Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1F)[CH:17]=[O:18]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:21]2[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][C:14]=2[F:13])=[CH:4][C:3]=1[C:9]([F:10])([F:11])[F:12]
Reactant: Oc1ccc(Cl)c(C(F)(F)F)c1
Reactant: O=Cc1ccc(F)c(F)c1
Product: O=Cc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)c(F)c1
Temperature: 80 °C
Yield: 80.2 %

Procedure:
The mixture of 4-chloro-3-(trifluoromethyl)phenol (7.61 g, 38.7 mmol), 3,4-difluorobenzaldehyde (5.0 g, 35.2 mmol) and CS2CO3 (11.46 g, 35.2 mmol) was heated with a microwave reactor at 80° C. for 1 h. Purification via a flash column chromatography then afforded the title compound (9.0 g, 80% yield). LCMS: rt=3.80 min, [M+H+]=319
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[CH:11][CH:12]=[C:13]([F:14])[C:7]=2[CH:6]=1)=O.[NH:15]1[CH2:19][CH2:18][NH:17][C:16]1=[S:20].C(O)(=O)C>C(O)C>[ClH:1].[F:14][C:13]1[C:7]2[CH:6]=[C:5]([C:3]3[N:17]4[CH2:18][CH2:19][N:15]=[C:16]4[S:20][CH:2]=3)[S:9][C:8]=2[CH:10]=[CH:11][CH:12]=1
Reactant: O=C(CCl)c1cc2c(F)cccc2s1
Reactant: S=C1NCCN1
Solvent: CCO
Solvent: CC(=O)O
Product: Cl
Product: Fc1cccc2sc(C3=CSC4=NCCN34)cc12
Temperature: 25 °C

Procedure:
A mixture of 2-chloro-1-(4-fluorobenzo[b]thiophen-2-yl]ethan-1-one (0.16 g; prepared in a manner similar to that described above), 2-imidazolidinethione (0.071 g), acetic acid (10 ml) and ethanol (5 ml) was heated under reflux for 2 hours then cooled to ambient temperature. The solvents were removed in vacuo and the residue was triturated with ether (10 ml). The resulting solid was collected by filtration and dried in vacuo at 60° C. for 2 hours to give 3-(4-fluorobenzo[b]thiophen-2-yl)-5,6-dihydroimidazo[2,1-b]thiazole hydrochloride (0.19 g) as pale pink solid, m.p. 220-224° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([C@H:13]([CH:17]([CH3:19])[CH3:18])[C:14]([NH2:16])=[O:15])[C:7]2=[O:12].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C@@H:27]([CH3:31])[C:28](O)=[O:29])=[CH:23][CH:22]=1.C(N(CC)C(C)C)(C)C.CN(C)C=O>C(Cl)Cl>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([C@@H:27]([CH3:31])[C:28]([NH:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][N:6]([C@H:13]([CH:17]([CH3:19])[CH3:18])[C:14]([NH2:16])=[O:15])[C:7]3=[O:12])=[O:29])=[CH:25][CH:26]=1
Reactant: C[C@@H](C(=O)O)c1ccc(Cl)cc1
Reactant: CC(C)[C@H](C(N)=O)n1ccc2c(N)cccc2c1=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)[C@H](C(N)=O)n1ccc2c(NC(=O)[C@H](C)c3ccc(Cl)cc3)cccc2c1=O

