled at −78° C. and 17 ml of 2.6M normal-butyllithium was dropped. After 0.5 hours, 12.6 g of zinc chloride tetramethylethylenediamine, and 200 ml of dehydrated THF were added. The solution was heated to room temperature, 10.63 g of 2,6-dibromopyridine and 0.6 g of Pd(PPh3)4 were added, and the solution was stirred for 24 hours. The reaction liquid was washed by an ammonium chloride aqueous solution, and the organic layer was concentrated in an evaporator. The concentrates were purified by column chromatography, and thus 4.2 g of 6-bromo-2,3′-bipyridine was obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[NH:16][CH:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]3([C:29]4[C:24](=[CH:25][C:26]([Br:30])=[CH:27][CH:28]=4)[NH:23][C:22]3=[O:31])[CH:13]2[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=2[F:39])=[O:11])=[C:5]([O:40][CH3:41])[CH:4]=1)#[N:2].[OH:42]O.[OH-].[Na+]>CS(C)=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[NH:16][CH:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]3([C:29]4[C:24](=[CH:25][C:26]([Br:30])=[CH:27][CH:28]=4)[NH:23][C:22]3=[O:31])[CH:13]2[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=2[F:39])=[O:11])=[C:5]([O:40][CH3:41])[CH:4]=1)(=[O:42])[NH2:2]
Reactant: COc1cc(C#N)ccc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3cc(Br)ccc32)C1c1cccc(Cl)c1F
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1cc(C(N)=O)ccc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3cc(Br)ccc32)C1c1cccc(Cl)c1F
Temperature: 10 °C
Reaction time: 1 h
Yield: 82.9 %

Procedure:
To the solution of rac-(2′S,3′R,4′S,5′R)-6-bromo-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-cyano-2-methoxy-phenyl)-amide (0.14 g, 0.22 mmol) prepared in Example 118 in DMSO (1 mL) at 0° C. was added an aqueous solution (30% Aldrich) of H2O2 (0.37 g, 3.3 mmol), then aqueous solution (1N) of NaOH (1.1 mL, 1.1 mmol) was added dropwise. The reaction mixture was stirred at 10° C. for 1 h. The mixture was partitioned between ethyl acetate and saturated aqueous Na2SO3 solution. The organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated. The residue was triturated with dichlormethane and hexanes to give rac-(2′S,3′R,4′S,5′R)-6-bromo-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-carbamoyl-2-methoxy-phenyl)-amide as a white solid (Yield 0.12 g, 83%)
Reaction SMILES: [CH3:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([NH2:17])=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)[CH2:3][CH3:4].[H-].[Na+].Cl[CH2:21][CH2:22][S:23](Cl)(=[O:25])=[O:24].O>C1COCC1.CCCCCC>[CH3:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3=[N:17][S:23](=[O:25])(=[O:24])[CH2:22][CH2:21][N:13]3[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)[CH2:3][CH3:4]
Reactant: CCC(C)c1ccc(-c2cccnc2N)cc1
Reactant: O=S(=O)(Cl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CCC(C)c1ccc(C2=CC=CN3CCS(=O)(=O)N=C23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
A mixture of 3-[4-(1-methylpropyl)phenyl]pyridin-2-amine (300 mg) in dehydrated THF (5 mL) was added to a mixture of sodium hydride (60%, 265 mg) and 2-chloroethanesulfonyl chloride (648 mg) in dehydrated THF (5 mL) under ice-cooling. The reaction mixture was stirred at room temperature overnight, and water and hexane were added. The resulting precipitate was collected by filtration, and washed with water and diisopropyl ether to give the title compound (376 mg) as a white solid. The obtained solid was crystallized from THF, acetonitrile and diisopropyl ether to give a white solid.
