Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[CH:4]=[O:5].Br[CH2:13][CH2:14][CH2:15][CH:16]([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(O)C>[CH:4]([C:3]1[C:6]([O:10][CH3:11])=[CH:7][CH:8]=[CH:9][C:2]=1[O:1][CH2:13][CH2:14][CH2:15][CH:16]([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:5]
Reactant: COc1cccc(O)c1C=O
Reactant: CCOC(=O)C(C)CCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)C(C)CCCOc1cccc(OC)c1C=O
Reaction time: 16 h

Procedure:
2-Hydroxy-6-methoxybenzaldehyde (3.74 g, 0.025 M), ethyl 5-bromo-2-methylpentanoate (5.58 g, 0.025 M), anhydrous potassium carbonate (3.72 g), sodium iodide (0.11 g) and ethanol (50 ml) were refluxed with stirring for 16 hr. The cooled reaction mixture was filtered and the solid washed well with ethanol. The filtrate was evaporated to dryness and the residue partitioned between ether and water. The organic layer was separated and washed with 2 N sodium hydroxide solution, water, dried (sodium sulphate) and evaporated to give (±)-ethyl 5-(2-formyl-3-methoxyphenoxy)-2-methylpentanoate, 5.3 g, 72%, as an oil.
Reaction SMILES: C(=O)(OCC)[O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([F:22])[CH:20]=3)[N:15]3[C:23]([C:26]#[N:27])=[CH:24][CH:25]=[C:14]3[CH:13]2[CH2:28][CH3:29])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[OH-:34].[Na+]>C(O)C>[CH2:28]([CH:13]1[N:12]([S:9]([C:6]2[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=2)(=[O:11])=[O:10])[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([F:22])[CH:20]=2)[N:15]2[C:23]([C:26]([NH2:27])=[O:34])=[CH:24][CH:25]=[C:14]12)[CH3:29]
Reactant: CCOC(=O)Oc1ccc(S(=O)(=O)N2c3cc(F)ccc3-n3c(C#N)ccc3C2CC)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: CCC1c2ccc(C(N)=O)n2-c2ccc(F)cc2N1S(=O)(=O)c1ccc(O)cc1
Yield: 14 %

Procedure:
0.25 g (0.53 mmol) of the product from Example 34 was dissolved in 15 ml of ethanol and 5 ml of 2N NaOH was added. The solution was heated to reflux for 3 hours, after which time it was concentrated then neutralized with 2N HCl. The mixture was extracted with ethyl acetate (2×20 ml) and the combined organic layers were dried (MgSO4) and concentrated. The crude solid was subjected to column chromatography on silica gel eluting with chloroform:methanol (95:5). The fractions containing product were combined and concentrated to yield a light tan solid, which was crystallized from ethyl acetate:hexane to yield 32 mg (14%) of product, mp 168-170° C. (d).
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H-].[Na+].Br[C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][N:12]=1>CN(C=O)C>[Br:17][C:14]1[CH:15]=[CH:16][C:11]([O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[N:12][CH:13]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CCCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCOc1ccc(Br)cn1
Temperature: 80 °C
Reaction time: 1 h
Yield: 100.7 %

