Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9](=[O:16])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: ClCc1ccccc1
Reactant: O=C(Cn1cncn1)c1c(Cl)cccc1Cl
Product: Clc1cccc(Cl)c1C(=Cn1cncn1)OCc1ccccc1

Procedure:
Analogously to Example 1a,b, after reacting 1-(2,6-dichlorophenyl)-2-[1,2,4]triazol-1-yl-ethanone with benzyl chloride there was obtained 1-[2-(2,6-dichloro-phenyl)-2-benzyloxy-vinyl]-1H-[1,2,4]triazole. After reaction with oxalic acid there was obtained a salt with the composition C17H13N3OCl2.C2H2O4, which decomposed at >71° C.
Reaction SMILES: [Br:1][C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[NH:4][CH:3]=1.[H-].[Na+].[CH3:13]I>CN(C=O)C.O>[Br:1][C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]([CH3:13])[CH:3]=1
Reactant: CI
Reactant: Brc1c[nH]c2cccnc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(Br)c2ncccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 84.7 %

Procedure:
A mixture of 3-bromo-1H-pyrrolo[3,2-b]pyridine (450 mg) in DMF (5 mL) was treated with a NaH (60% in oil, 100 mg) and the resulting mixture stirred at room temperature for 5 min. The mixture was cooled to 0° C., treated with MeI (324 mg) then allowed to warm to room temperature over a period of 1 h. After this time, the reaction was diluted with water (100 mL) and extracted with AcOEt (3×50 mL). The combined organics were washed with water (50 mL), 5% LiCl aqueous solution (50 mL) then brine (50 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (heptane to AcOEt) to give the title compound (408 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([C:21]2[S:22][C:23]([F:26])=[CH:24][N:25]=2)=[N:10]1.C1C(=O)N([Br:34])C(=O)C1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][Br:34])[NH:12][C:11]([C:21]2[S:22][C:23]([F:26])=[CH:24][N:25]=2)=[N:10]1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C1=C(C)NC(c2ncc(F)s2)=NC1c1ccc(F)cc1Br
Product: CCOC(=O)C1=C(CBr)NC(c2ncc(F)s2)=NC1c1ccc(F)cc1Br
Yield: 86 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-2-(5-fluorothiazol-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate (0.51 g, 1.16 mmol) was reacted with NBS (0.21 g, 1.16 mmol) according to the procedure as described in Example 1, Step B to give the title compound as a yellow solid (0.52 g, 86%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C@H:9]1[C@H:13]([O:14]CC2C=CC(OC)=CC=2)[C@@H:12]([CH2:24][O:25]CC2C=CC(OC)=CC=2)[S:11][CH:10]1[N:35]1[CH:42]=[CH:41][C:39]([NH2:40])=[N:38][C:36]1=[O:37]>ClCCl>[F:8][C@H:9]1[C@H:13]([OH:14])[C@@H:12]([CH2:24][OH:25])[S:11][CH:10]1[N:35]1[CH:42]=[CH:41][C:39]([NH2:40])=[N:38][C:36]1=[O:37]
Reactant: COc1ccc(COC[C@H]2SC(n3ccc(N)nc3=O)[C@@H](F)[C@@H]2OCc2ccc(OC)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccn(C2S[C@H](CO)[C@@H](O)[C@@H]2F)c(=O)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 67.6 %

