Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.NN.[CH:4]1([S:7][C:8]2[CH:13]=[CH:12][C:11]([C:14](=O)[C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)[CH2:6][CH2:5]1.[OH-].[K+].O>C(OCC)C>[CH:4]1([S:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: O=C(O)C(=O)c1ccc(SC2CC2)cc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: O=C(O)Cc1ccc(SC2CC2)cc1
Temperature: -78 °C
Yield: 84.5 %

Procedure:
Hydrazine hydrate (4.77 mL, 153.4 mmol) was placed in a three neck flask fitted with an overhead stirring rod and a reflux condenser and cooled in a dry ice acetone bath at −78° C. After the solution reached −50° C. the bath was removed and (4-cyclopropylsulfanyl-phenyl)-oxo-acetic acid (3.41 g, 15.34 mmol) was added in one portion. The temperature increased due to an exotherm and it was then heated in an oil bath to 80° C. After the reaction was at 80° C. it was treated with potassium hydroxide (593 mg, 9.20 mmol) and stirred vigorously. When the reaction returned to 80° C. a second portion of potassium hydroxide (593 mg, 9.20 mmol) was added and allowed to cool back to 80° C. This cycle was repeated two more times adding potassium hydroxide (593 mg, 9.20 mmol) each time. The reaction was then heated at 100° C. for 16 h over which time the reaction became a homogenous clear yellow solution. It was then cooled to 25° C. and water (3 mL) added to the reaction. It was then transferred to a separatory funnel and another portion of water (3 mL) was added and diethyl ether (10 mL). The layers were separated and the aqueous layer separated into a flask. The organic layer was then extracted with water (5 mL) and this aqueous layer combined with the first. To the aqueous layers was then added heptane (5 mL) and stirred vigorously. This solution was cooled to 0° C. in an ice bath and was treated dropwise with concentrated hydrochloric acid (˜7 mL) over 30 min until the aqueous layer was at pH=2 keeping the temperature of the solution below 50° C. during the addition process and it turned cloudy. It was then allowed to cool to 25° C. and stirred for 3 h. It was then filtered to remove the solids and the solids were washed with 1N aqueous hydrochloric acid (1.5 mL), water (2×1.5 mL), heptane (5 mL) and 1:1 heptane:diethyl ether (5 mL) and the solid was then dried in a vacuum oven to afford (4-cyclopropylsulfanyl-phenyl)-acetic acid (2.70 g, 85%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]([CH2:12][CH2:13][CH2:14][C:15]([O:17]CC)=O)[C:6](=[O:20])[N:5]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:4]=2[N:3]=1.O[NH:27][C:28](=[NH:35])[CH2:29][C:30]1[CH:34]=[CH:33][S:32][CH:31]=1.CC[O-].[Na+]>CCO>[Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]([CH2:12][CH2:13][CH2:14][C:15]3[O:17][N:35]=[C:28]([CH2:29][C:30]4[CH:34]=[CH:33][S:32][CH:31]=4)[N:27]=3)[C:6](=[O:20])[N:5]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:4]=2[N:3]=1
Reactant: N=C(Cc1ccsc1)NO
Reactant: CCCCCn1c(=O)n(CCCC(=O)OCC)c(=O)c2[nH]c(Cl)nc21
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCn1c(=O)n(CCCc2nc(Cc3ccsc3)no2)c(=O)c2[nH]c(Cl)nc21
Temperature: 140 °C
Yield: 30.7 %

Procedure:
A mixture of ethyl 4-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)butanoate (70 mg, 0.19 mmol), N-hydroxy-2-(3-thienyl)ethanimidamide (36 mg, 0.23 mmol), 21% solution of NaOEt in EtOH (78 μl, 0.21 mmol) and EtOH (1.5 ml) was heated in the microwave at 140° C. for 10 min. After cooling the reaction was partitioned between 2M HCl (aq) and EtOAc. The organic layer was separated and the aqueous layer extracted again with EtOAc. The combined extracts were concentrated and purified by MDAP. The title compound was freeze dried from 1,4-dioxane to give a white solid (27 mg, 31%).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:10][CH:9]=1.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl>[CH3:18][O:17][C:15](=[O:16])[CH2:14][C:11]1[CH:10]=[CH:9][C:8]([O:7][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:13][CH:12]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Product: COC(=O)Cc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.3 %