Procedure:
A solution of 300 mmol of 1-hexanol in 100 ml of DMF is added dropwise at 50° C. under a protective gas to a suspension of 300 mmol of sodium hydride (80 percent in mineral oil) in 100 ml of dry DMF. The mixture is stirred at 80° C. for 1 hour, and a solution of 200 mmol of 2,5-dibromopyridine in 150 ml of warm DMF is subsequently slowly added dropwise. The mixture is then stirred at 80° C. for 3-4 hours. For hydrolysis, the cooled reaction mixture is introduced into 1 l of ice/water, the mixture is extracted a number of times with dichloromethane, and the combined organic extracts are washed with sat. sodium chloride solution and dried using sodium sulfate. After the solvent has been removed in vacuo, the residue is chromatographed on silica gel 60 using dichloromethane as eluent, giving 52 g (quant. yield) of a viscous liquid.
Reaction SMILES: [H-].[Na+:2].[CH:3]1[C:16]2[NH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[S:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH2:17]1[CH2:23][S:20](=[O:22])(=[O:21])[O:19][CH2:18]1>O1CCCC1>[CH:13]1[C:14]2[N:15]([CH2:18][CH2:17][CH2:23][S:20]([O-:22])(=[O:21])=[O:19])[C:16]3[C:7](=[CH:6][CH:5]=[CH:4][CH:3]=3)[S:8][C:9]=2[CH:10]=[CH:11][CH:12]=1.[Na+:2]
Reactant: c1ccc2c(c1)Nc1ccccc1S2
Reactant: O=S1(=O)CCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)([O-])CCCN1c2ccccc2Sc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A portion of sodium hydride (17.7 g, 0.44 moles) dispersed in mineral oil is first washed with petroleum ether (b.p. 40-60° C.) and then suspended in 200 mL dry tetrahydrofuran, in a 2 L three-neck flask. A solution of phenothiazine (80.0 g, 0.4 moles) dissolved in tetrahydrofuran (400 mL) is added under argon through a cannula. The mixture is shaken, always under argon, for one hour at room temperature and then for 30 minutes at 50° C. The mixture acquires an orange colour, following the formation of the phenothiazine anion. After the suspension has cooled to 0° C., a solution of 1,3-propanesultone (35 mL, 0.4 moles) in tetrahydrofuran is added also through a cannula. The colour of the mixture changes almost immediately to clear yellow. The mixture is stirred at 0° C. for thirty minutes after the addition of the sultone and then at room temperature for another thirty minutes.
Reaction SMILES: [NH2:1][C@@H:2]1[C:21](=[O:22])[N:4]2[C:5]([P:17]([O-:20])(=[O:19])[O-:18])=[C:6]([CH2:9][S:10][C:11]3[N:15]([CH3:16])[N:14]=[N:13][N:12]=3)[CH2:7][S:8][C@H:3]12.C([O-])(O)=O.[Na+:27].[O:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[CH2:33][C:34](Cl)=[O:35].Cl>CC(C)=O.CCOC(C)=O.O>[O:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[CH2:33][C:34]([NH:1][C@@H:2]1[C:21](=[O:22])[N:4]2[C:5]([P:17]([O-:18])(=[O:20])[O-:19])=[C:6]([CH2:9][S:10][C:11]3[N:15]([CH3:16])[N:14]=[N:13][N:12]=3)[CH2:7][S:8][C@H:3]12)=[O:35].[Na+:27].[Na+:27]
Reactant: Cn1nnnc1SCC1=C(P(=O)([O-])[O-])N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: O=C(Cl)Cc1ccco1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: Cn1nnnc1SCC1=C(P(=O)([O-])[O-])N2C(=O)[C@@H](NC(=O)Cc3ccco3)[C@H]2SC1
Reaction time: 1 h

Procedure:
To a solution of 10 mmoles 7β-amino-3-(N-methyltetrazolylthiomethyl)-3-cephem-4-phosphonate in 100 ml. water and 100 ml. acetone containing 5 g. NaHCO3 is added 20 mmoles 2-furylacetyl chloride in 40 ml acetone at 0° C. After 1 hr. stirring at 0° and 2 hrs at 25° the acetone is pumped off in vacuo and the aqueous solution added to 100 ml. water and 200 ml. EtOAc. The pH is adjusted to 2 with HCl and the ethyl acetate layer separated, and evaporated. The residue is taken up in 50 ml water containing 1.6 g. NaHCO3 and lyophilized, providing the title compound.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[C:6]([NH:10][CH2:11][O:12][S:13]([CH2:16][CH2:17][CH3:18])(=[O:15])=[O:14])(=[O:9])[CH:7]=[CH2:8].[Na:19].S(OOS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].[OH-].[Na+:33]>O>[C:1]([O-:5])(=[O:4])[CH:2]=[CH2:3].[Na+:33].[C:6]([NH:10][CH2:11][O:12][S:13]([CH2:16][CH2:17][CH3:18])(=[O:15])=[O:14])(=[O:9])[CH:7]=[CH2:8].[Na:19]
Reactant: C=CC(=O)O
Agent: C=CC(=O)NCOS(=O)(=O)CCC
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Solvent: O
Product: C=CC(=O)[O-]

