Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=1)=[O:5].[CH2:16]([O:23][C:24]([NH:26][CH2:27][CH:28]1[CH2:33][CH2:32][CH:31]([C:34](O)=[O:35])[CH2:30][CH2:29]1)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C.O>[CH2:16]([O:23][C:24](=[O:25])[NH:26][CH2:27][CH:28]1[CH2:33][CH2:32][CH:31]([C:34](=[O:35])[NH:2][CH2:3][C:4](=[O:5])[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:13])([F:14])[F:15])[CH:7]=2)[CH2:30][CH2:29]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCC(=O)c1cccc(C(F)(F)F)c1
Reactant: O=C(NCC1CCC(C(=O)O)CC1)OCc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NCC1CCC(C(=O)NCC(=O)c2cccc(C(F)(F)F)c2)CC1)OCc1ccccc1
Reaction time: 8 h

Procedure:
To a solution of 2-Amino-1-(3-trifluoromethyl-phenyl)-ethanone hydrochloride (3.4 g, 0.0144 mol (prepared according to the procedure of Leclerc and Bizec (1980) J. Med. Chem. 23:783–744) and 4-(Benzyloxycarbonylamino-methyl)-cyclohexanecarboxylic acid (4.2 g, 0.0144 mol; for a preparation of this reagent see e.g., Svahn et. al. (1986) J. Med. Chem. 29:448–453) in DMF, Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent, 6.4 g, 0.0144 mol) was added, followed by triethylamine (4.0 mL, 0.0289 mol). The reaction was stirred overnight and then poured into water to produce a thick precipitate. The solid was collected on a sintered glass funnel and washed consecutively with H2O, 3N HCl (2×), H2O, NaHCO3 solution (2×) and H2O. The filter cake was air dried, added to a 500 mL round bottom flask with toluene and concentrated under reduced pressure. Additional toluene (200 mL) was added and the mixture was concentrated again under reduced pressure to yield {4-[2-Oxo-2-(3-trifluoromethyl-phenyl)-ethylcarbamoyl]-cyclohexylmethyl}-carbamic acid benzyl ester as a solid. 1H NMR (DMSO-d6): δ0.8–0.93 (m, 2H), 1.2–1.37 (m, 3H), 1.71 (br s, 4H), 2.14 (t, 1H), 2.84 (br s, 2H), 4.57 (br s, 2H), 4.99 (s, 2H), 7.2–7.38 (m, 5H), 7.77(t, 1H), 8.01 (d, J=8.0 Hz, 1H), 8.14–8.26 (m, 3H). MS 477 (M+H)+
Reaction SMILES: [O:1]=[C:2]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[CH2:3][N:4]1C(=O)C2C(=CC=CC=2)C1=O.[BH4-].[Na+].Cl>C(O)(C)C>[NH2:4][CH2:3][CH:2]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[OH:1]
Reactant: O=C(CN1C(=O)c2ccccc2C1=O)c1cccnc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: NCC(O)c1cccnc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of crude 2-(2-oxo-2-pyridin-3-ylethyl)isoindole-1,3-dione (Preparation 97, 5.0 g, ˜19.0 mmol) in aqueous isopropanol (210 ml, water/IPA: 1/6) was added sodium borohydride (10.2 g, 270 mmol) in 2 portions. The mixture was stirred at rt for 12 h before being carefully acidified (pH 2) with dilute hydrochloric acid (1M). After removal of the solvent the residue was taken up in distillated water (100 mL) and passed down a column filled with ion-exchange resin (Amberlite IR 120, H+-form, 300 g, eluent: 500 mL water then IL of 2 M aqueous ammonia solution). Concentration of the alkaline fractions gave the title compound as a yellow oil. δH (d6 DMSO): 2.74, 2.85 (2H, 2m), 4.66 (1H, m), 5.15 (3H, br s), 7.36 (1H, dd), 7.75 (1H, m), 8.46 (1H, m), 8.56 (1H, m); m/z (ES+)=139.11 [M+H]+; RT=0.21 min.
Reaction SMILES: [C:1]([C:3]1[C:4]2[N:13]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH:12]=[C:11]([C:19]3[CH:20]=[C:21]([C:24]([NH2:26])=[O:25])[S:22][CH:23]=3)[C:5]=2[C:6]([O:9]C)=[N:7][CH:8]=1)#[N:2].[I-].[Na+].Cl[Si](C)(C)C.O>C(#N)C>[C:1]([C:3]1[C:4]2[N:13]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH:12]=[C:11]([C:19]3[CH:20]=[C:21]([C:24]([NH2:26])=[O:25])[S:22][CH:23]=3)[C:5]=2[C:6](=[O:9])[NH:7][CH:8]=1)#[N:2]
Reactant: COc1ncc(C#N)c2c1c(-c1csc(C(N)=O)c1)cn2C1CCCC1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: N#Cc1c[nH]c(=O)c2c(-c3csc(C(N)=O)c3)cn(C3CCCC3)c12
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
To a solution of 4-(7-cyano-1-cyclopentyl-4-methoxy-1H-pyrrolo[3,2-c]pyridin-3-yl)thiophene-2-carboxamide (310 mg) in acetonitrile (40 mL) were added sodium iodide (254 mg) and chloro(trimethyl)silane (536 mL), and the mixture was stirred at 80° C. for 30 min. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (143 mg).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([Br:17])=[C:10]([S:13](Cl)(=[O:15])=[O:14])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH2:18]([N:20](CC)CC)C.CN.O>C1COCC1>[CH3:18][NH:20][S:13]([C:10]1[CH:11]=[C:12]2[C:7]([CH2:6][CH2:5][N:4]2[C:1](=[O:3])[CH3:2])=[CH:8][C:9]=1[Br:17])(=[O:15])=[O:14]
Reactant: CC(=O)N1CCc2cc(Br)c(S(=O)(=O)Cl)cc21
Reactant: CCN(CC)CC
Agent: CN
Solvent: C1CCOC1
Solvent: O
Product: CNS(=O)(=O)c1cc2c(cc1Br)CCN2C(C)=O
Reaction time: 1.5 h
Yield: 82.5 %