Procedure:
Cesium carbonate (5.35 g, 16.4 mmol, 3.00 equivalents) was added to a solution of methyl 4-hydroxyphenylacetate (1.00 g, 6.02 mmol, 1.10 equivalents) and benzyl bromide (0.65 mL, 5.47 mmol, 1.00 equivalents) in dichloromethane (40 mL) at 0° C. The mixture was allowed to warm to room temperature and stirred vigorously overnight. The reaction was extracted with 1N hydrochloric acid (2×100 mL) and brine (100 mL). The organic portion was dried over sodium sulfate and the solvent removed in vacuo. The resulting oily solid was chromatographed on a 40S Biotage column (20% ethyl acetate/Hexanes) to give the title ester as a clear colorless oil (1.35 g, 96%). 1H NMR (400 MHz, CDCl3) δ 3.56 (s, 2H), 3.67 (s, 3H), 5.04 (s, 2H), 6.91-6.94 (d, 2H), 7.17-7.19 (d, 2H), 7.3-7.4 (m, 5H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([Li])CCC.C[N:14]([O:21][CH3:22])[C:15](=O)[C:16]([F:19])([F:18])[F:17].Cl.O(N)C>CCOCC.CCCCCC.C1(C)C=CC=CC=1>[CH3:22][O:21]/[N:14]=[C:15](\[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)/[C:16]([F:19])([F:18])[F:17]
Reactant: Brc1cccnc1
Reactant: CON(C)C(=O)C(F)(F)F
Agent: CON
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CO/N=C(\c1cccnc1)C(F)(F)F
Temperature: 25 °C
Yield: 79.9 %

Procedure:
3-Bromopyridine (11.28 g, 0.0714 mol) in dry ether (50 ml) was added dropwise to a solution of n-butyl lithium (49.1 ml of a 1.6M solution in hexane, 0.0785 mol) in ether (150 ml) at -78° C. over 15 minutes. The resulting suspension was stirred for a further 15 minutes before N-methyl-N-methoxytrifluoroacetamide (D4, 11.22 g, 0.0715 mol) in ether (15 ml) was added dropwise. The reaction mixture was allowed to warm to room temperature over 1 h then poured into stirred ice-cold 2M hydrochloric acid (200 ml). The aqueous layer was separated and washed with ether (2×100 ml). The combined organic layers were extracted with 2M hydrochloric acid (150 ml). The combined aqueous layers were then carefully made basic then saturated with potassium carbonate and extracted with chloroform (4×250 ml). The combined chloroform extracts were dried (Na2SO4) and evaporated to give a semi-crystalline solid which was taken-up in toluene (300 ml) and treated with methoxylamine hydrochloride (18 g, 0.216 mol) at reflux under Dean-Stark conditions for 2 h. The reaction mixture was cooled and extracted with 2M hydrochloric acid (3×150 ml). The combined aqueous extracts were washed with ether (2×200 ml) then basified and partially saturated with potassium carbonate then extracted with chloroform (2×300 ml). The combined organic fractions were dried (Na2SO4) and evaporated to give an oil which was distilled to give the title compound (D7) as a colourless oil (11.64 g, 80%) b.p. 135° C. at 120 mmHg.
Reaction SMILES: [CH:1]1[N:5]=[CH:4][NH:3][C:2]=1/[CH:6]=[CH:7]/[C:8]([OH:10])=[O:9].[O-]P(OP([O-])([O-])=O)(=O)[O-].[NH2:20][C@@H](CCC(N[C@H](C(NCC(O)=O)=O)CS)=O)C(O)=O>[Cl-].[Cl-].[Zn+2].N[C@H](C(O)=O)CC1N=CNC=1>[NH3:3].[NH2:20][C@H:7]([C:8]([OH:10])=[O:9])[CH2:6][C:2]1[N:3]=[CH:4][NH:5][CH:1]=1
Reactant: N[C@@H](CCC(=O)N[C@@H](CS)C(=O)NCC(=O)O)C(=O)O
Reactant: O=C(O)/C=C/c1cnc[nH]1
Agent: N[C@@H](Cc1c[nH]cn1)C(=O)O
Agent: O=P([O-])([O-])OP(=O)([O-])[O-]
Agent: [Cl-]
Product: N
Reaction time: 0.08 h