Procedure:
(R)-2-(5-Amino-1-oxoisoquinolin-2(1H)-yl)-3-methylbutanamide (0.2 g, 0.0007 mol), (R)-2-(4-chlorophenyl)propanoic acid (0.16 g, 0.00088 mol) N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.33 g, 0.00088 mol), N,N-diisopropylethylamine (0.4 g, 0.003 mol) were stirred in N,N-dimethylformamide (3 mL, 0.04 mol) at room temperature over a weekend. The reaction mixture was diluted with CH2Cl2 (100 mL), washed with NaHCO3 (20 mL×3), dried over Na2SO4, purified via flash chromatography (12 g of silica gel, 0-90% EtOAc/Hexane) and then prep. HPLC gave a white solid. 1H NMR δ (CDCl3) δ: 8.24 (d, J=8.1 Hz, 1H), 7.99 (t, J=7.2 Hz, 1H), 7.53-7.33 (m, 6H), 7.07 (br, 1H), 6.26 (br, 1H), 6.06-6.03 (m, 1H), 5.31 (br, 1H), 5.14 (d, J=11.4 Hz, 1H), 3.82 (q, J=7.2 Hz, 1H), 2.55-2.48 (m, 1H), 1.62 (d, J=11.1 Hz, 3H), 1.13 (d, J=6.4 Hz, 3H), 0.76 (dd, J=2.1, 6.6 Hz, 3H). MS m/z 426.2 (M+H)+.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([Cl:22])[CH:16]=2)[CH2:9]1)(OC(C)(C)C)=O.C(=O)([O-])[O-].[K+].[K+].[CH2:29](Br)[C:30]#[CH:31].C1(S)C=CC=CC=1.C(=O)([O-])[O-].C(N(C(C)C)CC)(C)C>CC(C)=O>[Cl:22][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[O:21][CH2:31][C:30]#[CH:29])[CH2:14][C@H:10]1[O:11][CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: C#CCBr
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cc2ccc(O)c(Cl)c2)C1
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)=O
Product: C#CCOc1ccc(C[C@@H]2CNCCO2)cc1Cl
Temperature: 55 °C
Reaction time: 16 h

Procedure:
N-BOC-(R)-2-(3-chloro-4-hydroxybenzyl)morpholine, example 7, intermediate (a) (52 mg, 0.16 mmol), was dissolved in acetone (1.5 mL) with potassium carbonate (44 mg, 0.32 mmol) and propargyl bromide (53 uL, 0.47 mmol) added in one portion. The reaction was then heated to 55° C. and shaken at that temperature for 16 hrs. The reaction mixture was filtered, washing with acetone (1 mL×2) and the liquor evaporated under a high flow of nitrogen. The residue was dissolved in tetrahydrofuran: ethanol (1:1, 4 mL) and polymer supported thiophenol (0.43 g, 0.64 mmol), MP-carbonate (0.24 g, 0.64 mmol) and diisopropylethylamine (119 uL, 0.68 mmol) added. The reaction was shaken for 24 hrs, then filtered and concentrated under a high flow of nitrogen. The crude residue was dissolved in TFA (20% v/v solution in dichloromethane, 2.0 mL) and shaken for 3 hrs at room temperature. The reaction mixture was added directly to an SCX-2 column (2 g) and washed with dichloromethane (2 mL×2) and methanol (2 mL×2). The SCX-2 column was then washed with ammonia (2N in methanol, 3×2 mL). Combined ammonia washes were concentrated in vacuo to yield the desired morpholine example 39 as a colorless oil (20 mg).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8]C=1.[C:12]12([C:28](Cl)=[O:29])[CH2:21][C:16]3([C:22](Cl)=[O:23])[CH2:17][CH:18]([CH2:20][C:14]([C:25](Cl)=[O:26])([CH2:15]3)[CH2:13]1)[CH2:19]2>C(Cl)Cl>[N:1]1([C:28]([C:12]23[CH2:21][C:16]4([C:22]([N:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)=[O:23])[CH2:17][CH:18]([CH2:20][C:14]([C:25]([N:6]5[CH2:8][CH2:9][CH2:10][CH2:11]5)=[O:26])([CH2:15]4)[CH2:13]2)[CH2:19]3)=[O:29])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)C12CC3CC(C(=O)Cl)(C1)CC(C(=O)Cl)(C3)C2
Reactant: c1ccncc1
Reactant: C1CCNC1
Solvent: ClCCl
Product: O=C(N1CCCC1)C12CC3CC(C(=O)N4CCCC4)(C1)CC(C(=O)N1CCCC1)(C3)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
In a 500-ml flask equipped with a stirrer, a thermometer and a dropping funnel were placed 34.5 g (485 mmol) of pyrrolidine, 38.4 g (485 mmol) of pyridine and 140 ml of methylene chloride. To the stirred mixture under ice-cooling in a nitrogen atmosphere, 31.4 g (97 mmol) of 1,3,5-adamantanetricarbonyl trichloride in 190 ml of methylene chloride was added dropwise over 1 hour. This was warmed to room temperature, was stirred for further 1 hour and was washed with water, 1 N hydrochloric acid, and 10% aqueous sodium carbonate solution, and the solvent was removed under reduced pressure, to yield 37.2 g (87 mmol) of 1,3,5-tris(1-pyrrolidinylcarbonyl)adamantane in a yield of 90%.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[CH:7]=[CH:6][C:5]=2[N:4]=[C:3]1[CH3:15].[OH:17][S:18](O)(=[O:20])=[O:19]>[OH-].[Na+]>[S:18]([C:13]1[CH:12]=[CH:11][C:9]2[C:10]3[C:2]([CH3:16])([CH3:1])[C:3]([CH3:15])=[N:4][C:5]=3[CH:6]=[CH:7][C:8]=2[CH:14]=1)([OH:20])(=[O:19])=[O:17]
Reactant: CC1=Nc2ccc3ccccc3c2C1(C)C
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CC1=Nc2ccc3cc(S(=O)(=O)O)ccc3c2C1(C)C
Temperature: 180 °C