Procedure:
To a slurry of 1-acetyl-5-bromo-2,3-dihydro-1H-indole-6-sulfonyl chloride (see Preparation 43) (0.40 g, 1.2 mmol) in THF (3.38 mL) was added triethylamine (0.660 mL, 4.73 mmol) and 40% methylamine in water (0.18 mL, 2.4 mmol). The reaction was heated to reflux and stirred for 1.5 h, then cooled and concentrated. The residue was slurried in hot MeOH and filtered under vacuum washing with MeOH. The solid was dried in vacuo at 40° C., to give 1-acetyl-5-bromo-2,3-dihydro-1H-indole-6-sulfonic acid methylamide (0.33 g, 85%) as a colourless solid. This product (320 mg, 1.0 mmol) was slurried in 1,4-dioxane (0.98 mL) and concentrated hydrochloric acid (0.72 mL), heated to 100° C. for 1.5 h, then cooled to ambient temperature solvent removed in vacuo. The pH was adjusted to 7 with 1 M aqueous NaOH and the resulting precipitate collected by vacuum filtration, washed with water and dried in vacuo at 40° C., to give the title compound (0.176 g, 62%) as a beige solid; MS: [M+H]+ 291
Reaction SMILES: [C:1]([C:4]1[N:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=O)(=[O:3])[CH3:2].[C:13]1([NH:19][C:20](=[O:23])[NH:21][NH2:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CO>[C:13]1([NH:19][C:20](=[O:23])[NH:21][N:22]=[C:6]([OH:8])[C:5]2[CH:9]=[CH:10][CH:11]=[N:12][C:4]=2[C:1](=[O:3])[CH3:2])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(=O)c1ncccc1C(=O)O
Reactant: NNC(=O)Nc1ccccc1
Solvent: CO
Product: CC(=O)c1ncccc1C(O)=NNC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-acetylnicotinic acid (0.40 g, 2.4 mmol) in 7 ml of methanol is added a solution of 4-phenylsemicarbazide (0.37 g, 2.4 mmol) in 5 ml of methanol. The mixture is stirred at RT overnight, after which the solid precipitate is collected by filtration, washed with ethanol and dried to give 2-acetyl-nicotinic acid 4-phenylsemicarbazone, m.p. 174° (dec.) (compound 1, Table A).
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4]([OH:5])[CH:3]=1.[C:11]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=1[S:20](Cl)(=[O:22])=[O:21])#[N:12]>C([O-])(O)=O.[Na+].C(OCC)C.O>[C:11]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=1[S:20]([O:5][C:4]1[CH:3]=[C:2]([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=1)(=[O:21])=[O:22])#[N:12]
Reactant: Cc1ccc(C#N)c(S(=O)(=O)Cl)c1
Reactant: Cc1cc(O)cc(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: Cc1cc(O)cc(OS(=O)(=O)c2cc(C)ccc2C#N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.9 %

