Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)(O)[O-].[K+].[H][H].[N+](C1C=CC(C[O:16][C:17]([C@@H:19]2[N:23]3[C:24](=[O:40])[C@@H:25]([NH:26]C(OCC4C=CC([N+]([O-])=O)=CC=4)=O)[C@H:22]3[S:21][C@:20]2([CH2:42][O:43][C:44](=[O:46])[NH2:45])[CH3:41])=[O:18])=CC=1)([O-])=O>[Pd].C(OCC)(=O)C>[NH2:26][C@@H:25]1[C:24](=[O:40])[N:23]2[C@@H:19]([C:17]([OH:18])=[O:16])[C@@:20]([CH2:42][O:43][C:44](=[O:46])[NH2:45])([CH3:41])[S:21][C@H:22]12
Reactant: [H][H]
Reactant: C[C@@]1(COC(N)=O)S[C@@H]2[C@H](NC(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)N2[C@H]1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOC(C)=O
Product: C[C@@]1(COC(N)=O)S[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)O
Yield: 66 %

Procedure:
A suspension of 10% palladium on charcoal (0.50 g) in ethyl acetate (25 ml) and aqueous potassium bicarbonate (0.4%, 22.5 ml, 0.10 g inorganics) was prehydrogenated at 50 psi hydrogen for 15 minutes. The suspension was charged under nitrogen with (2R,3S,5R,6R) 6-(4-nitrobenzyloxycarbonyl)amino-2-carbamoyloxymethyl-2-methylpenam-3-carboxylic acid p-nitrobenzyl ester (0.54 g, 0.9 mmol) and the whole was shaken at 50 psi hydrogen pressure for 1.2 hours. The mixture (pH 5.0) was centrifuged and the aqueous phase was washed with methylene chloride (2×15 ml), combined with a water back extract (10 ml), and concentrated to about a 2 ml volume. The rich aqueous phase was diluted with deuterium oxide (4 ml) frozen on dry-ice and lyophilized to give a light yellow solid (0.25 g; theory=0.25 g+inorganics 0.10 g) in 66% product yield; nmr 100 MHz (D2O) ppm 4.63 (1, d, J=4.0 Hz, C6 --H), 4.46 (1, s, C3 --H), C5 --H under HOD, 4.18 (1, d, J=11.5, 1/2AB C2 --CHH--O), 4.01 (1, d, J=11.5, C2 --CHHO), and 1.53 (3, s, C2 --CH 3).
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6]([Br:8])[CH:7]=1.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Br:8][C:6]1[CH:7]=[C:2]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=1
Reactant: Cn1cc(Br)cc(Br)c1=O
Reactant: Nc1ccccn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cn1cc(Br)cc(Nc2ccccn2)c1=O
Temperature: 100 °C
Yield: 42.1 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer, nitrogen inlet and reflux condenser was charged with 3,5-dibromo-1-methylpyridin-2(1H)-one (936 mg, 3.51 mmol), 2-aminopyridine (300 mg, 3.19 mmol), cesium carbonate (3.11 g, 9.57 mmol) and 1,4-dioxane (20 mL). After bubbling nitrogen through the resulting solution for 20 minutes, Xantphos (184 mg, 0.319 mmol) and tris(dibenzylideneacetone)dipalladium(0) (146 mg, 0.160 mmol) were added, and the reaction mixture was heated at 100° C. for 3 h. After this time, the reaction was cooled to room temperature, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography to afford a 42% yield (376 mg) of 184a as an off-white solid: mp 153-154° C.; 1H NMR (300 MHz, DMSO-d6) d 8.75 (s, 1H), 8.69 (d, 1H, J=2.4 Hz), 8.26 (dd, 1H, J=5.4, 1.5 Hz), 7.61 (m, 1H), 7.54 (d, 1H, J=2.4 Hz), 7.33 (d, 1H, J=5.4 Hz), 6.86 (m, 1H), 3.45 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[I:13]N1C(=O)CCC1=O.O>C(O)(=O)C>[Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([I:13])[C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1
Reactant: CC(=O)c1cc(Cl)c(C)cc1O
Reactant: O=C1CCC(=O)N1I
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)c1cc(Cl)c(C)c(I)c1O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 96.6 %