Procedure:
1,1,2-Trimethyl-1H-benz[e]indole, 100 g. was added with stirring to 500 mL of concentrated H2SO4. The mixture was heated at 180° C. for 1/2 h, cooled to 60° C. and poured onto 2 Kg ice. Cautiously 500 ml of 50% aqueous NaOH was added. After 24 hours at room temperature the solid was filtered off, and 500 mL of saturated aqueous Na2SO4 was added. The resulting solid precipitate was collected, added to the previously filtered solid, and recrystallized from 2 L of H2O. Yield 25 g after overnight vacuum drying at 50° C. The location of the sulfo group was determined as being the 7-position by proton nuclear magnetic resonance measurements.
Reaction SMILES: [CH2:1]([N+:8]1[C:16]2[C:11](=[CH:12][C:13]([S:17]([O-:20])(=[O:19])=[O:18])=[CH:14][CH:15]=2)[C:10]([CH3:29])([CH2:21][CH2:22][CH2:23][CH2:24][S:25]([OH:28])(=[O:27])=[O:26])[C:9]=1[CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][N+:39]1[C:47]2[C:42](=[CH:43][C:44]([S:48]([O-:51])(=[O:50])=[O:49])=[CH:45][CH:46]=2)[C:41]([CH3:60])([CH2:52][CH2:53][CH2:54][CH2:55][S:56]([OH:59])(=[O:58])=[O:57])[C:40]=1[CH3:61])([OH:33])=[O:32].C(O)(=O)C.N1C=C[CH:69]=[CH:68][CH:67]=1.C(OC(=O)C)(=O)C>O>[CH2:1]([N+:8]1[C:16]2[C:11](=[CH:12][C:13]([S:17]([O-:20])(=[O:18])=[O:19])=[CH:14][CH:15]=2)[C:10]([CH3:29])([CH2:21][CH2:22][CH2:23][CH2:24][S:25]([OH:28])(=[O:27])=[O:26])[C:9]=1/[CH:30]=[CH:69]/[CH:68]=[CH:67]/[CH:61]=[C:40]1/[N:39]([CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][C:31]([OH:33])=[O:32])[C:47]2[C:42]([C:41]/1([CH3:60])[CH2:52][CH2:53][CH2:54][CH2:55][S:56]([OH:59])(=[O:57])=[O:58])=[CH:43][C:44]([S:48]([OH:51])(=[O:50])=[O:49])=[CH:45][CH:46]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccncc1
Reactant: CC1=[N+](Cc2ccccc2)c2ccc(S(=O)(=O)[O-])cc2C1(C)CCCCS(=O)(=O)O
Reactant: CC1=[N+](CCCCCC(=O)O)c2ccc(S(=O)(=O)[O-])cc2C1(C)CCCCS(=O)(=O)O
Solvent: CC(=O)O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC1(CCCCS(=O)(=O)O)C(/C=C/C=C/C=C2/N(CCCCCC(=O)O)c3ccc(S(=O)(=O)O)cc3C2(C)CCCCS(=O)(=O)O)=[N+](Cc2ccccc2)c2ccc(S(=O)(=O)[O-])cc21
Temperature: 90 °C
Reaction time: 8 h