Procedure:
Orcinol monohydrate (1.42 g, 10.0 mmol) and 2-cyano-5-methylbenzene-sulfonyl chloride (2.0 g, 9.0 mmol), as prepared in the preceding step, were mixed in saturated aqueous NaHCO3 (30 mL) and diethyl ether (30 mL). The biphasic mixture was stirred vigorously at ambient temperature overnight. The reaction mixture was diluted with water (50 mL) and extracted into ethyl acetate (3×50 mL). The organic phase was washed with brine (2×50 mL) and dried over Na2SO4. After removing the solvent in vacuo, the residue was purified by flash column chromatography (dichloromethane to 4% ethyl acetate in dichloromethane) to give the title compound as a pale yellow oil (2.1 g, 69%). 1H-NMR (300 MHz, CDCl3) δ 7.91 (s, 1H), 7.81 (d, J=7.8 Hz, 1H), 7.57 (d, J=7.9 Hz, 1H), 6.59 (s, 1H), 6.58 (s, 1H), 6.51 (s, 1H), 5.61 (s, 1H), 2.51 (s, 3H), 2.29 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[C:5]([CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1)[CH2:6][NH:7][C:8]([C:10]1[C:15]([Br:16])=[CH:14][N:13]=[C:12]([S:17][CH3:18])[N:11]=1)=[O:9].[CH3:28]N(C)C=O.CI.O>[Cl-].[Na+].O.C(Cl)Cl>[F:25][C:22]([F:24])([F:23])[C:20]1[CH:19]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:26])[F:27])[CH:21]=1)[CH2:6][N:7]([CH3:28])[C:8]([C:10]1[C:15]([Br:16])=[CH:14][N:13]=[C:12]([S:17][CH3:18])[N:11]=1)=[O:9]
Reactant: CSc1ncc(Br)c(C(=O)NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CI
Solvent: ClCCl
Solvent: O
Product: CSc1ncc(Br)c(C(=O)N(C)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reaction time: 1 h
Yield: 77.2 %

Procedure:
To a solution of 4.40 g (9.28 mmol) 5-bromo-2-methylsulfanyl-pyrimidine-4-carboxylic acid 3,5-bis-trifluoromethyl-benzylamide in 50 ml N,N-dimethylformamide 0.48 g (12.06 mmol) sodiumhydride (60% dispersion in mineral oil) was added and the reaction mixture stirred for 1 hr. After the addition of 0.92 ml (14.85 mmol) methyl iodide at 0°, the reaction mixture was stirred for 3 hrs. at RT. The reaction mixture was distributed between 100 ml H2O, 100 ml brine and 100 ml CH2Cl2. The phases were separated, the aqueous layer washed twice with 100 ml CH2Cl2. The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2/ethyl acetate 40:1) to give 3.50 g (77%) 5-bromo-2-methylsulfanyl-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)(OCC)[O:22][CH2:23][CH3:24].C(=O)([O-])O.[Na+]>C(O)CO.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C>[CH2:1]([O:8][CH2:9][C:10]1([CH2:12][O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[O:22][CH2:23][CH2:24][O:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(COCc1ccccc1)COCc1ccccc1
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: OCCO
Product: c1ccc(COCC2(COCc3ccccc3)OCCO2)cc1
Temperature: 50 °C
Reaction time: 14 h
Yield: 81.6 %