Procedure:
HAL enzyme activity can be determined as described in Baedeker & Schulz (Eur. J. Biochem 2002, 269, 1790-1797), wherein enzyme activity was determined as the rate of urocanate formation, measured spectrophotometrically at 277 nm. For a standard assay, the enzyme was preincubated at 25° C. for 5 min in 2.5 mL buffer containing 0.1 M pyrophosphate (pH 9.3), 10 μM ZnCl2 and 2 mM glutathione. The reaction was started by adding 200 μL of 0.5 M histidine solution and then monitored for approximately 5 minutes.
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([C:25](O)=[O:26])[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.ON1C2C=CC=CC=2N=N1.Cl.[NH2:40][C:41]1[N:46]([CH2:47][CH2:48][CH2:49][CH3:50])[C:45](=[O:51])[N:44]([CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=2[F:59])[C:43](=[O:60])[C:42]=1[NH:61][C:62](=[O:71])[CH2:63][C:64]1[CH:69]=[CH:68][C:67]([NH2:70])=[CH:66][CH:65]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[NH2:40][C:41]1[N:46]([CH2:47][CH2:48][CH2:49][CH3:50])[C:45](=[O:51])[N:44]([CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=2[F:59])[C:43](=[O:60])[C:42]=1[NH:61][C:62]([CH2:63][C:64]1[CH:65]=[CH:66][C:67]([NH:70][C:25]([C:23]2[N:22]=[CH:21][N:20]([C:1]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:24]=2)=[O:26])=[CH:68][CH:69]=1)=[O:71]
Reactant: O=C(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CCCCn1c(N)c(NC(=O)Cc2ccc(N)cc2)c(=O)n(Cc2ccccc2F)c1=O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCn1c(N)c(NC(=O)Cc2ccc(NC(=O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)cc2)c(=O)n(Cc2ccccc2F)c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 111.5 %

Procedure:
A solution of 1-trityl-1H-imidazole-4-carboxylic acid (67 mg, 0.19 mmol) in N,N-dimethylformamide (1.0 mL) at 25 ° C. was treated with 1-hydroxybenzotriazole hydrate (25.4 mg, 0.19 mmol) and O-benzotriazol-1-yl-N,N,N′N′-tetramethyluronium hexafluorophosphate (71 mg, 0.19 mmol). This solution was cooled to 0° C. and then was treated with N-[6-amino-1-butyl-3-(2-fluoro-benzyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl]-2-(4-amino-phenyl)-acetamide hydrochloride salt (81.5 mg, 0.17 mmol) and N,N-diisopropylethylamine (0.15 mL, 0.85 mmol). The reaction was stirred at 0° C. for 1 h and then at 25° C. for 4 h. At this time, the reaction was concentrated in vacuo. The residue was dissolved in ethyl acetate (100 mL) and was washed with a saturated aqueous sodium bicarbonate solution (1×25 mL). Some residual solids were then removed by filtration. The filtrate was washed with a saturated aqueous sodium chloride solution. The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 1-trityl-1H-imidazole-4-carboxylic acid (4-{[6-amino-1-butyl-3-(2-fluoro-benzyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-ylcarbamoyl]-methyl}-phenyl)-amide (147 mg, quant.) as a pale yellow foam: LR-MS for C23H18N2O2 (M−H)+ at m/z=353.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.CC(C)([O-])C.[Na+].[C:19]([C:23]1[O:27]/[C:26](=[N:28]\[C:29](=[O:41])[C:30]2[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][C:31]=2F)/[N:25]([CH2:42][C@H:43]2[CH2:47][CH2:46][CH2:45][O:44]2)[CH:24]=1)([CH3:22])([CH3:21])[CH3:20]>C1COCC1.O>[C:19]([C:23]1[O:27]/[C:26](=[N:28]\[C:29]([C:30]2[CH:35]=[C:34]([C:36]([F:38])([F:37])[F:39])[CH:33]=[CH:32][C:31]=2[O:1][CH:2]2[CH2:3][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:5]2)=[O:41])/[N:25]([CH2:42][C@H:43]2[CH2:47][CH2:46][CH2:45][O:44]2)[CH:24]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Reactant: CC(C)(C)c1cn(C[C@H]2CCCO2)/c(=N/C(=O)c2cc(C(F)(F)F)ccc2F)o1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(Oc2ccc(C(F)(F)F)cc2C(=O)/N=c2\oc(C(C)(C)C)cn2C[C@H]2CCCO2)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 94.8 %