Procedure:
0.2 mL of trifluoroacetic acid was added to a solution of 8.8 mg of 1-(2-deoxy-2-fluoro-3,5-bis-O-(4-methoxybenzyl)-4-thio-D-arabinofuranosyl)cytosine in 2 mL of dichloromethane, and the obtained mixture was then stirred at room temperature for 1.5 hours. Thereafter, the solvent was distilled away from the reaction mixture under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH column, chloroform/methanol=90/10 to 60/40), so as to obtain 3.1 mg of 1-(2-deoxy-2-fluoro-4-thio-D-arabinofuranosyl)cytosine in the form of a white solid.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([C:9]2[N:18]=[C:17]([C:19](O)=[O:20])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:6]=[CH:7][CH:8]=1.Cl.[OH:25][C:26]1[C:35]([N:36]([CH3:38])[CH3:37])=[CH:34][CH:33]=[C:32]2[C:27]=1[CH2:28][CH2:29][NH:30][CH2:31]2>>[F:22][C:2]([F:23])([F:1])[C:3]1[CH:4]=[C:5]([C:9]2[N:18]=[C:17]([C:19]([N:30]3[CH2:29][CH2:28][C:27]4[C:32](=[CH:33][CH:34]=[C:35]([N:36]([CH3:38])[CH3:37])[C:26]=4[OH:25])[CH2:31]3)=[O:20])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CN(C)c1ccc2c(c1O)CCNC2
Reactant: O=C(O)c1nc(-c2cccc(C(F)(F)F)c2)nc2ccccc12
Agent: Cl
Product: CN(C)c1ccc2c(c1O)CCN(C(=O)c1nc(-c3cccc(C(F)(F)F)c3)nc3ccccc13)C2
Yield: 5 %

Procedure:
Reaction of 2-(3-(trifluoromethyl)phenyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-dimethylamino-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 55 (5% yield) as a brown solid. 1H NMR (300 MHz, CDCl3) δ 2.71 and 2.77 (2s, 6H), 2.85 and 3.11 (2t, 2H), 3.59 and 4.22 (2t, 2H), 4.49 and 5.11 (2s, 2H), 6.36 and 6.86 (2d, 1H), 6.99-7.17 (m, 2H), 7.62-7.70 (m, 2H), 7.77-7.80 (m, 1H), 7.96-8.07 (m, 2H), 8.16-8.21 (m, 1H), 8.82-8.96 (m, 2H); MS (ESI) m/z 493 ([M+H]+).
Reaction SMILES: O.[C:2]([C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:9]=[CH:8][C:7]=1[OH:16])([CH3:5])([CH3:4])[CH3:3].[C:17](O)(=[O:20])[CH:18]=[O:19].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:12]([C:10]1[CH:11]=[C:6]([C:2]([CH3:5])([CH3:4])[CH3:3])[C:7]2[O:16][C:18](=[O:19])[CH:17]([OH:20])[C:8]=2[CH:9]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Reactant: O=CC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)OC(=O)C2O

Procedure:
A 15 l multi-necked vessel with stirrer, dropping funnel, water separator, condenser and thermometer is charged with stirring and in succession with 300 ml of toluene, 212 g of 97% 2,4-di-tert-butylphenol (Aldrich 99%), 121.9 ml of 50% strength aqueous glyoxylic acid and 0.5 g of p-toluenesulfonic acid monohydrate. The reaction mixture is subsequently refluxed vigorously with thorough stirring. This is accompanied by the separation of the water present in the glyoxylic acid, and the water of reaction from the first stage. After a reflux time of about 3 h, the separation of water ends, to leave a homogeneous, pale yellow solution of 5,7-di-t-butyl-3-hydroxybenzofuran-2-one. Thereafter, the toluene is distilled off under atmospheric pressure and with a heating-bath temperature of up to 142° C. The crystalline solid is subsequently dried at 80° C./50 mbar.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH2:3][CH2:4][NH:5][C:6]1[C:11]([NH2:12])=[CH:10][CH:9]=[CH:8][N:7]=1.[C:14](N1C=CN=C1)(N1C=CN=C1)=[O:15]>CN(C=O)C>[CH3:1][N:2]([CH3:13])[CH2:3][CH2:4][N:5]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:11]2[NH:12][C:14]1=[O:15]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CN(C)CCNc1ncccc1N
Solvent: CN(C)C=O
Product: CN(C)CCn1c(=O)[nH]c2cccnc21
Temperature: 77.5 °C
Reaction time: 24 h