Procedure:
The 1,3-bis(benzyloxy)acetone (30 g, 111 mmol) obtained in the step (4a) was mixed with ethylene glycol (64 ml, 1.148 mmol) and triethyl orthoformate (19 ml, 114 mmol), and p-toluenesulfonic acid monohydrate (591 mg, 3.11 mmol). The mixture was stirred at 50° C. for 14 hours. To the mixture, a saturated aqueous solution of sodium hydrogen carbonate and ethyl acetate were added. The organic layer was washed with water and a saline solution, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: heptane/ethyl acetate=1/0-4/1 gradient) and desired fractions were concentrated to obtain the title compound (28.46 g, yield: 81.6%) as a colorless oil.
Reaction SMILES: [CH2:1]([N:3]([CH3:11])[C:4]([N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1)=[O:5])[CH3:2].[CH3:12][I:13]>C(#N)C>[I-:13].[CH2:1]([N:3]([C:4]([NH+:6]1[CH:10]=[CH:9][N:8]([CH3:12])[CH2:7]1)=[O:5])[CH3:11])[CH3:2]
Reactant: CCN(C)C(=O)n1ccnc1
Reactant: CI
Solvent: CC#N
Product: CCN(C)C(=O)[NH+]1C=CN(C)C1
Product: [I-]
Temperature: 22.5 °C
Reaction time: 2.5 h

Procedure:
To the cooled solution of N-ethyl-N-methyl-1H-imidazole-1-carboxamide (22.2 g, 145.25 mmol) in acetonitrile (40 mL) was charged slowly with methyl iodide (22.3 g, 157.4 mmol) while keeping internal temperature below 10° C. The reaction mixture was stirred at 20-25° C. for 2-3 hours and then it was evaporated under vacuum to yield 1-[[N-ethyl-(N-methyl)amino]carbonyl]-3-methyl-1H-imidazolium iodide. 1H NMR (CDCl3) δ 10.23 (s, 1H); 7.75 (s, 1H); 7.66 (s, 1H); 4.29 (s, 3H); 3.59 (q, J=7.2 Hz, 2H), 3.30 (s, 3H), 1.32 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[C:9]([NH:12][CH2:13][CH2:14][Cl:15])(=[O:11])[CH3:10].ClC1C=CC=C(C(OO)=[O:24])C=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[Cl-:15].[C:9]([NH:12][CH2:13][CH2:14][N+:6]1[CH:7]=[CH:8][C:3]([S:2]([CH3:1])=[O:24])=[CH:4][CH:5]=1)(=[O:11])[CH3:10]
Reactant: CSc1ccncc1
Reactant: CC(=O)NCCCl
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)NCC[n+]1ccc(S(C)=O)cc1
Product: [Cl-]

Procedure:
The starting material may be obtained as follows: Reaction of 4-methylthiopyridine with 4 equivalents of N-acetyl-2-chloroethylamine at 80° for 4 hours gave, after precipitation from CH2Cl2 solution with EtOAc, 1-(2-acetylaminoethyl)-4-methylthiopyridinium chloride in solvent B: 1.76(s, 3H); 2.69(s, 3H); 3.6(t, 2H); 4.5(t, 2H); 7.87(d, 2H); 8.64(d, 2H). This compound was reacted with one equivalent of metachlorperbenzoic acid in CH2Cl2 /TFA at 0° to ambient temperature for 30 minutes. The product was precipitated from CH2Cl2 /MeOH solution with ether to give 1-(2-acetylaminoethyl)-4-methanesulphinylpyridinium chloride. n.m.r. in solvent B: 1.76(s, 3H); 3.0(s, 3H); 3.66(t, 2H); 4.74(t, 2H); 8.47(d, 2H); 9.22(d, 2H).
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:13]I>>[CH3:13][N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]([CH:11]=[O:12])=[C:2]1[Cl:1]
Reactant: O=Cc1c(Cl)[nH]c2ccccc12
Reactant: CI
Product: Cn1c(Cl)c(C=O)c2ccccc21
Yield: 93.8 %