Procedure:
To a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (167 mg, 0.965 mmol) in THF (2 mL) was added sodium tert-butoxide (93 mg, 0.965 mmol). The reaction was stirred at room temperature for 20 min. The reaction was cooled to 0° C. and a solution of Example 95A (200 mg, 0.483 mmol) in THF (1 mL) was added. The reaction was stirred at 0-5° C. for 2 hours. The reaction mixture was diluted with H2O and extracted with EtOAc (2×). The organic layer was combined and dried over MgSO4, filtered and concentrated to afford the title compound 260 mg (93%). MS (DCI/NH3) m/z 568 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([NH:16][C:17](=[O:26])[C:18]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=1[F:25])[CH2:9][CH2:10]OS(C)(=O)=O.C(N(CC)CC)C.O>O1CCOCC1>[F:24][C:23]1[CH:22]=[CH:21][CH:20]=[C:19]([F:25])[C:18]=1[C:17]1[O:26][CH2:10][CH2:9][CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Br:1])[N:16]=1
Reactant: CS(=O)(=O)OCCC(NC(=O)c1c(F)cccc1F)c1ccccc1Br
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(CC)CC
Product: Fc1cccc(F)c1C1=NC(c2ccccc2Br)CCO1
Yield: 88.4 %

Procedure:
To a solution of 18.0 g of N-[1-(2-bromophenyl)-3-(methylsulfonyloxy)propyl]-2, 6-difluorobenzamide in 150ml of dioxane at room temperature, was added dropwise 4.5 g of triethylamine. The reaction mixture was refluxed for 2.5 hours. After cooling, the reaction mixture was poured into iced water and extracted with ethyl acetate. The ethyl acetate solution was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to afford 12.5 g of 2-(2,6-difluorophenyl)-4-(2-bromophenyl)-5,6-dihydro-4H-1,3-oxazine.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[N:8]3[CH2:13][CH:12]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=4)[S:11][C:9]3=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:25]>>[CH3:1][C:2]1[C:7]2[N:8]3[CH2:13][CH:12]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=4)[S:11](=[O:25])[C:9]3=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2nc3n(c12)CC(c1ccccn1)S3
Reactant: O=C(OO)c1cccc(Cl)c1
Product: Cc1cccc2nc3n(c12)CC(c1ccccn1)S3=O
Yield: 70 %

Procedure:
In a similar manner to Example 4 2,3-dihydro-5-methyl-2-(2-pyridyl)thiazolo[3,2-a]-benzimidazole (1.07 g) was reacted with m-chloroperoxybenzoic acid to give the title compound (0.74 g, 70%) mp 148.5° C.
Reaction SMILES: C([N:8]1[CH2:13][C:12](=[O:14])[NH:11][C:10](=[O:15])[CH2:9]1)C1C=CC=CC=1.[ClH:16]>CO.O.CO.[Pd]>[ClH:16].[NH:11]1[C:12](=[O:14])[CH2:13][NH:8][CH2:9][C:10]1=[O:15]
Reactant: O=C1CN(Cc2ccccc2)CC(=O)N1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Product: O=C1CNCC(=O)N1
Reaction time: 8 h

Procedure:
To a solution of 4-benzylpiperazine-2,6-dione (which may be prepared in accordance with the experimental described in Example 4, step 1; 2.0 g, 9.8 mmol) in a mixture of methanol/H2O (65 mL/28 mL) were added a solution of HCl 1N in methanol (23.8 mL) and Pd/C (10% wet, 0.2% wt., 400 mg). The reaction mixture was degassed 3 times with hydrogen/vacuum prior to its overnight stirring under hydrogen (P=1 atm). The reaction mixture was then filtered on Clarcel® and washed with methanol. The filtrate was finally concentrated to dryness and the residue was precipitated from a mixture of methanol and ether. The title product was obtained as a beige solid (418 mg, 28%).
Reaction SMILES: [CH:1](=[O:10])[C:2]1[C:3]([O:8][CH3:9])=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH2:11](Br)[CH3:12].[Mg].O1CCCC1.[Cl-].[NH4+].O>O1CCCC1>[CH3:9][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH:1]([OH:10])[CH2:11][CH3:12]
Reactant: COc1ccccc1C=O
Reactant: CCBr
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CCC(O)c1ccccc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
o-Anisaldehyde (2.72 g) was dissolved in tetrahydrofuran (50 ml), and 0.93M magnesium ethylbromide—tetrahydrofuran solution (31.3 ml) was added dropwise under ice-cooling over 10 min. The mixture was stirred at room temperature for 2 hr. The reaction mixture was ice-cooled, and saturated aqueous ammonium chloride solution (40 ml) and water (40 ml) were added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1) to give the title compound (3.15 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]2[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[C:16]([F:24])[CH:15]=2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:30]1[N:31]=[CH:32][S:33][CH:34]=1)CCC.[Cl-]>O1CCOCC1.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>[F:24][C:16]1[CH:15]=[C:14]([C:9]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([C:30]4[N:31]=[CH:32][S:33][CH:34]=4)=[CH:3][CH:4]=3)[C:12]([CH3:13])=[CH:11][CH:10]=2)[CH:19]=[CH:18][C:17]=1[S:20]([CH3:23])(=[O:22])=[O:21]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cscn1
Reactant: Cc1ccc(-c2ccc(S(C)(=O)=O)c(F)c2)n1-c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1COCCO1
Product: Cc1ccc(-c2ccc(S(C)(=O)=O)c(F)c2)n1-c1ccc(-c2cscn2)cc1
Yield: 68.7 %