Procedure:
To a stirred solution of 1-(5-chloro-2-hydroxy-4-methylphenyl)ethanone (from Oakwood, 50.0 g, 271 mmol) in acetic acid (300 mL) was added N-iodosuccinimide (73.1 g, 325 mmol) and the resulting mixture was stirred on a heating mantle between 60˜80° C. over 3.5 hours then cooled to room temperature and stirred overnight. Water (500 mL) was added to the mixture in portions, which caused a dark solid to form. After stirring for 10 minutes, the solids were filtered, washing with additional water. The light to dark brown solids were dried under vacuum for 4 hours then air dried over the weekend to give 81.3 g (97%) of the desired product. LCMS calculated for C9H9ClI2 (M+H)+: m/z=310.9; Found: 311.0. 1H NMR (300 MHz, CDCl3): δ 13.21 (s, 1H), 7.71 (s, 1H), 2.65 (s, 3H), 2.63 (s, 3H) ppm.
Reaction SMILES: [CH:1]([CH:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])([CH3:3])[CH3:2].CN(P(N(C)C)N(C)C)C.[H-].[Na+].[CH2:27](Cl)[C:28](=[CH2:30])[CH3:29]>C1(C)C=CC=CC=1.CN(P(N(C)C)N(C)C)C.C1(C)C=CC=CC=1>[CH:1]([C:4]([CH2:29][C:28]([CH3:30])=[CH2:27])([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(C(=O)OCC)C(C)C
Reactant: C=C(C)CCl
Agent: CN(C)P(N(C)C)N(C)C
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=C(C)CC(C(=O)OCC)(C(=O)OCC)C(C)C
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A solution of diethyl isopropylmalonate (8.1g) in 25 ml of a 25% solution of HMPT (hexamethylphosphorus triamide) in toluene was added dropwise over 15 minutes to a suspension of sodium hydride (50 mM) in 25% HMPT/toluene (50 ml) at room temperature. The mixture was then stirred at 60° C. for 1/2 hour, cooled to 25° C. and methallyl chloride (4.0g) in 25% HMPT/toluene was added over 10 minutes. The mixture was stirred at 80°-85° C. overnight, cooled to room temperature and poured onto a mixture of ice/hydrochloric acid. The product was extracted with ether, the ethereal extracts washed with water, followed by 2N sodium hydroxide and then water, and dried over magnesium sulphate. Removal of solvent gave diethyl isopropyl-2-methylprop-2-enylmalonate as a pale yellow liquid. R.I. nD21 1.4467.
Reaction SMILES: N1C=CC=CC=1.[C:7](OC(=O)C)(=[O:9])[CH3:8].[F:14][C:15]1[CH:25]=[CH:24][C:18]([O:19][CH2:20][CH2:21][CH2:22][NH2:23])=[C:17]([N+:26]([O-:28])=[O:27])[CH:16]=1.Cl>O.ClCCl>[F:14][C:15]1[CH:25]=[CH:24][C:18]([O:19][CH2:20][CH2:21][CH2:22][NH:23][C:7](=[O:9])[CH3:8])=[C:17]([N+:26]([O-:28])=[O:27])[CH:16]=1
Reactant: NCCCOc1ccc(F)cc1[N+](=O)[O-]
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)NCCCOc1ccc(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 15 h
Yield: 89.1 %