Reaction SMILES: O[CH:2]1[CH2:6][CH2:5][C:4]([CH2:7][PH:8](=[O:13])[O:9][CH:10]([CH3:12])[CH3:11])=[CH:3]1.CCOC(/[N:19]=N/C(OCC)=O)=O.N=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC=CC=1.C1COCC1.O>[NH2:19][CH:2]1[CH2:6][CH2:5][C:4]([CH2:7][PH:8](=[O:13])[O:9][CH:10]([CH3:12])[CH3:11])=[CH:3]1
Reactant: CCOC(=O)/N=N/C(=O)OCC
Reactant: CC(C)O[PH](=O)CC1=CC(O)CC1
Agent: [N-]=[N+]=N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: CC(C)O[PH](=O)CC1=CC(N)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 68.7 %

Procedure:
To a solution of (±)-isopropyl (3-hydroxycyclopentenyl)methylphosphinate (3) (2.5 g, 12.25 mmol), DEAD (4.0 cm3,26.95 mmol) and HN3 (12.9 cm3 of a 1.9 M solution in benzene) in anhydrous THF (100 cm3) at 0° C. was added triphenylphosphine (12.8 g, 49 mmol) in small portions over a period of 1 h. The reaction mixture was allowed to warm to room temperature and stirring continued for 12 h. The reaction mixture was then heated to 50° C. for 3 h after which time water (2 cm3) was added and heating continued for a further 2 h. The reaction mixture was cooled to room temperature and the solvent removed in vacuo. The residue was partitioned between HCl (1M, 40 cm3) and DCM (40 cm3). The organic layer was separated and further extracted with water (3×30 cm3). The combined aqueous fractions were washed with DCM (2×30 cm3) and concentrated in vacuo. The crude product was purified by ion exchange chromatography (Dowex 50 H+ form), eluting first with water until the eluate was neutral and then with aqueous ammonium hydroxide (1 M) collecting ninhydrin positive fractions. The solvent was removed in vacuo to yield the title compound as a pale yellow oil (8) (1.71 g, 68%): 1H NMR (300 MHz; CD3OD) δ 1.26 and 1.27 (3H, d, J=6.0 and 6.0 Hz, POCHCH3), 1.31 and 1.32 (3H, d, J=6.3 and 6.3 Hz, POCHCH3), 1.51 and 1.53 (3H, d, J=14.4 and 14.1 Hz, PCH3) 1.59-1.79 (1H, m, C(4)—H, 2.33-2.55 (2H, m, C(5)—H, C(5)—H′), 2.54-2.72 (1H, m, C(4)—H′) 4.05 (1H, m, C(3)—H), 4.48 (1H, m, C(2)—H), 6.52 (1H, dm, J=9.9 Hz, PCCH), 13C NMR (75.46 MHz, CD3OD) δ 13.92 and 14.10 (PCH3, d, JPC=102.1 and 101.6 Hz), 24.54 and 24.60 (POCHCH3, 2×d, 3JPOCC=46 Hz), 24.9 (POCHCH3, d, 3JPOCC=3.4 Hz), 32.86 and 32.88 (C(4), d, 3JPC=12.6 and 12.3 Hz), 35.0 and 35.13 (C(5), 2×d, 2JPC=10.0 Hz) 59.83 and 60.07 (POCHCH3, d, 2JPOC=5.7 and 5.7 Hz), 71.36 and 71.39 (C(3), d, 3JPC=6.3 and 6.3 Hz), 137.96 (C(1), d, JPC=125.7 Hz), 150.84 and 150.95 (C(2), d, 2JPC=10.9 and 11.1 Hz), 31 P NMR (121 MHz, CD3OD) δ 45.9, MS (EI) m/z 204 (38%) (MH+), 147 (30), 105 (100) (ESI) 204.1151 (MH+-C9H19NO2P requires 204.1153).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:17](=[O:25])[NH:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1.[CH3:26][O:27][CH2:28][CH2:29][CH2:30][NH2:31]>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12](=[O:14])[NH:31][CH2:30][CH2:29][CH2:28][O:27][CH3:26])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:17]([NH:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)=[O:25]
Reactant: Nc1ncc(-c2ccc(C(=O)O)cc2)cc1C(=O)Nc1ccncc1
Reactant: COCCCN
Product: COCCCNC(=O)c1ccc(-c2cnc(N)c(C(=O)Nc3ccncc3)c2)cc1

Procedure:
Reaction of 4-[6-amino-5-(pyridin-4-ylcarbamoyl)-pyridin-3-yl]-benzoic acid with 3-methoxy-propylamine gives “A94”; method 1: HPLC/MS: 1.30 min, [M+H]=406;
Reaction SMILES: Cl.[C:2](=[NH:7])([O:4][CH2:5][CH3:6])[CH3:3].C(N(CC)CC)C.[C:15](Cl)(=[O:17])[CH3:16].CCOCC>C(Cl)Cl>[C:15]([N:7]=[C:2]([O:4][CH2:5][CH3:6])[CH3:3])(=[O:17])[CH3:16]
Reactant: CC(=O)Cl
Reactant: CCOC(C)=N