Procedure:
To a stirred solution of 1-(4-bromophenyl)-2-[3-fluoro-4-(methylsulfonyl)phenyl]-5-methyl-1H-pyrrole (0.318 g, 0.78 mmol, Example 35, step 3) in 1,4-dioxane (12 mL) was added 4-(tributylstannyl)thiazole (0.35 g, 0.94 mmol), lithiun chloride (0.083 g, 1.95 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.090 g, 0.078 mmol) at room temperature under nitrogen. The mixture was heated at reflux temperature for 3.5 hours. After cooling, volatiles were removed by evaporation. The residue was redissolved in ethyl acetate (30 mL) and the whole washed with water and brine. After dried over MgSO4 and concentration in vacuo. The crude mixture was purified by flash chromatography eluting with hexane/ethyl acetate (3/1). The resulting solid was recrystallized from ethyl acetate-hexane to give the title compound (0.221 g, 68.8% yield).
Reaction SMILES: [H][H].[CH3:3][C@@:4]12[C@H:13]3[CH2:14][C@@H:15]([OH:29])[C@:16]4([CH3:28])[C@@H:20]([C:21]5[CH2:26][O:25][C:23](=[O:24])[CH:22]=5)[CH2:19][CH2:18][C@:17]4([OH:27])[C@@H:12]3[CH2:11][CH2:10][C@@H:9]1[CH2:8][C@@H:7]([OH:30])[CH2:6][CH2:5]2.O=O>O.CC(C)=O.[Pt]=O>[CH3:3][C@@:4]12[CH:13]3[CH2:14][C@@H:15]([OH:29])[C@:16]4([CH3:28])[C@@H:20]([C:21]5[CH2:26][O:25][C:23](=[O:24])[CH:22]=5)[CH2:19][CH2:18][C@:17]4([OH:27])[CH:12]3[CH2:11][CH2:10][C@@H:9]1[CH2:8][C:7](=[O:30])[CH2:6][CH2:5]2
Reactant: [H][H]
Reactant: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2C[C@@H](O)[C@]2(C)[C@@H](C3=CC(=O)OC3)CC[C@]12O
Agent: O=[Pt]
Agent: O=O
Solvent: CC(C)=O
Solvent: O
Product: C[C@]12[C@H](O)CC3C(CC[C@@H]4CC(=O)CC[C@]34C)[C@@]1(O)CC[C@@H]2C1=CC(=O)OC1

Procedure:
Platinum oxide (Adams' catalyst) (500 mg.) was suspended in water (50 ml.) and a continuous stream of hydrogen passed for 1 hour. The hydrogen was displaced by nitrogen and digoxigenin (2.0 g.), in acetone (200 ml.) and water (50 ml.), added. A continuous stream of oxygen was passed through the mixture for 18 hours. The catalyst was removed by filtration, washed with acetone, the washings added to the filtrate and the filtrate concentrated in vacuo. The residue was dissolved in chloroform, washed with water and the solution dried (magnesium sulphate). Evaporation of the solvent in vacuo gave a gum which crystallised from acetone/ether. The 3-dehydrodigoxigenin melted at 251.2°C. and had [α] D25 + 39.1° (c = 0.48 in methanol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2F)[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([C:25]2[N:26]=[N:27][N:28]([CH2:30][CH2:31][O:32][CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][O:34]3)[CH:29]=2)[CH:22]=[CH:21][C:20]=1[CH3:39])=[O:18].ClC1C=C(NC2C=CC(F)=CC=2)C=CC=1C(C1C=C(C#C)C=CC=1C)=O.N(CCOC1CCCCO1)=[N+]=[N-]>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=2)[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([C:25]2[N:26]=[N:27][N:28]([CH2:30][CH2:31][O:32][CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][O:34]3)[CH:29]=2)[CH:22]=[CH:21][C:20]=1[CH3:39])=[O:18]
Reactant: Cc1ccc(-c2cn(CCOC3CCCCO3)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Agent: C#Cc1ccc(C)c(C(=O)c2ccc(Nc3ccc(F)cc3)cc2Cl)c1
Agent: [N-]=[N+]=NCCOC1CCCCO1
Product: Cc1ccc(-c2cn(CCOC3CCCCO3)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2)cc1Cl