Procedure:
Pyridine (1.5 ml, 18.6 mmol) and acetic anhydride (0.97 g, 10.3 mmol) were added to a dichloromethane solution of 3-(4-fluoro-2-nitrophenoxy)propylamine (2.0 g, 9.33 mmol), while being cooled with ice, and then dichloromethane (4 ml) was further added. The resulting mixture was stirred at room temperature for 15 hours. 2N-hydrochloric acid (9.5 ml) was added to the reaction mixture, and the mixture was stirred. Water was added to the mixture, and the resulting mixture was extracted with dichloromethane. After being washed with a saturated sodium chloride aqueous solution, the organic layer was concentrated under reduced pressure. The residue was then purified by silica gel column chromatography (dichloromethane:methanol=30:1→20:1). The purified product was concentrated under reduced pressure to thereby obtain 2.13 g of oily yellow N-[3-(4-fluoro-2-nitrophenoxy)propyl]acetamide (yield: 89%).
Reaction SMILES: C(OC([N:6]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[NH:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[N:14]=2)[CH2:8][CH2:7]1)=O)C.Br.[IH:23].O>C(O)C.C(OCC)C>[IH:23].[NH:14]1[C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=[C:13]1[N:9]1[CH2:10][CH2:11][CH2:12][NH:6][CH2:7][CH2:8]1
Reactant: CCOC(=O)N1CCCN(c2nc3ccccc3[nH]2)CC1
Agent: Br
Agent: I
Solvent: O
Solvent: CCO
Solvent: CCOCC
Product: c1ccc2[nH]c(N3CCCNCC3)nc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Combine 1-ethoxycarbonyl-4-(1H-benzimidazol-2- yl)[1,4]diazepane (16.7 g, 58 mmol) and aqueous 48% hydrobromic acid solution (80 mL). Heat to reflux. After 3 hours, cool to ambient temperature, add to ethanol (700 mL), and cool to 0° C. to give a solid. Combine the solid with aqueous 48% hydriodic acid (80 mL) and water (150 mL). Heat on a steam bath. After about 1 hour, cool to ambient temperature, dilute with ethanol (500 mL), and add to diethyl ether (8 L) to give a solid. Collect solid by filtration and dry in vacuo to give the title compound: mp; >290° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH:11]=O)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:19]1[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]1[CH3:28])=[N:6][C:7]=2[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[CH2:29]1[C:32]2([CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH2:31][CH:30]1[OH:38].C(OC)(OC)OC.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:1][N:2]1[C:10]([CH2:11][N:35]2[CH2:36][CH2:37][C:32]3([CH2:31][CH:30]([OH:38])[CH2:29]3)[CH2:33][CH2:34]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:19]1[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]1[CH3:28])=[N:6][C:7]=2[N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Reactant: OC1CC2(CCNCC2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC4(CC3)CC(O)C4)n(C)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.5 %

Procedure:
To a solution of 9-methyl-2-(2-methylbenzoimidazol-1-yl)-6-morpholin-4-yl-9H-purine-8-carbaldehyde (134 mg, 0.35 mmol) in DCE (5 mL) was added 7-azaspiro[3.5]nonan-2-ol (60 mg, 0.43 mmol), trimethyl orthoformate (0.19 mL, 1.77 mmol) and acetic acid (0.02 mL, 0.35 mmol). The reaction mixture was stirred at room temperature for 3 h, sodium triacetoxyborohydride (113 mg, 0.53 mmol) was added and the resulting mixture stirred for a further 2 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then the desired product eluted with 2 M NH3 in MeOH. The resulting residue was purified by column chromatography (Si—PCC, 0-20% MeOH in EtOAc) to give 343 as a white solid (80 mg, 45%). LCMS (Method G): RT=5.23 min, [M+H]+ 503.2. 1H NMR (400 MHz, CHCl3-d): δ 8.11-8.06 (m, 1 H), 7.73-7.68 (m, 1 H), 7.30-7.24 (m, 2 H), 4.37-4.24 (m, 4 H), 3.90-3.83 (m, 7 H), 3.72 (s, 2 H), 2.94 (s, 3 H), 2.58-2.31 (m, 4 H), 2.30-2.23 (m, 2 H), 1.75-1.55 (m, 8 H)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:5]([CH:20]([CH3:22])[CH3:21])=[C:6]([CH:17]=[CH:18][CH:19]=1)[O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=1.[CH:23](=O)[CH2:24][CH2:25][CH2:26][CH3:27].[BH4-].[Na+]>>[CH:20]([C:5]1[C:4]([CH2:3][CH2:2][NH:1][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:19][CH:18]=[CH:17][C:6]=1[O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=1)([CH3:22])[CH3:21]
Reactant: CCCCC=O
Reactant: CC(C)c1c(CCN)cccc1Oc1ccc(C(N)=O)cn1
Agent: [BH4-]
Agent: [Na+]
Product: CCCCCNCCc1cccc(Oc2ccc(C(N)=O)cn2)c1C(C)C
Yield: 66.3 %