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(C)=NC(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A slurry of 50.0 gm (405 mmol) of ethyl acetimidate hydrochloride in 500 ml of methylene chloride was mechanically stirred and treated dropwise with 81.9 gm (809 mmol) of triethylamine while keeping the temperature at less than 25° C. The resulting slurry was then treated dropwise with 31.8 gm (405 mmol) of acetyl chloride while keeping the temperature at less than 30° C. The white slurry was stirred for one hour at room temperature, after which the methylene chloride was removed in vacuo. The white, oily mass obtained was then stirred with 400 ml of ether and filtered. The white solid obtained was washed with additional ether and the combined filtrate was concentrated in vacuo to afford 48.6 gm (93 percent) of a pale, yellow oil. IR and NMR spectra were consistent with the assigned structure.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([NH:12][NH2:13])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[N:14]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)=[C:15]=[S:16]>CCO>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([NH:12][NH:13][C:15](=[S:16])[NH:14][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: NNC(=O)c1ccc2[nH]ccc2c1
Reactant: COc1ccc(CN=C=S)cc1
Solvent: CCO
Product: COc1ccc(CNC(=S)NNC(=O)c2ccc3[nH]ccc3c2)cc1
Yield: 50.3 %

Procedure:
A solution of 1H-indole-5-carbohydrazide (0.7 g, 3.98 mmol) and 1-isothiocyanatomethyl-4-methoxy-benzene (1.0 g, 5.56 mmol) in EtOH (10 mL) was heated to reflux for 2 h. The solvent was then removed in vacuo and the residue was triturated with EtOH (5 mL) to give 2-(1H-indole-5-carbonyl)-N-(4-methoxybenzyl)-hydrazinecarbothioamide (0.7 g, 2.0 mmol, 51%) as a white solid. MS (ESI, pos. ion) m/z: 355 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:22]([F:40])([F:39])[C:23]([F:38])([F:37])[C:24]([F:36])([F:35])[C:25]([F:34])([F:33])[C:26]([F:32])([F:31])[C:27]([F:30])([F:29])[F:28])=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]([N:15]([CH3:21])[CH2:16][C:17]([O:19][CH3:20])=[O:18])=O)=[CH:8][CH:7]=[CH:6]2.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:42].N1C=CC=CC=1>O>[CH3:1][O:2][C:3]1[C:4]([C:22]([F:40])([F:39])[C:23]([F:38])([F:37])[C:24]([F:36])([F:35])[C:25]([F:34])([F:33])[C:26]([F:32])([F:31])[C:27]([F:30])([F:29])[F:28])=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13](=[S:42])[N:15]([CH3:21])[CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:8][CH:7]=[CH:6]2
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: COC(=O)CN(C)C(=O)c1cccc2c(C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c(OC)ccc12
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)CN(C)C(=S)c1cccc2c(C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c(OC)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
N-[[6-methoxy-5-(tridecafluorohexyl)-1-naphthalenyl]carbonyl-N-methylglycine, methyl ester (100 mg, 0.165 mmol), prepared as in Example 5, phosphorus pentasulfide (67 mg) and dry pyridine (2 ml) were refluxed for 2 hours. After stirring overnight at room temperature, the mixture was refluxed for 2 additional hours, poured into water and extracted with ether. The ether extract was washed with 1N aqueous hydrochloric acid, water, saturated sodium bicarbonate and brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated giving 92.8 mg of the crude N-[[6-methoxy-5-(tridecafluorohexyl)-1-naphthalenyl]thioxomethyl]-N-methylglycine, methyl ester, which was used in the next preparation without further purification. ms: m/e 622 (M+H)+, 562, 519, 503, 352. nmr (CDCl3): δ2.84 & 3.04 (2s, 3H, N--CH3, rotamers); δ3.82 & 3.95 (2s, 3H, O--CH3, rotamers) δ3.4 & 5.5 (2d, 2 H, CH2, J=17); δ7.3 (m, 3H, Har); δ8.2 (m, 2H, Har).