Procedure:
1-Benzyl-2,3-dimethyl-3-(4-sulphobutyl)-3H-indolium-5-sulphonate salt (2 g), 1-(5-carboxypentyl)-2,3-dimethyl-3-(4-sulphobutyl)-3H-indolium-5-sulphonate (2 g) and malonaldehyde bis-phenylimine (2 g) were dissolved in acetic acid: pyridine: acetic anhydride (4.5:4.5:1) (100 ml). The mixture was heated at 90° C. for 2 hours. The mixture went blue/green immediately. A small sample was diluted in water for UV measurement. UV/Vis absorption spectroscopy observed a peak at 650 nm showing formation of Cy5. The reaction mixture was stored overnight at +2° C. The mixture was rotary evaporated to yield an oil. This was pumped under vacuum for several hours to ensure dryness. The sticky solid was washed with acetonitrile (4×500 ml) to yield a dry powder that was filtered and washed with more acetonitrile. The solid was dried under vacuum. Yield: 3.05 g.
Reaction SMILES: C1(C[O:8][C:9]2[CH:17]=[CH:16][C:15]3[N:14]([CH3:18])[C:13]4[CH2:19][CH:20]([CH2:22][OH:23])[CH2:21][C:12]=4[C:11]=3[CH:10]=2)C=CC=CC=1.[H][H]>C(O)C.[Pd]>[OH:23][CH2:22][CH:20]1[CH2:19][C:13]2[N:14]([CH3:18])[C:15]3[CH:16]=[CH:17][C:9]([OH:8])=[CH:10][C:11]=3[C:12]=2[CH2:21]1
Reactant: [H][H]
Reactant: Cn1c2c(c3cc(OCc4ccccc4)ccc31)CC(CO)C2
Agent: [Pd]
Solvent: CCO
Product: Cn1c2c(c3cc(O)ccc31)CC(CO)C2
Yield: 68.2 %

Procedure:
To a suspension of 10% Pd/C (1.2 g) in 50 ml of ethanol was added a solution of 1,2,3,4-tetrahydro-7-phenylmethoxy-4-methylcyclopent[b]indole-2-methanol (8.4 g, 0.027 mole) in 200 ml of ethanol in a Parr hydrogenation bottle. After shaking at 50° C., under 50 psi hydrogen for two hours, the mixture was cooled, filtered, and then concentrated to a dark oil. The oil was eluted on a silica gel column with ethyl acetate/dichloromethane (1:2) via HPLC. The desired fractions were combined and then concentrated to a light yellow solid. The material was triturated with ether and dried to give 4.0 g (66%) of the product as an off-white solid, m.p. 153°-4° C.
Reaction SMILES: C(OC([N:6]1[CH2:15][CH2:14][C:13]2[C:12]3[NH:16][CH:17]=[CH:18][C:11]=3[S:10][C:9]=2[CH2:8][CH2:7]1)=O)C.[OH-].[K+]>CCO.O>[CH:18]1[C:11]2[S:10][C:9]3[CH2:8][CH2:7][NH:6][CH2:15][CH2:14][C:13]=3[C:12]=2[NH:16][CH:17]=1
Reactant: CCOC(=O)N1CCc2sc3cc[nH]c3c2CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: c1cc2sc3c(c2[nH]1)CCNCC3
Temperature: 100 °C