Procedure:
Using a method similar to Example 710, Step 4, using 6-[3-(2-amino-ethyl)-2-isopropyl-phenoxy]-nicotinamide (299 mg, 1.00 mmol), valeraldehyde (112 mg, 1.30 mmol), and NaBH4 (57 mg, 1.50 mmol) gave the title compound (245 mg) as a colorless glass. Mass spectrum (ion spray): m/z=370 (M+1); 1HNMR (DMSO-d6): 8.59 (s, 1H), 8.22 (d, 1H), 8.00 (s, 1H), 7.44 (s, 1H), 7.10 (t, 1H), 7.01 (m, 2H), 6.80 (d, 1H), 3.24 (m, 1H), 2.76 (m, 2H), 2.63 (m, 2H), 2.50 (m, 2H), 1.38 (m, 2H), 1.25 (m, 4H), 1.16 (d, 6H), 0.84 (t, 3H).
Reaction SMILES: [C:1]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)(OCC1C=CC=CC=1)=O.[C:19]([O:24][CH2:25][C@@H:26]1[O:28]C1)(=[O:23])CCC>O1CCCC1>[F:18][C:14]1[CH:13]=[C:12]([N:11]2[CH2:1][C@H:25]([CH2:26][OH:28])[O:24][C:19]2=[O:23])[CH:17]=[CH:16][CH:15]=1
Reactant: CCCC(=O)OC[C@H]1CO1
Reactant: O=C(Nc1cccc(F)c1)OCc1ccccc1
Solvent: C1CCOC1
Product: O=C1O[C@@H](CO)CN1c1cccc(F)c1
Reaction time: 8 h

Procedure:
A mixture of N-(carbobenzyloxy)-3-fluoroaniline (1.000 g, 4.08 mmol) in dry tetrahydrofuran (10 ml) is cooled with a dry ice/acetone bath to about -78° and then nbutyllithium (1.87 ml of a 1.6M mixture in hexanes, 2.91 mmol) is added. (R)-glycidyl butyrate (0.420 g or 0.413 ml, 2.91 mmol) is then added via syringe and the cooling bath allowed to dissipate overnight, with the reaction mixture reaching 20°-25°. The reaction mixture is quenched by the careful addition of saturated aqueous ammonium chloride, the entire mixture transferred to a separatory funnel with dichloromethane washings, and the mixture extracted with dichloromethane. The combined organic extracts are dried over sodium sulfate, filtered and concentrated under reduced pressure to give a concentrate which is purified by chromatography over silica gel, eluting with acetonitrile/chloroform (10/90) containing 1% methanol, to give the title compound.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][CH3:6])=[O:4].[C:7]([OH:13])(=O)[CH2:8][C:9]([OH:11])=O.C(OC(=O)C)(=O)C.C(O)C>C(O)(=O)C>[CH3:1][N:2]1[C:7](=[O:13])[CH2:8][C:9](=[O:11])[N:5]([CH3:6])[C:3]1=[O:4]
Reactant: CNC(=O)NC
Reactant: O=C(O)CC(=O)O
Solvent: CCO
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CN1C(=O)CC(=O)N(C)C1=O
Reaction time: 6 h
Yield: 73.4 %

Procedure:
That is, 276 g (3.14 moles) of 1,3-dimethylurea and 376 g (3.62 moles) of malonic acid were dissolved in 600 ml of glacial acetic acid at 60° to 70° C., and then, after adding thereto 1250 ml of acetic anhydride, the temperature of the mixture was gradually increased to 90° C. Then, after stirring the mixture for 6 hours at the same temperature, the reaction mixture was allowed to stand overnight at room temperature and glacial acetic acid and acetic anhydride were distilled off under reduced pressure. The residue thus formed was added to 500 ml of ethanol while still hot and the crystals thus precipitated were collected by filtration, heat-refluxed for 2 hours with 380 ml of concentrated hydrochloric acid and 400 ml of water, and then allowed to stand for 6 hours under ice-cooling. The crystals thus precipitated were collected by filtration and washed with a small amount of ethanol to provide 360 g of 1,3-dimethylbarbituric acid.
Reaction SMILES: C(OC([NH:11][C@@H:12]1[CH2:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[CH2:15][N:14]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[NH:36][C:37]([NH:39][CH3:40])=[O:38])=[CH:26][CH:25]=2)[C:13]1=[O:41])=O)C1C=CC=CC=1.FC(F)(F)C(O)=O>C(O)C.[Pd]>[NH2:11][C@@H:12]1[CH2:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[CH2:15][N:14]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[NH:36][C:37]([NH:39][CH3:40])=[O:38])=[CH:26][CH:25]=2)[C:13]1=[O:41]
Reactant: CNC(=O)Nc1ccccc1-c1ccc(CN2Cc3ccccc3C[C@@H](NC(=O)OCc3ccccc3)C2=O)cc1
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: CNC(=O)Nc1ccccc1-c1ccc(CN2Cc3ccccc3C[C@@H](N)C2=O)cc1