Procedure:
Prepared from (1) (18 g), methyl iodide (17.1 g) and Nail (2.88 g) yielding (3) (18.2 g), m.p. 88°-90° C.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CSC.[Cl:12][C:13]1[CH:14]=[C:15]([CH:19]=[N+]=[N-])[CH:16]=[CH:17][CH:18]=1>C([O-])(=O)C.[Rh+2].C([O-])(=O)C.ClCCl>[Cl:12][C:13]1[CH:14]=[C:15]([CH:19]2[CH:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[O:8]2)[CH:16]=[CH:17][CH:18]=1
Reactant: O=Cc1ccccc1
Reactant: [N-]=[N+]=Cc1cccc(Cl)c1
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CSC
Product: Clc1cccc(C2OC2c2ccccc2)c1
Yield: 53 %

Procedure:
To a slurry of rhodium (II) acetate (0.001 g) and dichloromethane (4 ml) were added benzaldehyde (0.025 ml) and dimethylsulphide (0.009 ml). The solution of 3-chlorophenyldiazomethane (produced above) was added to this mixture over 24 hours. The solvent was removed in vacuo and the residue chromatographed on silica (Merck grade 60, 230-400 mesh) eluting with dichloromethane:hexane 2:3 to give the title compound as a colourless oil (0.0305 g, 53% yield) δH (CDCl3): 7.55(8H); 7.45(1H), 4.0(2H)ppm.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH2:9][C@@H:10]2[CH2:13][CH2:12][N:11]2C(O[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=O)=[CH:6][CH:5]=[C:4]([F:24])[N:3]=1.O.C1(C)C([S:32]([OH:35])(=[O:34])=[O:33])=CC=CC=1>CCO.[Pd]>[S:32]([C:21]1[CH:22]=[CH:23][C:18]([CH3:17])=[CH:19][CH:20]=1)([OH:35])(=[O:34])=[O:33].[F:1][C:2]1[C:7]([O:8][CH2:9][C@@H:10]2[CH2:13][CH2:12][NH:11]2)=[CH:6][CH:5]=[C:4]([F:24])[N:3]=1
Reactant: O=C(OCc1ccccc1)N1CC[C@H]1COc1ccc(F)nc1F
Reactant: Cc1ccccc1S(=O)(=O)O
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)O)cc1
Product: Fc1ccc(OC[C@@H]2CCN2)c(F)n1
Reaction time: 16 h
Yield: 32.6 %

Procedure:
2,6-Difluoro-3-(1-Cbz-2-(S)-azetidinylmethoxy)pyridine from Example 116b (640 mg, 1.9 mmol) was combined with 10% Pd on C (50 mg) and p toluenesulfonic acid monohydrate (1.1 g, 5.7 mmole) in 30 mL of EtOH, and the mixture was stirred under an H2 atmosphere for 16 hours. The mixture was concentrated, triturated with ether and then recrystallized from ethyl acetate/ether to yield 231 mg (32.4%) of the title compound: mp 140-143° C. 1H NMR (D2O 300 MHz) 6: 2.40 (s, 3H), 2.69 (m, 2H), 4.12 (m, 2H), 4.46 (d, J=4.5, 2H), 4.94 (m, 1H), 7.01 (m, 1H), 7.38 (d,J=8.0, 2H), 7.70 (d,J=8.0, 2H), 7.81 (m, 1H). MS (DCI/NH3) m/e 201 (M+H)+, 218 (M+NH4)+. Anal. calcd. for C9H10F2N2O.C7H8O3S: C, 51.61H, 4.87 N, 7.52 Found: C, 51.37 H, 4.89; N, 7.40. [α]D -1.44 (c 1, MeOH).
Reaction SMILES: [NH:1]1C=NC=N1.P(Cl)(Cl)(Cl)=[O:7].[N:11]1([C:19]2([O:36][CH2:35][C@H:22]([O:23][CH2:24][P:25]([O:31][CH:32]([CH3:34])[CH3:33])([O:27][CH:28]([CH3:30])[CH3:29])=[O:26])[CH2:21]2)[OH:20])[CH:18]=[CH:17][C:15](=O)[NH:14][C:12]1=[O:13]>N1C=CC=CC=1>[O:36]=[CH:35][C@H:22]([C@@H:21]([CH2:19][OH:20])[OH:7])[OH:23].[N:11]1([C:19]2([O:36][CH2:35][C@H:22]([O:23][CH2:24][P:25]([O:27][CH:28]([CH3:30])[CH3:29])([O:31][CH:32]([CH3:34])[CH3:33])=[O:26])[CH2:21]2)[OH:20])[CH:18]=[CH:17][C:15]([NH2:1])=[N:14][C:12]1=[O:13]
Reactant: CC(C)OP(=O)(CO[C@H]1COC(O)(n2ccc(=O)[nH]c2=O)C1)OC(C)C
Reactant: c1nc[nH]n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)OP(=O)(CO[C@H]1COC(O)(n2ccc(N)nc2=O)C1)OC(C)C
Product: O=C[C@@H](O)[C@H](O)CO
Reaction time: 0.17 h
Yield: 145 %

