Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH2:18])[CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:20]1[CH:25]=[CH:24][N:23]=[C:22]([NH2:26])[N:21]=1>C(O)C>[C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH:18][C:20]2[CH:25]=[CH:24][N:23]=[C:22]([NH2:26])[N:21]=2)[CH3:17])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1nccc(Cl)n1
Reactant: C[C@H](N)c1nc2ccccc2n1-c1ccccc1
Solvent: CCO
Product: C[C@H](Nc1ccnc(N)n1)c1nc2ccccc2n1-c1ccccc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 45.9 %

Procedure:
Into a 25-mL round-bottom flask was placed a solution of (S)-1-(1-phenyl-1H-benzo[d]imidazol-2-yl)ethanamine from Example 4 (238 mg, 1.00 mmol, 1.00 equiv) in ethanol (8 mL) and 4-chloropyrimidin-2-amine (130 mg, 0.99 mmol, 0.98 equiv, 98%). The resulting solution was stirred overnight at 100° C. and concentrated under vacuum. The crude product was applied onto a C18 Column (water/acetonitrile) to afford 150 mg (44%) of 145 as a white solid. LC-MS (ES, m/z): 331 [M+H]+ H-NMR (300 MHz, CD3OD, ppm): δ 7.83 (d, 1H), 7.57 (m, 8H), 6.11 (q, 1H), 5.61 (q, 1H), 1.67 (d, 3H)
Reaction SMILES: C([O:8][C:9]1[CH:32]=[CH:31][C:12]([CH2:13][N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([CH2:23][CH:24]3[S:28][C:27](=[O:29])[NH:26][C:25]3=[O:30])=[CH:15]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.B(Br)(Br)Br.C(=O)([O-])O.[Na+]>C(Cl)Cl>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([CH2:23][CH:24]3[S:28][C:27](=[O:29])[NH:26][C:25]3=[O:30])=[CH:15]2)=[CH:31][CH:32]=1
Reactant: O=C1NC(=O)C(Cc2cn(Cc3ccc(OCc4ccccc4)cc3)c3ccccc23)S1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C1NC(=O)C(Cc2cn(Cc3ccc(O)cc3)c3ccccc23)S1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.9 %

Procedure:
There was dissolved, in 30 ml of methylene chloride, 259 mg of 5-[1-(4-benzyloxybenzyl)indol-3-yl]methyl-2,4-thiazolidinedione prepared in Example 265 and the resulting solution was cooled to -78° C. After dropwise addition of a solution of boron tribromide (1.0M) in methylene chloride (10.17 ml), the temperature of the mixture was slowly raised up to room temperature. After stirring the mixture for 2 hours, a saturated sodium hydrogen carbonate aqueous solution was added followed by extraction with ethyl acetate. The resulting organic phase was washed with a saturated common salt solution, dried over anhydrous sodium sulfate and the solvent was removed by evaporation under reduced pressure to give 105 mg of 5-[1-(4-hydroxybenzyl)indol-3-yl]methyl-2,4-thiazolidinedione as a yellow amorphous substance. The yield thereof was found to be 51%.
Reaction SMILES: Cl[C:2]1[CH:8]2[CH2:9][CH:5]([CH2:6][CH2:7]2)[C:4](=[O:10])[CH:3]=1.[CH3:11][O:12][CH2:13][CH2:14][O:15][CH2:16][C:17]1[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:18]=1[C:19]([OH:21])=[O:20].C(N(C(C)C)CC)(C)C.C1(C)C=CC=CC=1>[Cl-].[Cl-].[Zn+2].ClCCl>[CH3:11][O:12][CH2:13][CH2:14][O:15][CH2:16][C:17]1[C:18]([C:19]([O:21][C:2]2[CH:8]3[CH2:9][CH:5]([CH2:6][CH2:7]3)[C:4](=[O:10])[CH:3]=2)=[O:20])=[CH:22][CH:23]=[C:24]([C:26]([F:29])([F:27])[F:28])[N:25]=1
Reactant: O=C1C=C(Cl)C2CCC1C2
Reactant: COCCOCc1nc(C(F)(F)F)ccc1C(=O)O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COCCOCc1nc(C(F)(F)F)ccc1C(=O)OC1=CC(=O)C2CCC1C2
Temperature: 25 °C