Procedure:
A solution of N-[2-(dimethylamino)ethyl]pyridine-2,3-diamine (1.49 g, 8.3 mmol) in DMF is treated with carbonyldiimidazole (CDI) (2.01 g, 12.4 g) under nitrogen, stirred at 75-80° C. for 24 h, cooled to room temperature and concentrated in vacuo. The resultant residue is chromatographed, eluting with 10:90 conc. NH4OH:ethanol to afford a solid which is triturated with ethanol:ethyl acetate to afford the title compound as a tan solid, 0.387 g, mp 141-142° C., identified by NMR and mass spectral analyses.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[NH:28]1[CH:32]=[CH:31][N:30]=[C:29]1[C:33]1[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=1>>[NH:28]1[CH:32]=[CH:31][N:30]=[C:29]1[C:33]1[CH:39]=[CH:38][C:36]([NH:37]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:35][CH:34]=1
Reactant: Nc1ccc(-c2ncc[nH]2)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(-c2ncc[nH]2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(imidazol-2-yl)-aniline Rf value: 0.5 (silica gel, methylene chloride/methanol=10:1) C26H20N4O3
Reaction SMILES: C(O[C:4](=[O:21])[CH:5]([N:7]1[C:12]2[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=S)[CH3:6])C.O.[NH2:23][NH2:24]>CCO>[CH3:6][CH:5]1[N:7]2[C:8]([CH2:9][O:10][C:11]3[C:12]2=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=3)=[N:24][NH:23][C:4]1=[O:21]
Reactant: NN
Reactant: CCOC(=O)C(C)N1C(=S)COc2ccc([N+](=O)[O-])cc21
Solvent: CCO
Solvent: O
Product: CC1C(=O)NN=C2COc3ccc([N+](=O)[O-])cc3N21
Temperature: 80 °C
Reaction time: 3 h
Yield: 67.8 %

Procedure:
To a solution of 2-(6-nitro-3-thioxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester (133.0 g, 450 mmol) in EtOH (1.5 L) was added hydrazine hydrate (45.0 g, 900 mmol, 98%) and the mixture was heated to 80° C. and stirred for 3 h. The reaction mixture was cooled to ambient temperature and filtered. The filtrate was washed with cold EtOH (3×50 mL) to give 4-methyl-6-nitro-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one as a yellow solid (80.0 g, 68%). 1H NMR (DMSO-d6, 400 MHz): δ 10.91 (s, 1H), 7.98 (d, J=2.8 Hz, 1H), 7.86 (dd, J=2.8 Hz, J=8.8 Hz, 1H), 7.23 (d, J=8.8 Hz, 1H), 4.99 (q, J=6.4 Hz, 1H), 4.78 (d, J=12.8 Hz, 2H), 1.36 (d, =6.8 Hz, 3H).
Reaction SMILES: [N:1]1([CH:6]([F:17])[C:7]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])=O)[CH:5]=[N:4][CH:3]=[N:2]1.[C:18](=O)([O-])[O-].[K+].[K+].O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[F:16][C:10]1[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:9]=1[C:7]([CH:6]([F:17])[N:1]1[CH:5]=[N:4][CH:3]=[N:2]1)=[CH2:18]
Reactant: O=C([O-])[O-]
Reactant: O=C(c1ccc(F)cc1F)C(F)n1cncn1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C=C(c1ccc(F)cc1F)C(F)n1cncn1

Procedure:
2-(1H-1,2,4-Triazol-1-yl)-2,2',4'-trifluoroacetophenone (10 g), anhydrous potassium carbonate (7.3 g), and methyltriphenylphosphonium bromide (15.5 g) were heated under reflux for 16 hours in 1,4-dioxan (250 ml), to which water (1.0 g) had been added.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.[CH:10]1([NH2:13])[CH2:12][CH2:11]1>C(O)C>[CH:10]1([NH:13][CH2:5][C:4]2[CH:7]=[CH:8][CH:9]=[C:2]([I:1])[CH:3]=2)[CH2:12][CH2:11]1
Reactant: BrCc1cccc(I)c1
Reactant: NC1CC1
Solvent: CCO
Product: Ic1cccc(CNC2CC2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 81.6 %