Procedure:
To a stirred solution of the product from step (g) (0.049 g, 0.19 mmol) in EtOH (2 ml) was added 40% aqueous KOH (2 ml). The reaction mixture was heated to 100° C. until LCMS indicated no starting material present (usually 16-32 hours). The reaction mixture was cooled to RT, diluted with water (30 ml) and extracted with DCM (3×). The combined DCM extracts were dried (MgSO4), filtered, and solvent evaporated in vacuo to give the crude product. Purification by preparative LCMS gave the title compound as a tan solid. 1H NMR (CDCl3) δ 8.05 (bs, 1H), 6.95-6.90 (m, 1 H), 6.41-6.36 (m, 1H), 3.10-3.02 (m, 4H), 3.00-2.94 (m, 2 H), 2.92-2.82 (m, 2 H); MS: ESI (positive): 193 (M+H).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2([CH3:12])[CH3:11])=[CH:4][C:3]=1[O:13][CH3:14].C([Li])CCC.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:30])(=O)=O)=CC=1.O>C1COCC1>[F:30][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2([CH3:12])[CH3:11])=[CH:4][C:3]=1[O:13][CH3:14]
Reactant: COc1cc2c(cc1Br)C(C)(C)CC2
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2c(cc1F)C(C)(C)CC2
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 66.7 %

Procedure:
To a solution of 6-bromo-5-methoxy-1,1-dimethyl-indan (2.77 g, 10.8 mmol) (see Example 5) in THF (40 mL) at −78° C. was slowly added n-butyllithium (5.56 ml, 2.5M). The resulting solution was stirred at −78° C. for 0.5 h and a solution of N-fluorobenzenesulfonimide (4.11 g, 13.0 mmol) in THF (40 mL) was added. After an additional 2 h at −78° C., the reaction was warmed to room temperature, poured into water (50 mL), and extracted with ethyl acetate (2×80 mL). The combined organic layers were washed with water (100 mL), dried over sodium sulfate, filtered, and concentrated. Silica gel chromatography (2% ethyl acetate/heptanes) afforded 1.40 g of the title compound as yellow oil.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(N=C=NC2CCCCC2)CCCCC1.ClCCl.[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:31](O)=[O:32]>CN(C)C1C=CN=CC=1.C(OCC)C>[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:31]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:32]
Reactant: Oc1ccccc1
Reactant: O=C(O)c1cccs1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(Oc1ccccc1)c1cccs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Phenol (5.0 g, 39.0 mmol), a 1M solution of 1,3-dicyclohexylcarbodiimide in dichloromethane (39.0 mL, 39.0 mmol) and 4-dimethylaminopyridine (0.5 g, 3.9 mmol) were added to a solution of thiophene-2-carboxylic acid (5.0 g, 39.0 mmol) in diethyl ether (400 mL) at about 0° C. The reaction mixture was stirred overnight while being allowed to warm to room temperature. The precipitate was collected by filtration and was washed with diethyl ether. The combined filtrates were washed successively with water, 5% aqueous acetic acid, water and brine, dried (MgSO4), filtered and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel using hexane/ethyl acetate (5:1) as the mobile phase to provide phenyl thiophene-2-carboxylate. MS (DCI-NH3): m/z 222 (M+NH4)+.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:9]1[N:10]=[N:11][C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=3)[CH2:17][CH2:16]2)=[CH:13][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:27][C:23]1[CH:22]=[C:21]([N:18]2[CH2:17][CH2:16][N:15]([C:12]3[N:11]=[N:10][C:9]([O:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[CH:14][CH:13]=3)[CH2:20][CH2:19]2)[CH:26]=[CH:25][CH:24]=1
Reactant: Cc1cccc(N2CCN(c3ccc(Cl)nn3)CC2)c1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1cccc(N2CCN(c3ccc(Oc4ccccc4)nn3)CC2)c1
Temperature: 150 °C
Yield: 60 %