Procedure:
The reaction was carried out similarly as described in the preparation of compound 101, using compound 432 (2.06 mmol) and compound 408 (2.06 mmol). The crude product was purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) 50:50 to 50:50 as the eluent to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](=[N:10]/O)/[CH3:9])=[C:4]([OH:12])[CH:3]=1.BrC1C=CC(C(=O)C)=C(O)C=1.C([O-])(=O)C.[Na+].Cl.NO>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]([CH3:9])=[N:10][O:12][C:4]=2[CH:3]=1
Reactant: C/C(=N\O)c1ccc(Br)cc1O
Agent: CC(=O)[O-]
Agent: CC(=O)c1ccc(Br)cc1O
Agent: Cl
Solvent: O
Product: Cc1noc2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.4 %

Procedure:
(E)-1-(4-Bromo-2-hydroxyphenyl)ethanone oxime. To a solution of 1-(4-bromo-2-hydroxyphenyl)ethanone (2.8 g, 13.02 mmol) and water (10 mL) was added sodium acetate (1.602 g, 19.53 mmol) and hydroxylamine hydrochloride (1.176 g, 16.93 mmol). The mixture was allowed to stir at ambient temperature for 16 h. The solution was condensed under reduced pressure and diluted with water and sonicated. The resultant solid was filtered and dried under vacuum oven conditions to afford the title compound (1.90 g, 8.26 mmol, 63.4% yield). MS (ESI) m/z 230.3 [M]+, 232.4 [M+2]+.
Reaction SMILES: C([NH:5][C:6]([NH:8][CH:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH2:10]O)=[S:7])(C)(C)C.Cl.O.C(O)C>C(OCC)C>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH:9]2[CH2:10][S:7][C:6]([NH2:5])=[N:8]2)=[CH:13][CH:14]=1
Reactant: COc1ccc(C(CO)NC(=S)NC(C)(C)C)cc1
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Solvent: O
Product: COc1ccc(C2CSC(N)=N2)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 6.6 %

Procedure:
A mixture of 1.3 g of N-(tert-butyl)-N′-[1-(4-methoxyphenyl)-2-hydroxyethyl]thiourea in 12.3 cm3 of aqueous 6N hydrochloric acid is heated with stirring at a temperature in the region of 100° C. for 1 hour. The dense oil which precipitates is separated out after settling from the supernatant hydrochloric aqueous phase. After cooling to about 20° C., this aqueous phase is extracted with 5 cm3 of ethyl acetate and the resulting aqueous phase is then evaporated under reduced pressure (5 kPa) at a temperature in the region of 50° C. An oil is obtained, which is freed of its residual water by azeotropic entrainment first with 10 cm3 of ethanol and then with 10 cm3 of diethyl ether, each repetition being followed by concentrating under the above conditions. 6 cm3 of 1N sodium hydroxide are added to the oil obtained and the mixture is then extracted with 30 cm3 of diethyl ether containing 15 cm3 of ethyl acetate. The organic phase is separated out after settling has taken place and evaporated under reduced pressure (5 kPa) at a temperature in the region of 40° C. 0.1 g of oxalic acid predissolved in 1 cm3 of acetone is added to the residue obtained. The white precipitate formed is separated out by filtration, washed once with acetone, twice with chloroform and then once with ethyl acetate, and dried under reduced pressure (10 Pa) at a temperature in the region of 40° C. 0.063 g of 4-(4-methoxyphenyl)-4,5-dihydro-1,3-thiazol-2-ylamine is obtained in the form of a white solid melting at 180° C. [1H NMR spectrum (300 MHz, d6-(CD3)SO, δ in ppm): 3.40 (dd, J=14 and 8.5 Hz 1H); 3.80 (s: 3H); 3.93 (dd, J=14 and 8.5 Hz: 1H); 4.22 (unres. mult.: 2H); 3.58 (t, J=8.5 Hz : 1H); 7.00 (d, J=8.5 Hz: 2H); 7.34 (d, J=8.5 Hz : 2H)].