Procedure:
A solution of 3-iodobenzyl bromide (Aldrich, 3.2 g, 10.77 mmol) in ethanol (20 mL) was treated with cyclopropyl amine (7 mL, 101.5 mmol) and the resulting reaction mixture was stirred over 3 days at ambient temperature. The volatiles were evaporated in vacuo, the residue was diluted with ethyl acetate and washed with saturated, aqueous sodium bicarbonate solution, water and brine, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to an oil that was subjected to flash column chromatography over silica gel (230-400 mesh) using 10-20% ethyl acetate in hexane as the eluent afford the title product (2.4 g, 81%).
Reaction SMILES: C1([NH:7][NH2:8])C=CC=CC=1.[C:9]1([CH:15]=[CH:16][C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(O)C>[C:9]1([CH:15]=[CH:16][C:17](=[N:7][NH2:8])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(C=Cc1ccccc1)c1ccccc1
Reactant: NNc1ccccc1
Solvent: CCO
Product: NN=C(C=Cc1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 125.2 %

Procedure:
Another colorant stabilizer of the present invention is a basic fuschin hydrazone, prepared as follows. To a 500 ml round bottom flask, fitted with a magnetic stirrer and a heating mantle, was placed 50 g (0.46 mole) phenyl hydrazine (Aldrich), 96.3 g (0.46 mole) chalcone (Aldrich), and 300 ml. of anhydrous ethanol. The reaction mixture refluxed overnight and then cooled to room temperature. A white precipitate formed and was filtered to yield a white solid which was washed with cold ether. 128 g (93%) chalcone hydrazone was obtained. This reaction is shown below. ##STR44##
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[C:7]1([OH:17])[C:16]2[CH2:15][CH:14]=[CH:13][CH2:12][C:11]=2[CH:10]=[CH:9][CH:8]=1.S(OC)(OC)(=O)=O>C(O)C>[CH3:1][O:17][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[CH2:15][CH:14]=[CH:13][CH2:12]2
Reactant: O=C([O-])[O-]
Reactant: Oc1cccc2c1CC=CC2
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CCO
Product: COc1cccc2c1CC=CC2
Temperature: 40 °C
Yield: 92.5 %

Procedure:
Add powdered potassium carbonate (193.1 g, 1.397 mol) to a solution of commercially available 5,8-dihydronaphthalen-1-ol [68.08 g, 90% potency based on 1H-NMR, 0.4657 mol, from Societa Italiana Medicinala Scandicci, s.r.l., Reggello (Firenze), Italy] in ethanol (700 mL). Cool the solution to 0° C. with ice water and add dimethyl sulfate (88.1 g, 66.1 mL, 0.699 mol) dropwise, maintaining the temperature between 5° C. and 10° C. Heat the reaction mixture to 40° C. until TLC shows the absence of starting material (about 2 hr). Filter off the solids by vacuum filtration and concentrate. Dilute the residual brown oil with diethyl ether (500 mL), wash with 10% aqueous ammonium hydroxide (500 mL), water (500 mL), brine (500 mL), dry (sodium sulfate) and concentrate to give the crude product as a brown oil (73 g). Purify the crude product by short path distillation under vacuum (bp 120-130° C./5 Torr) to give the title compound as a clear oil (69.0 g, 92.5% potency corrected) (contains some 1,2,3,4-tetrahydro-5-methoxynaphthalene as an impurity).
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[CH:16]([C:17]3[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=3)[CH2:15][CH2:14][CH2:13][CH:12]2[C:24]2[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][N:25]=2)=[CH:6][CH:5]=1.O.[OH-].[Na+].Cl>CO>[CH3:30][C:29]1[C:24]([CH:12]2[CH2:13][CH2:14][CH2:15][CH:16]([C:17]3[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=3)[N:11]2[CH2:10][C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:31])=[O:2])=[CH:9][CH:8]=2)=[N:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)c1ccc(CN2C(c3ncccc3C)CCCC2c2ncccc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cccnc1C1CCCC(c2ncccc2C)N1Cc1ccc(C(=O)O)cc1
Temperature: 25 °C
Yield: 108.5 %