Procedure:
36.1 g of acrylic acid was dissolved in 16.0 g of water and neutralized with 53.0 g of a 30 wt. % aqueous sodium hydroxide solution under cooling. Thereafter, 101.3 g of a 40 wt. % aqueous sodium acrylamidomethylpropanesulfonate solution was added thereto, and 10.7 g of a 2.8 wt. % aqueous potassium persulfate solution was added thereto to prepare a homogeneous solution as the aqueous monomer/initiator solution. Thereafter, the same procedure as that of Example 4 was repeated, thereby providing 93.5 g of sodium acrylate/sodium acrylamidomethylpropanesulfonate copolymer. The resultant polymer was in the form of distorted granular particles having an average diameter of 550 μm and a bulk density of 0.45 g/ml.
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[S:13][C:12]([C@H:14]([OH:18])[CH2:15][C:16]#[N:17])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CCOCC>[NH2:17][CH2:16][CH2:15][C@H:14]([C:12]1[S:13][C:9]([O:8][CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:10][CH:11]=1)[OH:18]
Reactant: N#CC[C@@H](O)c1ccc(OCC2CCCCC2)s1
Solvent: CCOCC
Product: NCC[C@@H](O)c1ccc(OCC2CCCCC2)s1

Procedure:
Reduction of (R)-3-(5-(cyclohexylmethoxy)thiophen-2-yl)-3-hydroxypropanenitrile following the method used in Example 1, with the exception that Et2O was used as the solvent, gave after purification by flash chromatography (4%-20% 7N NH3/MeOH—CH2Cl2 gradient) Example 5 as a colorless oil. Yield (0.0185 g, 9%); 1H NMR (400 MHz, CD3OD) δ 6.54-6.59 (m, 1H), 6.00-6.40 (m, 1H), 4.77 (t, J=7.2 Hz, 1H), 3.80 (d, J=5.9 Hz, 2H), 2.86-2.77 (m, 2H), 1.65-1.96 (m, 8H), 1.18-1.36 (m, 3H), 1.00-1.12 (m, 2H); RP-HPLC tR=10.01 min; ESI-MS m/z 252.2 [M−H2O+H]+.
Reaction SMILES: C1O[C:4]2([CH2:9][CH2:8][CH:7]([CH:10]3[CH2:15][CH2:14][C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=4[F:23])=[CH:12][CH2:11]3)[CH2:6][CH2:5]2)[O:3]C1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O1CCOCC1>O>[F:23][C:17]1[C:18]([F:22])=[CH:19][CH:20]=[CH:21][C:16]=1[C:13]1[CH2:14][CH2:15][CH:10]([CH:7]2[CH2:6][CH2:5][C:4](=[O:3])[CH2:9][CH2:8]2)[CH2:11][CH:12]=1
Reactant: Fc1cccc(C2=CCC(C3CCC4(CC3)OCCO4)CC2)c1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Solvent: O
Product: O=C1CCC(C2CC=C(c3cccc(F)c3F)CC2)CC1
Yield: 81.3 %

Procedure:
First, 8 g of 4-[4-(2,3-difluorophenyl)-3-cyclohexenyl]cyclohexanone ethylene ketal, 0.5 g of p-toluenesufonic acid, 40 ml of dioxane, and 110 ml of water were placed in a 300 ml flask. The mixture was stirred under reflux for 5 hours. The reaction mixture was extracted with ether. The ether layer was washed with water and dried over anhydrous sodium sulfate. Then, the solvent was distilled away. The residue was recrystallized from hexane to obtain 5.65 g of 4-[4-(2,3-difluorophenyl)-3-cyclohexenyl]cyclohexanone (Y: 81.4%). The compound thus obtained had a purity of 98.4% by GC.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=O)[C:10](=[CH:13]N(C)C)[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1.[N+]([O-])(O)=O.[OH:23][CH2:24][CH2:25][C:26]1[CH:27]=[C:28]([NH:32][C:33]([NH2:35])=[NH:34])[CH:29]=[CH:30][CH:31]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:34]=[C:33]([NH:32][C:28]4[CH:29]=[CH:30][CH:31]=[C:26]([CH2:25][CH2:24][OH:23])[CH:27]=4)[N:35]=[CH:13][C:10]=3[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1
Reactant: CN(C)C=C1CC(=O)Nc2cc(Cl)ccc2C1=O
Reactant: N=C(N)Nc1cccc(CCO)c1
Solvent: O=[N+]([O-])O
Product: O=C1Cc2cnc(Nc3cccc(CCO)c3)nc2-c2ccc(Cl)cc2N1