Procedure:
A mixture of 200 mg (1.15 mmol) of 4-chlorobicyclo[3.2.1]oct-3-en-2-one, 16 mg (0.12 mmol) of ZnCl2, 324 mg (1.15 mmol) of 2-methoxyethoxymethyl-6-trifluoromethylnicotinic acid, 166 mg (1.27 mmol) of diisopropylethylamine and 5 ml of toluene is stirred at room temperature under a nitrogen atmosphere until a clear brown solution having a white sediment is formed. With stirring, the reaction mixture is then maintained under moderate reflux for 26 hours in an oil bath. The reaction mixture is then cooled to ambient temperature and 30 ml of dichloromethane are added. The solution is then washed twice with water (20 ml each time), then twice with 0.1M hydrochloric acid (20 ml each time) and again twice with water (15 ml each time). After drying the organic solution using magnesium sulfate and concentrating in vacuum, 284 mg of 4-(2-methoxyethoxymethyl-6-trifluoromethyl-pyridin-3-ylcarbonyloxy)-bicyclo[3.2.1]oct-3-en-2-one are obtained in the form of a brown oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@@:4]1([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.[S:34](N)([NH2:37])(=[O:36])=[O:35]>O1CCOCC1>[NH2:37][S:34]([NH:1][CH2:2][CH2:3][C@@:4]1([C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1)(=[O:36])=[O:35]
Reactant: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCN)(c2ccc(F)cc2)OC1=O
Reactant: NS(N)(=O)=O
Solvent: C1COCCO1
Product: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCNS(N)(=O)=O)(c2ccc(F)cc2)OC1=O
Yield: 25 %

Procedure:
A mixture of (R)-6-(2-aminoethyl)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluoro phenyl)-1,3-oxazinan-2-one (40 mg, 0.09 mmol) and sulfamide (44 mg, 0.45 mmol) in 1,4-dioxane (10 mL) was heated to reflux overnight. When the reaction was over, the solvent was removed to give the residue, which was purified by preparative HPLC to give the desired product (12 mg, 25%). 1H NMR (CDCl3): 1.54 (m, 3H), 2.26 (m, 5H), 3.08 (m, 3H), 4.56 (s, 2H), 5.67 (m, 1H), 6.89 (m, 2H), 7.05 (m, 4H), 7.28 (m, 5H). LC-MS Method 3 tR=1.24 min, m/z=534.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:6]=1[C:12](=O)[CH3:13].[CH3:15]C(C)([O-])C.[K+]>>[I:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][OH:1])=[C:6]([C:12]([CH3:13])=[CH2:15])[CH:7]=1
Reactant: CC(=O)c1cc(I)ccc1OCCO
Reactant: CC(C)(C)[O-]
Agent: [K+]
Product: C=C(C)c1cc(I)ccc1OCCO

Procedure:
The product was prepared analogously to Example 11.1b starting from 1-[2-(2-hydroxyethoxy)-5-iodophenyl]ethanone and using potassium tert-butoxide as base. Yield: 2.50 g (43% of theoretical); C11H13IO2 (M=304.124); calc.: molpeak (M+H)+: 305; found: molpeak (M+H)+: 305; HPLC-MS: 5.65 minutes (method B).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[S:17][CH:18]=[C:19]([C:21](O)=[O:22])[N:20]=3)[CH2:12][CH2:11]2)=[O:9])[N:5]=[C:4]([C:24]([F:27])([F:26])[F:25])[CH:3]=1.C(Cl)(=O)C([Cl:31])=O>ClCCl.CN(C)C=O>[CH3:1][C:2]1[N:6]([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[S:17][CH:18]=[C:19]([C:21]([Cl:31])=[O:22])[N:20]=3)[CH2:12][CH2:11]2)=[O:9])[N:5]=[C:4]([C:24]([F:27])([F:26])[F:25])[CH:3]=1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)O)cs2)CC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)Cl)cs2)CC1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 99.6 %