Procedure:
To a solution of 4-(3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-benzoic acid methyl ester (0.420 g, 1.01 mmol) in MeOH (5 mL) was added water (5 mL) and solid NaOH (0.448 g, 11.21 mmol). The resultant mixture was heated to reflux overnight then cooled to room temperature. The mixture was adjusted to pH ˜5 with 6 N HCl (˜2 mL) and extracted with CH2Cl2 (5×20 mL). The combined organic extracts were dried (Na2SO4) and concentrated and provided 0.440 g (quantitative yield) of 4-(3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-benzoic acid as a white solid. 1H NMR (CDCl3) δ 1.80-2.05 (m, 6H), 2.42 (s, 6H), 3.83 (br s, 2H), 4.55 (br s, 2H) 6.79 (d, 2H, J=8.1 Hz), 7.02 (dd, 2H, J=7.5, 5.1 Hz), 7.34 (d, 2H, J=7.5 Hz), 7.65 (d, 2H, J=7.8 Hz), 8.42 (d, 2H, J=3.9 Hz); ES-MS m/z 402 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][NH:11][CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:23]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:24]>C(Cl)Cl>[C:26]1([O:25][C:23](=[O:24])[N:11]([CH2:10][CH2:9][S:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH:12]([CH3:14])[CH3:13])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)NCCSc1ccc(Cl)cc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)N(CCSc1ccc(Cl)cc1)C(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.6 %

Procedure:
To a solution of 22.8 g (0.1 mole) of N-[2-[(4-chlorophenyl)thio]ethyl]-1-methylethanamine (oil in Preparation 1) and 10.1 g (0.1 mole) of triethylamine in 300 ml of methylene chloride was added dropwise with stirring a solution of 15.7 g (0.1 mole) phenyl chloroformate in 100 ml of methylene chloride. The resulting solution was stirred overnight at room temperature. The methylene chloride layer was extracted with 5% sodium hydroxide solution followed by 1N sulfuric acid. The methylene chloride layer was concentrated to give an oil which crystallized to a white solid. Recrystallization from isopropyl ether gave white crystalline product, m.p. 54°-56° C. in 79.6% yield.
Reaction SMILES: [NH3:1].[Na].[F:3][C:4]1[CH:18]=[CH:17][C:7]([C:8](/[C:10](=[C:13](/OC)\[CH3:14])/[C:11]#[N:12])=[O:9])=[CH:6][CH:5]=1>>[NH2:1]/[C:13](/[CH3:14])=[C:10](/[C:8](=[O:9])[C:7]1[CH:17]=[CH:18][C:4]([F:3])=[CH:5][CH:6]=1)\[C:11]#[N:12]
Reactant: CO/C(C)=C(\C#N)C(=O)c1ccc(F)cc1
Reactant: N
Agent: [Na]
Product: C/C(N)=C(/C#N)C(=O)c1ccc(F)cc1
Reaction time: 1 h