Procedure:
In a manner similar to that described for method I, 8-chloro-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (v-j) and N-[3-(2-hydroxy-ethyl)-phenyl]-guanidine nitrate were converted to I-80 (65%): HRMS Calcd. for C20H17ClN4O2: 381.1118, Found 381.1126.
Reaction SMILES: [OH-].[Na+].[C:3]([C:5]1[CH:6]=[C:7]([C:15]2[S:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([O:30]CC)=[O:29])=[CH:22][C:21]=3[CH3:33])[N:16]=2)[CH:8]=[CH:9][C:10]=1[S:11][CH:12]([CH3:14])[CH3:13])#[N:4].Cl>C(O)C>[C:3]([C:5]1[CH:6]=[C:7]([C:15]2[S:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:22][C:21]=3[CH3:33])[N:16]=2)[CH:8]=[CH:9][C:10]=1[S:11][CH:12]([CH3:14])[CH3:13])#[N:4]
Reactant: CCOC(=O)CCc1ccc(N2CSC(c3ccc(SC(C)C)c(C#N)c3)=N2)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(CCC(=O)O)ccc1N1CSC(c2ccc(SC(C)C)c(C#N)c2)=N1
Temperature: 50 °C
Reaction time: 1 h
Yield: 31.3 %

Procedure:
Sodium hydroxide (5 N) (0.44 mmol, 0.1 mL) was added to a solution of ethyl 3-(4-(5-(3-cyano-4-isopropylthiophenyl)-1,3,4-thiadiazol-3-yl)-3-methylphenyl)propanoate (0.09 mmol, from Step D) in ethanol (2 mL). The reaction mixture was stirred at 50° C. for 1 h. The reaction was acidified to a pH<7 with 2 N HCl and the product was extracted with EtOAc (20 mL). The organics were dried over magnesium sulfate, filtered and concentrated in vacuo. Silica gel chromatography eluting with 10% methanol/methylene chloride yielded 12 mg of the title compound: 1H NMR (500 MHZ, CDCl3) δ 8.26 (s, 1H), 8.24 (d, J=8.3, H), 7.74 (d, J=7.7, 1H), 7.62 (d, J=8.3, 1H), 7.28 (s, 1H), 7.24 (d, J=8.0, 1H), 3.70-3.78 (m, 1H), 3.02-3.10 (m, 2H), 2.76-2.82 (m, 2H), 2.68 (s, 3H), 1.47 (d, J=6.4, 6H); ESI-MS (m/z) 423.9; HPLC A: 3.79 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][C:39]=1[F:40])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([O:34][CH3:35])[C:10](=[O:33])[N:11]3[CH2:21][CH2:20][CH2:19][CH2:18][N:17]([CH2:22][CH2:23][O:24]CC4C=CC=CC=4)[C:16](=[O:32])[C:12]3=2)[C:7]1=[O:36].[H][H]>C(OCC)(=O)C.[Rh]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][C:39]=1[F:40])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([O:34][CH3:35])[C:10](=[O:33])[N:11]3[CH2:21][CH2:20][CH2:19][CH2:18][N:17]([CH2:22][CH2:23][OH:24])[C:16](=[O:32])[C:12]3=2)[C:7]1=[O:36]
Reactant: COc1c2c(c3n(c1=O)CCCCN(CCOCc1ccccc1)C3=O)CCN(Cc1ccc(F)c(Cl)c1)C2=O
Reactant: [H][H]
Agent: [Rh]
Solvent: CCOC(C)=O
Product: COc1c2c(c3n(c1=O)CCCCN(CCO)C3=O)CCN(Cc1ccc(F)c(Cl)c1)C2=O