Procedure:
A mixture of 1.9 parts of phenol. 2.9 parts of 3-chloro-6-[4-(3-methylphenyl)-1-piperazinyl]pyridazine and 2.76 parts of potassium carbonate was stirred and heated for 7 hours in an oil bath at 150° C. After cooling, water was added. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was crystallized from a mixture of 2-propanol and 2,2'-oxybispropane. The product was filtered off and dried, yielding 2 parts (60%) of 3-[4-(3-methylphenyl)-1-piperazinyl]-6-phenoxypyridazine; mp. 123.4° C. (compound 264).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:8][C:9]1[C:14]([S:15](Cl)(=[O:17])=[O:16])=[CH:13][C:12]([N+:19]([O-:21])=[O:20])=[CH:11][CH:10]=1>O>[C:1]1([O:7][S:15]([C:14]2[C:9]([Cl:8])=[CH:10][CH:11]=[C:12]([N+:19]([O-:21])=[O:20])[CH:13]=2)(=[O:16])=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1
Reactant: Oc1ccccc1
Solvent: O
Product: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Oc2ccccc2)c1
Reaction time: 3.5 h

Procedure:
To 37.6 parts of phenol stirring in 780 parts water at pH 9.0 and at 5°-10° C. was added 100 parts 6-chloro-3-nitrobenzenesulphonyl chloride. A few drops of Calsolene oil wetting agent were added and the mixture was stirred at pH 9.5°-10° and 5°-10° C. for 3.5 hours, cooled and filtered. The solid was washed with cold water, and dried to give 116 parts of the desired product.
Reaction SMILES: C[O:2][C:3](=O)[C:4]([CH3:17])([CH3:16])[NH:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[N+:13]([O-])=O.[H][H].C1(C)C=CC(S(O)(=O)=O)=CC=1>[Pd].CO>[F:12][C:10]1[CH:11]=[C:6]2[C:7](=[CH:8][CH:9]=1)[NH:13][C:3](=[O:2])[C:4]([CH3:17])([CH3:16])[NH:5]2
Reactant: COC(=O)C(C)(C)Nc1cc(F)ccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: CC1(C)Nc2cc(F)ccc2NC1=O

Procedure:
A mixture of N-(5-fluoro-2-nitrophenyl)-2-methylalanine methyl ester (XI, EXAMPLE 7, 11.2 g), palladium on carbon (10%, 0.63 g), and methanol (350 ml) is shaken under 44 psi of hydrogen pressure for 1.5 hr. Additional palladium on carbon (10%, 0.23 g) is added and the mixture is shaken at 36 psi for another 45 min. p-Toluenesulfonic acid (0.46 g) is added and the catalyst is filtered off. The filtrate is concentrated to about 150 ml and warmed at 80° for 75 min. The solvent is then removed under reduced pressure and the residue is chromatographed on silica gel (700 ml) eluting with dichloromethane/methanol (98/2). aaa a solid. The product is crystallized from methanol/dichloromethane/hexane to give the title compound, mp 148.5°-149.0°; NMR (CDCl3) 1.42, 3.80, 6.40, 6.46, 6.66 and 8.35 δ.
Reaction SMILES: I[C:2]1[N:6]2[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C(OCC)(=O)C.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>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[N:6]3[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=[CH:10][C:5]3=[N:4][CH:3]=2)=[CH:19][CH:18]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: COC(=O)c1ccc2ncc(I)n2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COC(=O)c1ccc2ncc(-c3ccc(OC)cc3)n2c1
Yield: 55.9 %