Procedure:
Approximately 50 ml. of liquid ammonia is condensed in a three-neck flask cooled to -78° in a dry ice-acetone bath. To this is added 200 mg. of sodium metal, followed by 100 mg. of ferric chloride hexahydrate. When the blue color had vanished, 6.2 g. of 2-(p-fluorobenzoyl)-3-methoxycrotononitrile is added. After stirring for one hour, the reaction is allowed to warm and the solvent evaporate. The residue is dissolved in hot ethyl acetate and filtered through Celite®. The filtrate is concentrated on the steam bath and diluted with hexane. Upon cooling, the crystalline product precipitates, is filtered and dried.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]2[O:13][CH:14]=[C:15]([CH2:17][OH:18])[N:16]=2)=[CH:6][CH:5]=1.CC(C)([O-])C.[Na+].Cl[C:28]1[N:29]=[N:30][C:31]([CH2:34][CH2:35][CH2:36][CH2:37][N:38]2[CH:42]=[CH:41][N:40]=[N:39]2)=[CH:32][CH:33]=1.C(OCC)(=O)C>O1CCCC1>[N:38]1([CH2:37][CH2:36][CH2:35][CH2:34][C:31]2[N:30]=[N:29][C:28]([O:18][CH2:17][C:15]3[N:16]=[C:12]([CH:11]=[CH:10][C:7]4[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:19])[F:20])=[CH:5][CH:6]=4)[O:13][CH:14]=3)=[CH:33][CH:32]=2)[CH:42]=[CH:41][N:40]=[N:39]1
Reactant: OCc1coc(C=Cc2ccc(OC(F)(F)F)cc2)n1
Reactant: Clc1ccc(CCCCn2ccnn2)nn1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: FC(F)(F)Oc1ccc(C=Cc2nc(COc3ccc(CCCCn4ccnn4)nn3)co2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
{2-[2-(4-Trifluoromethoxy-phenyl)-vinyl]-oxazol-4-yl}-methanol (0.050 g, 0.17 mmol) is dissolved in anhydrous tetrahydrofuran (THF) (2 ml) followed by addition of sodium tert-butoxide (NaOtBu) (0.019 g, 0.19 mmol). After stirring for 15 min at r.t. 3-chloro-6-(4-[1,2,3]triazol-1-yl-butyl)-pyridazine (0.035 g, 0.15 mmol) is added slowly and stirred for further 4 h at 60° C. Ethyl acetate (20 ml) is added, the mixture is washed with saturated ammonium chloride (NH4Cl), dried over Na2SO4 and concentrated in vacuo. After flash column chromatography (ethyl acetate/methanol 97:3) 3-(4-[1,2,3]triazol-1-yl-butyl)-6-{2-[2-(4-trifluoromethoxy-phenyl)-vinyl]-oxazol-4-ylmethoxy}-pyridazine is isolated as a colorless solid. Yield 0.049 g (69%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:13]([OH:15])=[O:14])=[C:6]2[C:11]=1[S:10](=O)[CH2:9][CH2:8][NH:7]2.C(OCC)(=O)C>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:13]([OH:15])=[O:14])=[C:6]2[C:11]=1[S:10][CH2:9][CH2:8][NH:7]2
Reactant: O=C(O)c1ccc(Cl)c2c1NCCS2=O
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(O)c1ccc(Cl)c2c1NCCS2
Yield: 19.3 %