Procedure:
A mixture of 11-(3-chloro-4-fluorobenzyl)-9-methoxy-2-[2-(benzyloxy)ethyl]-3,4,5,6,12,13-hexahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,8,10(11H)-trione (0.55 g, 0.97 mmol) and 5% rhodium on carbon (1.10 g) in ethyl acetate (22 mL) was stirred under a balloon of hydrogen at room temperature overnight. The product mixture was filtered through a pad of Celite. The filtrate was concentrated under vacuum to afford the title compound. This material was used in the following reaction without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([NH2:25])=[C:8](C(OC(C)(C)C)=O)[N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[CH:10]=1)=[O:5])[CH3:2].[CH2:26]([N:28]=[C:29]=[O:30])[CH3:27]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([NH:25][C:29]([NH:28][CH2:26][CH3:27])=[O:30])=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCN=C=O
Reactant: CCOC(=O)c1cn(-c2cccc(F)c2)c(C(=O)OC(C)(C)C)c1N
Product: CCNC(=O)Nc1cn(-c2cccc(F)c2)cc1C(=O)OCC
Yield: 73 %

Procedure:
Following general method 4, employing 3-amino-1-(3-fluorophenyl)-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester and ethyl isocyanate, afforded the title compound as a cream solid (0.192 g, 73%); LCMS (method B): RT=3.61 min, M+H+=320; 1H NMR (CDCl3, 300 MHz): 8.41 (s, 1H), 7.62 (d, J=2.7 Hz, 1H), 7.44 (d, J=2.7 Hz, 1H), 7.38 (dt, J=8.2, 6.2 Hz, 1H), 7.21 (dd, J=8.2, 2.4 Hz, 1H), 7.14 (dt, J=9.9, 2.4 Hz, 1H), 6.98 (td, J=8.2, 2.4 Hz, 1H), 4.73 (s, 1H), 4.31 (q, J=7.1 Hz, 2H), 3.35-3.26 (m, 2H), 1.37 (t, J=7.1 Hz, 3H), 1.21 (t, J=7.1 Hz, 3H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:24])[C@H:5]([CH2:17][CH2:18][CH2:19][NH:20][C:21](=[NH:23])[NH2:22])[NH:6][S:7]([C:10]1[CH:16]=[CH:15][C:13]([CH3:14])=[CH:12][CH:11]=1)(=[O:9])=[O:8].P([O-])([O-])([O-])=O.NO.NO.Cl.[OH-].[Na+].[Cl:37][C:38](Cl)(Cl)C(O)=O.Cl>>[ClH:37].[CH2:2]([O:3][C:4](=[O:24])[C@H:5]([CH2:17][CH2:18][CH2:19][NH:20][C:21](=[NH:22])[NH2:23])[NH:6][S:7]([C:10]1[CH:16]=[CH:15][C:13]([CH3:14])=[CH:12][CH:11]=1)(=[O:8])=[O:9])[CH3:38]
Reactant: O=C(O)C(Cl)(Cl)Cl
Reactant: COC(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1ccc(C)cc1
Agent: Cl
Agent: NO
Agent: O=P([O-])([O-])[O-]
Product: CCOC(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1ccc(C)cc1
Reaction time: 0.5 h

Procedure:
To 0.1 ml of thrombin were added 0.3 ml of Nα-tosyl-L-arginine methyl ester hydrochloride solution (10 micromoles/0.4 ml of 5% DMSO) and 0.6 ml of phosphate buffer solution (pH 7.4), and the resulting mixture was subjected to incubation at 37° C. for 30 min, after which 1.5 ml of a hydroxylamine solution (a mixture of equal amounts of 2 M NH2OH hydrochloride and 3.5 M NaOH) was added thereto. The resulting mixture was allowed to stand at room temperature for 15 min. Thereto were added 1 ml of 18% trichloroacetic acid solution, 1 ml of 4 N hydrochloric acid, and 1 ml of 10% ferric chloride solution. The resulting mixture was thoroughly stirred and then centrifuged at 3,000 r.p.m. for 10 min. The color thus developed of the supernatant was measured as absorbance (530 l nm) by means of a spectrophotometer. The value obtained corresponds to the amount of the substrate remaining unhydrolyzed with thrombin, and therefore, and activity of the enzyme corresponds to the difference between the value obtained when no enzyme was used (control) and the value obtained after the enzyme reaction.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([O-:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[Na+].[N+]([C:15]1C=CC([O-])=CC=1)([O-])=O.[Na+]>>[N+:1]([C:4]1[CH:5]=[C:6]([O:10][CH3:15])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc([O-])cc1
Reactant: O=[N+]([O-])c1cccc([O-])c1
Agent: [Na+]
Product: COc1cccc([N+](=O)[O-])c1
Yield: 85 %