Procedure:
To the solution of 1,2,4-triazole (662 mg, 9.6 mmol) in 15 mL pyridine was added phosphorousoxychloride (223 μL, 2.4 mmol) at room temperature. The mixture was stirred for 10 minutes. Then the solution of 21 (289 mg, 0.80 mmol) was added to the mixture. The reaction mixture was stirred for 4 hours. Then ammonia gas was bubbled in to the reaction mixture for 1-3 hours and the reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (CH2Cl2:MeOH=12:1) to give compound 22 (220 mg, 0.58 mmol) as a colorless foam, in 73% yield, which was characterized as follows:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6](=[C:22]1[S:26][C:25](=[S:27])[N:24]([CH2:28][C:29]([OH:31])=[O:30])[C:23]1=[O:32])[C:7]1[N:8]=[C:9]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:14])[S:10][CH:11]=1)=[O:5])[CH3:2].C(N(CC)CC)C.[CH2:40](Br)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.CN(C)P(=O)(N(C)C)N(C)C>O>[CH2:1]([O:3][C:4]([C:6](=[C:22]1[S:26][C:25](=[S:27])[N:24]([CH2:28][C:29]([O:31][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:30])[C:23]1=[O:32])[C:7]1[N:8]=[C:9]([NH:12][C:13]([NH:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:14])[S:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C(=C1SC(=S)N(CC(=O)O)C1=O)c1csc(NC(=O)Nc2ccccc2)n1
Reactant: BrCc1ccccc1
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=C1SC(=S)N(CC(=O)OCc2ccccc2)C1=O)c1csc(NC(=O)Nc2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture comprising 1 g of 5-{1-ethoxycarbonyl-1-[2-(3-phenylureido)thiazol-4-yl]methylene}rhodanine-3-acetic acid, 0.25 g of triethylamine, 0.7 g of benzyl bromide and 10 ml of hexamethylphosphoric triamide was stirred at room temperature overnight. The reaction mixture was then poured into water and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated off under reduced pressure. The residue was purified by silica gel column chromatography, using as eluent a 2:1 by volume mixture of hexane and ethyl acetate. The resulting product was a yellow powder having the following physical properties.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[OH:10].Cl.[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1>N1C=CC=CC=1>[OH:10][C:3]1[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=1[NH:1][C:12](=[O:19])[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1
Reactant: COc1ccc(O)c(N)c1
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(O)c(NC(=O)c2ccncc2)c1
Temperature: 0 °C

Procedure:
A mixture of 2.5 g of a crude product of 2-amino-4-methoxyphenol, 3.2 g of isonicotinic acid chloride hydrochloride and 20 ml of pyridine was heated to reflux for 12 hours. The reaction mixture was poured into ice water, and precipitated deposits are collected by filtration. The obtained solid was dissolved in ethyl acetate, washed with water and a saturated sodium chloride solution, and dried over magnesium sulfate. Activated carbon was added thereto, followed by filtration through Celite™. The filtrate was concentrated under reduced pressure to give N-(2-hydroxy-5-methoxyphenyl)isonicotinamide.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH2:7][O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:16]([O:18]C)=[O:17].[OH-].[Na+].Cl>C(O)C.O>[CH:1]1[C:11]2[CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH2:7][O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:16]([OH:18])=[O:17]
Reactant: COC(=O)c1ccc2c(c1)Cc1ccccc1CO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc2c(c1)Cc1ccccc1CO2