Procedure:
A solution of 310 mg (0.552 mmol) of the intermediate obtained in Step J in 5 mL of ethanol with 0.1 mL of trifluoroacetic acid was hydrogenated at 40 psi and ambient temperature in the presence of 100 mg of 10% palladium on carbon for 4 hours. The mixture was filtered through Celite and solvent removed under vacuum to give the product. 1H NMR (400 MHz, CD3OD): δ2.69 (s, 3H), 3.24 (m, 1H), 3.44 (dd; 6, 16 Hz; 1H), 4.11 (s, 2H), 4.13 (d, 17 Hz, 1H), 4.68 (d, 14 Hz, 1H), 4.86 (d, 14 Hz, 1H), 5.14 (m, 1H), 5.18 (d, 17 Hz, 1H), 6.95 (d, 8 Hz, 1H), 7.07 (t, 8 Hz, 1H), 7.15-7.25 (m, 5H), 7.28 (m, 1H), 7.28 (d, 8 Hz, 2H), 7.33 (t, 8 Hz, 1H), 7.38 (d, 8 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([S:9]C#N)[CH:6]=[CH:5][C:3]=1[NH2:4].O.O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+].Cl>C(O)C.O>[Cl:1][C:2]1[CH:8]=[C:7]([SH:9])[CH:6]=[CH:5][C:3]=1[NH2:4]
Reactant: N#CSc1ccc(N)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [S-2]
Solvent: O
Solvent: CCO
Product: Nc1ccc(S)cc1Cl
Temperature: 50 °C

Procedure:
A solution of 2-chloro-4-thiocyanoaniline (36.9 g., 0.20 mole) in ethanol (100-200 ml.) is added to a stirred solution of sodium sulfide nonahydrate (48.04 g., 0.20 mole) in water (100 ml.) and the mixture warmed (50° C.) for 90 minutes. The cool reaction mixture is poured into water (1 liter) and dilute hydrochloric acid added to bring the pH up to 6.0-6.5. The product is extracted with ether, the ether washed with water and then dried. Removal of the drying agent and ether leaves 2-chloro-4-mercaptoaniline as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:10][CH:9]=[C:8]([C:11](=O)[CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH:7]=1)=[O:5])[CH3:2].C([SiH](CC)CC)C>C(O)(C(F)(F)F)=O>[CH2:1]([O:3][C:4]([C:6]1[NH:10][CH:9]=[C:8]([CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(C(=O)CCC(=O)O)c[nH]1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc(CCCC(=O)O)c[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.3 %

Procedure:
Into a 2000-mL 4-necked round-bottom flask was placed a solution of 113g (105 g, 438.92 mmol, 1.00 equiv) in CF3COOH (1000 mL), followed by the addition of triethylsilane (204 g, 1.75 mol, 4.00 equiv) dropwise with stirring at room temperature over 30 min (FIG. 14). The resulting solution was stirred at room temperature for 8 h, concentrated under vacuum and diluted with 500 mL of water and 500 mL of ethyl acetate. The pH value of the solution was adjusted to 7 with saturated aqueous sodium bicarbonate. The resulting solution was extracted with 3×500 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to afford 30 g (30%) of 113h as a light brown solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]1=[O:21].[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[C:32](Cl)=[O:33].C(N(CC)CC)C>O1CCCC1.C(OCC)(=O)C>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[C:2]([NH:1][C:32]([C:23]2[CH:24]=[CH:25][C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:22]=2)=[O:33])[CH:7]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)cc2N)c1=O
Reactant: O=C(Cl)c1ccc2ccccc2c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)cc2NC(=O)c2ccc3ccccc3c2)c1=O
Yield: 70.8 %

Procedure:
A solution of 3-(2-amino-4-chlorophenyl)-1-methyl-6-trifluoromethyl-2,4(1H, 3H)-pyrimidinedione (0.4 g), 2-naphthoyl chloride (0.29 g) and triethyl amine (0.19 g) in anhydrous tetrahydro furan (30 ml) was heated at reflux temperature overnight under nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate (200 ml), washed with brine (×2) and dried over anhydrous sodium sulfate. The solvent was removed unded reduced pressure and the residue was purified by column chromatography on silica gel using ethyl acetate and hexane (1:3) as the eluent give a pale yellow solid. The solid was recrystallized from ethyl acetate-hexane to give the title compound as a white crystal (0.42 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8]O)=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:10]P(Br)Br>C(Cl)Cl>[Br:10][CH2:8][C:7]1[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCc1cccnc1Cl
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: Clc1ncccc1CBr
Temperature: 0 °C