Procedure:
The procedure and reactants of Example 1 were used except that sodium m-nitrophenolate was substituted for sodium p-nitrophenolate. 0.6 grams of m-nitroanisole (about 85 percent) were obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([NH:12][C@H:13]1[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]1)=[N:9][C:8]([C:25]1[NH:29][C:28](=[O:30])[NH:27][N:26]=1)=[CH:7]2.[ClH:31]>CCOC(C)=O>[ClH:31].[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([NH:12][C@H:13]1[CH2:17][CH2:16][NH:15][CH2:14]1)=[N:9][C:8]([C:25]1[NH:29][C:28](=[O:30])[NH:27][N:26]=1)=[CH:7]2
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(-c3n[nH]c(=O)[nH]3)cc3cccc(F)c23)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=c1[nH]nc(-c2cc3cccc(F)c3c(N[C@H]3CCNC3)n2)[nH]1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 99.2 %

Procedure:
To a mixture of (S)-tert-butyl 3-((8-fluoro-3-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)isoquinolin-1-yl)amino)pyrrolidine-1-carboxylate (300 mg, 0.72 mmol) in EtOAc (5 mL) was added a 4M solution of HCl in EtOAc (5 mL). The reaction mixture was stirred at RT for 45 minutes. The solvent was removed in vacuo to give an HCl salt of the title compound (250 mg, 99.2%). ESI-MS m/z [M+H]+ 315.2.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]23[CH2:17][CH2:16][CH:15](O)[CH:7]2[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=2[CH2:14]3)[N:3]=[CH:2]1.Cl.[H][H]>C(O)C.[Pd]>[CH2:17]1[C:6]2([C:4]3[N:3]=[CH:2][NH:1][CH:5]=3)[CH2:14][C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[CH:7]2[CH2:15][CH2:16]1
Reactant: [H][H]
Reactant: OC1CCC2(c3c[nH]cn3)Cc3ccccc3C12
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: c1ccc2c(c1)CC1(c3c[nH]cn3)CCCC21
Temperature: 25 °C
Yield: 25.7 %