Procedure:
A mixture of methyl 3-iodoimidazo[1,2-a]pyridine-6-carboxylate (1.40 g, 4.63 mmol), (4-methoxyphenyl)boronic acid (845 mg, 5.56 mmol), tetrakis(triphenylphosphine)palladium(0) (268 mg, 0.232 mmol), 2 M aqueous sodium carbonate solution (4.63 mL) and 1,2-dimethoxyethane (50 mL) was heated under reflux under an argon atmosphere overnight. After cooling, the reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1-0/1) to give the title compound (730 mg, yield 56%) as colorless crystals.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]3[NH:22][C:21](=[O:23])[O:20][C:19]([CH3:25])([CH3:24])[C:18]=3[CH:26]=2)=[CH:4][CH:3]=1.[OH:27]O>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]3[NH:22][C:21](=[O:23])[O:20][C:19]([CH3:24])([CH3:25])[C:18]=3[CH:26]=2)=[O:27])=[CH:6][CH:7]=1
Reactant: OO
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCSc3ccc(O)cc3)cc21
Product: CC1(C)OC(=O)Nc2ccc(OCCCCS(=O)c3ccc(O)cc3)cc21

Procedure:
Prepared analogously to Example 2 from 6-[4-(4-hydroxy-phenylmercapto)-butoxy]-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]([O:20][CH3:21])=[O:19])=[CH:12]2.CI>O1CCCC1>[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:1])[C:13]([C:18]([O:20][CH3:21])=[O:19])=[CH:12]2
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)c1cc2cc(OC)ccc2[nH]1
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)c1cc2cc(OC)ccc2n1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
100 ml of a 1N solution of potassium tert-butoxide in tetrahydrofuran is added dropwise to a solution, cooled to -20° C., of 0,1 mol of methyl 5-methoxy-1H-indolecarboxylate in tetrahydrofuran. The medium is stirred for 30 minutes at this temperature, followed by dropwise addition of a solution of 0.1 mol of methyl iodide in tetrahydrofuran. Once the addition is complete, the medium is warmed slowly to room temperature, stirred for 1 h at this temperature and filtered. The expected product is obtained after concentration of the solvent.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:24](O)=[O:25])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8].O[N:28]=[C:29]([NH2:31])[CH3:30]>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:10][CH:11]([C:24]3[O:25][N:31]=[C:29]([CH3:30])[N:28]=3)[CH2:12][N:13]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]3)=[O:16])[CH2:14]2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CC(N)=NO
Reactant: Cc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCC(O)CC3)C2)cc1C
Product: Cc1noc(C2CC(c3ccc(C)c(C)c3)CN(C(=O)N3CCC(O)CC3)C2)n1

Procedure:
200 mg (0.54 mmol) of the compound from Example 128A and 62 mg (0.81 mmol) of N′-hydroxyacetamidine were reacted according to the General Method 2. Yield: 154 mg (69% of theory)
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[C:3]([SH:6])([CH3:5])[CH3:4].[OH-].[Na+].C(O)(C)(C)C.[C:17]([O:21][C:22](=O)[O:23]C(C)(C)C)([CH3:20])([CH3:19])[CH3:18]>O>[C:22]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[C:3]([SH:6])([CH3:5])[CH3:4])([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:23]
Reactant: CC(C)(S)[C@H](N)C(=O)O
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(C)(C)S
Reaction time: 6 h
Yield: 95.5 %

Procedure:
5.0 G of L-penicillamine (33.6 mmol) was dissolved in 5 ml of water containing 1.3 g of sodium hydroxide (33.6 mmol, 1 eq.). To this was added 10 ml of tert.-butanol. 8.0 G of di-tert.-butylcarbonate (37 mmol, 1.1 eq.) was added dropwise over 30 minutes. The reaction was allowed to proceed at room temperature for 6 hours. The turbid reaction mixture was diluted with 50 ml of water and extracted with hexane (3×50 ml), acidified to pH 3 with solid sodium bisulfate and extracted with ethyl acetate (3×50 ml). The combined ethyl acetate extracts were dried over sodium sulfate and, then, evaporated to dryness, yielding 8.0 g of Boc-L-penicillamine (96%): nmr (CDCl3) 1.45 ppm and 1.57 ppm, over-lapping singlets, t-butyl and beta-dimethyl protons, 4.32 ppm, br. doublet, alpha proton.