Procedure:
In a 250 mL round bottom flask was dissolved (2-chloropyridin-3-yl)methanol (6.7 g, 47 mmol) in CH2Cl2 (100 mL). The reaction was cooled to 0° C., to which was slowly added tribromophosphine (4.8 mL, 51 mmol), and allowed to warm to RT overnight. The reaction was quenched by addition of ice, extracted into CH2Cl2, washed 1×NaHCO3, 2×H2O, dried with Mg2SO4, filtered through fritted funnel and filtrate was concentrated. The crude was purified by silica gel chromatography eluting with 15-45% EtOAc/Hex. The product fraction were concentrated down to yield 3-(bromomethyl)-2-chloropyridine as off-white solid. MS m/z=206, 208 [M+1]+. Calc'd for C6H5BrClN, 206.47.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([N+:12]([O-])=O)[C:5]([Br:15])=[CH:4][CH:3]=1.C(O)C.C(O)(=O)C.C(O)=O>C(Cl)Cl.O.[Fe]>[Br:15][C:5]1[C:6]([NH2:12])=[C:7]([C:2]([NH2:1])=[CH:3][CH:4]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1c(N)ccc(Br)c1[N+](=O)[O-]
Agent: [Fe]
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: COC(=O)c1c(N)ccc(Br)c1N
Yield: 75.2 %

Procedure:
Iron powder (4.07 g) was added slowly with stirring and cooling to a solution of methyl 6-amino-3-bromo-2-nitrobenzoate (prepared according to Brock et al, Tetrahedron, 1963, 19, 1911, 2.0 g) in a mixture of absolute ethanol (49 mL), acetic acid (5 mL), formic acid (0.7 mL) and water (15 mL). On completion of the addition, the mixture was stirred at room temperature for 2 hours. The mixture was diluted with DCM and water (1:1) then filtered through Celite. The layers were separated and the aqueous layer was extracted with DCM. The combined organic layers were washed with 1M aqueous sodium hydroxide solution, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was triturated with ether and cyclohexane (1:1) and the solid was collected by filtration to give methyl 3-bromo-2,6-diaminobenzoate (1.34 g) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6](/[C:8](=[CH:11]/[C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][C:20]=2[F:21])[NH:17][N:16]=[C:15]3[CH3:22])/[C:9]#[N:10])=O)=[CH:4][CH:3]=1.[NH2:25][C:26]([CH:30]([F:32])[F:31])=[CH:27][C:28]#[N:29].C(O)(=O)C>CC(O)C>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]2[NH:25][C:26]([CH:30]([F:32])[F:31])=[C:27]([C:28]#[N:29])[CH:11]([C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][C:20]=3[F:21])[NH:17][N:16]=[C:15]4[CH3:22])[C:8]=2[C:9]#[N:10])=[CH:4][CH:3]=1
Reactant: N#CC=C(N)C(F)F
Reactant: Cc1n[nH]c2cc(F)c(/C=C(\C#N)C(=O)c3ccc(Cl)cc3)cc12
Solvent: CC(=O)O
Solvent: CC(C)O
Product: Cc1n[nH]c2cc(F)c(C3C(C#N)=C(c4ccc(Cl)cc4)NC(C(F)F)=C3C#N)cc12
Reaction time: 6 h

Procedure:
A mixture of 200 mg (0.542 mmol) (2E)-2-(4-chlorobenzoyl)-3-(6-fluoro-3-methyl-1H-indazol-5-yl)prop-2-enenitrile (Example 6A) and 66 mg (0.542 mmol) 3-amino-4,4-difluorobut-2-enenitrile [obtainable by Thorpe reaction of acetonitrile with 2,2-difluoroacetonitrile, cf. Org. React. 15, 1 (1967), ibid. 31, 1 (1984)] in 2-propanol (1 ml) was stirred at reflux for 12 h. Then, acetic acid (1.5 ml) was added, and stirring at reflux was continued for 6 h. Upon cooling, the mixture was concentrated under reduced pressure, and the residue was directly purified by preparative RP-HPLC (methanol/water+0.1% TFA gradient, final mixture 80:20 v/v) to yield 33 mg (14% of th.) of the racemic title compound.