Procedure:
A solution of 8a-(1H-imidazol-4-yl)-1,2,3,3a,8,8a-hexahydrocyclo-penta[a]inden-3-ol (0.5 g) in 20 ml of ethanol containing 5 ml of 20% hydrochloric acid was heated at reflux for 3 hours. The solution was allowed to cool to room temperature and 50 mg of 10% palladium on carbon catalyst was added. The reaction mixture was hydrogenated at 50-55° C. until no more hydrogen was consumed. The catalyst was filtered off and the solvent removed under reduced pressure. The residue was dissolved in water and the solution was basified with sodium hydroxide solution. The basic reaction solution was extracted with methylene chloride (3×100 ml), dried over sodium sulfate and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography using methylene chloride/methanol (97:3) as eluent. Recrystallization from ethyl acetate afforded 120 mg of product, m.p. 171-174° C.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C@H:6]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].O.Cl>ClCCl>[C:1]([NH:5][C@H:6]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)C[C@H](N)c1cccc(F)c1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C[C@H](NC(C)=O)c1cccc(F)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Acetyl chloride (7.9 ml, 111 mmol) in dichloromethane (50 ml) was added dropwise to a cold (0° C.) solution of ethyl (3S)-3-amino-3-(3-fluorophenyl)propanoate (WO99/31099, Scheme 3 page 97) (25.2 g, 102 mmol) in dichloromethane (200 ml). The reaction was stirred for 2 hours at 0° C., then water (100 ml) was added. The reaction mixture was adjusted to pH1 with 2 N hydrochloric acid and the organic layer separated. The dichloromethane layer was washed with saturated sodium hydrogencarbonate solution (50 ml), water (50 ml) and then dried (MgSO4). Solvent was evaporated under reduced pressure to afford a thick oil which was purified by column chromatography (silica gel, eluting with diethyl ether) to give the title compound as a clear, colourless oil, 25.1 g.
Reaction SMILES: [I:1][C:2]1[C:3]([CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[N:4][CH:5]=[C:6]([O:9][CH3:10])[C:7]=1[NH2:8].[C:17]([N:25]=[C:26]=[S:27])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC(C)=O>[C:17]([NH:25][C:26]([NH:8][C:7]1[C:6]([O:9][CH3:10])=[CH:5][N:4]=[C:3]([CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:2]=1[I:1])=[S:27])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: COc1cnc(C2CCOCC2)c(I)c1N
Solvent: CC(C)=O
Product: COc1cnc(C2CCOCC2)c(I)c1NC(=S)NC(=O)c1ccccc1
Temperature: 25 °C
Yield: 80.4 %

Procedure:
To a stirred solution of 725 mg (2.17 mmol) 3-iodo-5-methoxy-2-(tetrahydro-pyran-4-yl)-pyridin-4-ylamine in 14 ml acetone was added dropwise 0.35 ml (2.60 mmol) benzoyl isothiocyanate at room temperature. The reaction mixture then heated at reflux for 2 h before being cooled to room temperature concentrated in vacuo. Flash chromatography (ethyl acetate/heptane) afforded 868 mg (80%) 1-benzoyl-3-[3-iodo-5-methoxy-2-(tetrahydro-pyran-4-yl)-pyridin-4-yl]-thiourea as a white crystalline solid. ES-MS m/e (%): 498 (M+H+, 100).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10](Cl)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C(N(CC)CC)C.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl>ClCCl.C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([S:10]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: Nc1ccccc1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc(S(=O)(=O)Nc2ccccc2)c1
Reaction time: 16 h
Yield: 43.4 %

Procedure:
To a solution of 3-nitrobenzenesulfonyl chloride (3.08 g, 13.9 mmol) in 28 mL of dichloromethane was added triethylamine (3.88 mL, 27.8 mmol) and aniline (1.39 mL. 15.3 mmol). After 16 hours, the reaction was poured into ethyl acetate and 10% HCl solution, then washed with brine, dried (MgSO4) and concentrated in vacuo to provide the crude product. Purification by chromatography on silica gel (25-50% CH2Cl2 /hexane, then 5% MeOH/CH2Cl2) provided 1.68 g of the desired product as an off-white solid.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:18]2[C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:20]CCOC)[C:10](=[O:25])[C:9]=2[CH:8]=[CH:7][CH:6]=1)([CH3:3])[CH3:2]>S(=O)(=O)(O)O.O>[CH:1]([NH:4][C:5]1[C:18]2[C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[OH:20])[C:10](=[O:25])[C:9]=2[CH:8]=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: COCCOc1cccc2c1C(=O)c1c(NC(C)C)cccc1C2=O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(C)Nc1cccc2c1C(=O)c1c(O)cccc1C2=O

Procedure:
25 g of 1-isopropylamino-8-(β-methoxy-ethoxy)-anthraquinone are dissolved in 75 ml of 75% strength sulphuric acid and the solution is stirred at 130°-135° until no further starting material is detectable in a worked-up sample (approx. 90 minutes being required). The mixture is stirred until it has cooled to 80° and is diluted with 85 ml of water at the same temperature, it is left until the product precipitates as crystals and diluted with a further 41 ml of water at above 50°, the product is filtered off at 50° and rinsed with 35% strength sulphuric acid, the filter residue is decomposed in water and the product is filtered off, washed until neutral and dried in vacuo. Yield: 15.5 g. Quality: 98% pure.