Procedure:
A mixture of 8-chloro-3,4-dihydro-2H-1,4-benzothiazine-5-carboxylic acid-1-oxide (2.5 g) and stannous chloride dihydrate (4.51 g) in methanol (20 ml) was refluxed for 21 hours. To the reaction mixture was added ethyl acetate (200 ml), washed with water and dried over anhydrous sodium sulfate. After concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography eluting with dichloromethane-ethanol (9:1) to give the title compound (450 mg, 19.6%). This compound was recrystallized from ethanol to give yellow needles, mp 220° C.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]2[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:8]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[C:17]([CH3:25])[CH:16]=3)=[N:7][C:6]=12.[C:26]([C:28]1[CH:29]=[N:30][C:31]([NH2:34])=[N:32][CH:33]=1)#[CH:27]>>[CH3:25][C:17]1[CH:16]=[C:15]([C:8]2[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[N:5]3[N:4]=[CH:3][C:2]([C:27]#[C:26][C:28]4[CH:29]=[N:30][C:31]([NH2:34])=[N:32][CH:33]=4)=[C:6]3[N:7]=2)[CH:20]=[CH:19][C:18]=1[C:21]([F:24])([F:23])[F:22]
Reactant: C#Cc1cnc(N)nc1
Reactant: Cc1cc(-c2cc(C(F)(F)F)n3ncc(I)c3n2)ccc1C(F)(F)F
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C#Cc4cnc(N)nc4)c3n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 3-iodo-5-(3-methyl-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (example C.32) (236 mg, 0.5 mmol) and 5-ethynyl-pyrimidin-2-ylamine (example D.2) (60 mg, 0.5 mmol) according to general procedure II. Obtained as an orange solid (139 mg, 60%). MS (EI) 462.1 [(M)+]; mp 240° C.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[NH2:15][C:16]1[CH:17]=[C:18](O)[CH:19]=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:45][CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1>O1CCCC1>[N:48]1([CH2:47][CH2:46][O:45][C:19]2[CH:18]=[CH:17][C:16]([NH2:15])=[C:21]([N+:22]([O-:24])=[O:23])[CH:20]=2)[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1
Reactant: OCCN1CCOCC1
Reactant: Nc1cc(O)ccc1[N+](=O)[O-]
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1ccc(OCCN2CCOCC2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Diisopropyl azodicarboxylate (1.1 equivalents) was added dropwise to a stirred solution of 3-amino-4-nitrophenol (1.0 equivalent), triphenylphosphine (1.1 equivalents), and an alcohol, e.g. N-(2-hydroxyethyl)morpholine (1.0 equivalent), in tetrahydrofuran at 0° C. The mixture was allowed to warm to room temperature and stirred for 18 hours. The solvent was evaporated, and the product was purified by silica gel chromatography (98:2 CH2Cl2:methanol) to yield 4-(2-morpholin-4-ylethoxy)-2-nitrophenylamine as a dark reddish-brown oil. LC/MS m/z 268.0 (MH+), Rt 1.01 minutes. The nitroamine was reduced as in Method 1 to give the crude product which was used without further purification. LC/MS m/z 238.3 (MH+), Rt 0.295 minutes.
Reaction SMILES: [CH3:1][CH:2]([S:4](Cl)(=[O:6])=[O:5])[CH3:3].[NH2:8][CH2:9][C:10]([C:13]1[CH:18]=[CH:17][C:16]([I:19])=[CH:15][CH:14]=1)([OH:12])[CH3:11].O>C(Cl)Cl>[OH:12][C:10]([C:13]1[CH:14]=[CH:15][C:16]([I:19])=[CH:17][CH:18]=1)([CH3:11])[CH2:9][NH:8][S:4]([CH:2]([CH3:3])[CH3:1])(=[O:6])=[O:5]
Reactant: CC(O)(CN)c1ccc(I)cc1
Reactant: CC(C)S(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Product: CC(C)S(=O)(=O)NCC(C)(O)c1ccc(I)cc1
Temperature: 0 °C
Yield: 19.4 %

Procedure:
Into a 250 mL 3 necked flask fitted with a stirrer and thermometer, was added dropwise 2-propanesulfonyl chloride (1.60 g, 0.011 mol) to 1-amino-2-(4-iodophenyl)propan-2-ol (2.77 gm, 0.01 mol) in 125 mL CH2Cl2 while stirring at 0° C. under nitrogen. The reaction was then allowed to warm to room temperature and stirred overnight at this temperature. In the morning, the mixture was poured into H2O and the layers were separated. The organic layer was washed once with H2O, dried over anhydrous Na2SO4, filtered, and concentrated under reduced vacuum. The resulting semi-solid was purified via silica gel chromatography employing the Prep. LC-2000 and eluting with a solvent of Hexane/EtOAc 3:1 to provide the intermediate title compound (744 mg, 19%) as a solid material. FDMS 382 (M*).