Procedure:
Dissolve 1.4 gm of the ester of Step A in 15 ml of ethanol and add 15 ml of 20% aqueous sodium hydroxide. Warm gently on a steam bath until complete solution is obtained. Strip to dryness and dissolve in water. Acidify with concentrated hydrochloric acid and separate the precipitate by filtration. Crystallize from methanol to obtain the title product (m.p. 240°-244° C.)
Reaction SMILES: [CH:1]([C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)([CH3:3])[CH3:2].[CH3:13][NH:14][CH3:15].C=O.[C:18](=O)([O-])[O-].[K+].[K+]>C(O)C.C(O)(=O)C>[CH3:13][N:14]([CH2:18][C:12]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]=1[CH:1]([CH3:3])[CH3:2])[CH3:15]
Reactant: CC(C)c1cc2ccccc2[nH]1
Reactant: O=C([O-])[O-]
Reactant: CNC
Agent: C=O
Agent: [K+]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)c1[nH]c2ccccc2c1CN(C)C
Temperature: 5 °C
Reaction time: 1 h

Procedure:
To a well-stirred solution of 2-isopropylindole (9.9 g.) in ethanol (30 ml.) at 0° C., there was added a 33% (w./w.) solution of dimethylamine in ethanol (10 ml.) and glacial acetic acid (3.5 ml.). A solution of 40% (w./v.) aqueous formaldehyde (5 ml.) was then added dropwise to the mixture, and the resulting solution was stirred at 5° C. for a period of one hour. Ice/water was next added to the reaction mixture, followed by excess solid potassium carbonate to give an orange oil. The liquid was then repeatedly extracted with diethyl ether (three times), using 50 ml. portions for each extraction. The combined ethereal extracts were then dried over anhydrous sodium sulfate and evaporated to give crude 3-(dimethylaminomethyl)-2-isopropylindole (4.5 g.) as a brown oil. The latter substance was used directly in Example I (as a starting material) without any further purification being necessary.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]([O:24]C)=O)[CH:20]=3)[NH:15][C:14]=2[OH:26])=[N:11][CH:12]=1)[CH2:4][CH3:5])[CH3:2].[ClH:27].[NH2:28][CH2:29][CH2:30][S:31]([CH3:34])(=[O:33])=[O:32]>C(#N)C>[ClH:27].[CH3:34][S:31]([CH2:30][CH2:29][NH:28][C:22]([C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([OH:26])=[C:13]2[C:10]1[CH:9]=[CH:8][C:7]([CH2:6][N:3]([CH2:1][CH3:2])[CH2:4][CH3:5])=[CH:12][N:11]=1)=[O:24])(=[O:33])=[O:32]
Reactant: CCN(CC)Cc1ccc(-c2c(O)[nH]c3ccc(C(=O)OC)cc23)nc1
Reactant: CS(=O)(=O)CCN
Agent: Cl
Solvent: CC#N
Product: CCN(CC)Cc1ccc(-c2c(O)[nH]c3ccc(C(=O)NCCS(C)(=O)=O)cc23)nc1

Procedure:
The title compound was prepared as described for Example 67 using methyl 3-{5-[(diethylamino)methyl]pyridin-2-yl}-2-hydroxy-1H-indole-5-carboxylate (0.071 g, 0.2 mmol) and (2-aminoethyl)methylsulfone hydrochloride (0.080 g, 0.5 mmol) as starting materials. The base was obtained after preparative HPLC purification (XTerra®PrepMS C8 columns 10 μm, 19×300 mm; 0.1 M NH4OAc buffer/acetonitrile, from 90:10 to 40:60, as eluent gradient) as an orange yellow solid (0.030 g, 34% yield), which was transformed to the yellow hydrochloride salt (0.023 g, 72% yield): 1H NMR (CD3OD, 400 MHz) δ 8.21 (s, 1H), 8.11 (s, 1H), 7.95 (s, 2H), 7.60 (dd, J=8.0, 1.2 Hz, 1H), 7.14 (d, J=8.0 Hz, 1H), 4.35 (s, 2H), 3.93 (t, J=6.4 Hz, 2H), 3.51 (t, J=6.4 Hz, 2H), 3.29 (m, 4H), 3.09 (s, 3H), 1.43 (t, J=7.2 Hz, 6H); MS (EI) m/z 445 (M++1).