Procedure:
A stirred solution of 2-[1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinyl]-4-thiazolecarboxylic acid (2.55 g, 5.87 mmol) (i.e. the product of Example 2, Step C) in dichloromethane (100 mL) was cooled to −10° C., and 1 drop of N,N-dimethyl-formamide was added. A solution of oxalyl chloride (0.60 mL, 6.8 mmol) in dichloromethane (10 mL) was added dropwise to the stirred reaction mixture. The reaction mixture was stirred at −10° C. for 30 minutes more, and then allowed to warm to room temperature and stir an additional 16 h. The resulting homogeneous mixture was evaporated in vacuo, and the residue was placed under high vacuum for several hours to give 2.46 g of the title compound as a light yellow solid. This compound was of sufficient purity to use in subsequent reactions.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:31])[CH:5]=[C:6]([Cl:30])[C:7]=1[CH2:8][C@H:9]([O:20][C:21]([C:23]1[S:24][C:25]([CH:28]=O)=[CH:26][CH:27]=1)=[O:22])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1.[F:32][C:33]1[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=1[NH2:35].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.O>[Cl:30][C:6]1[CH:5]=[N+:4]([O-:31])[CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C@H:9]([O:20][C:21]([C:23]1[S:24][C:25]([CH2:28][NH:35][C:34]2[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=2[F:32])=[CH:26][CH:27]=1)=[O:22])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1
Reactant: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)c2ccc(C=O)s2)cc1OC
Reactant: Nc1ccccc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)c2ccc(CNc3ccccc3F)s2)cc1OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 32.7 %

Procedure:
A stirred solution of [(1S)-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl]5-formylthiophene-2-carboxylate (128 mg, 0.265 mmol) in dichloromethane (5 mL) was added with 2-fluoroaniline (29 mg, 0.265 mmol) followed by glacial acetic acid (0.015 mL, 0.265 mmol). The reaction was stirred at room temperature for 6 h. Sodium triacetoxyborohydride (140 mg, 0.662 mmol) was added and the reaction was stirred at room temperature for 18 h. Water was added to quench the reaction and the organic layer was washed with brine, passed through a hydrophobic frit and the solvent was removed in vacuo. The crude material was purified by silica gel column chromatography, eluting with 0-100% EtOAc in DCM, to afford the title compound (50 mg, 32%) as a yellow oil.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[C:6]([Mg]Cl)([CH3:9])([CH3:8])[CH3:7].C([O-])(O)=[O:13].[Na+]>C(OCC)C>[CH3:7][C:6]([CH3:9])([C:1](=[O:4])[CH:2]([OH:13])[CH3:3])[CH3:8]
Reactant: CCC(=O)Cl
Reactant: CC(C)(C)[Mg]Cl
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: CC(O)C(=O)C(C)(C)C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
0.24 g of cuprous chloride was suspended in 100 mL diethyl ether and then 22.1 g of propionyl chloride was added. The reaction was heated to reflux and 88 mL of t-butyl magnesium chloride was added slowly to maintain reflux. The reaction was stirred overnight then poured into 200 g ice and the pH adjusted to 8 with solid NaHCO3. The reaction was extracted with ether, washed with 10% aq. NaHCO3, water and then brine followed by MgSO4 drying. The product was purified by distillation to give 12.5 g of the ketone.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Cl:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([Cl:17])[C:8]=1[NH:18][NH:19][C:20](=O)[CH2:21][Cl:22]>C1(C)C=CC=CC=1>[Cl:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([Cl:17])[C:8]=1[NH:18][N:19]=[C:20]([Cl:3])[CH2:21][Cl:22]
Reactant: O=C(CCl)NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: FC(F)(F)c1cc(Cl)c(NN=C(Cl)CCl)c(Cl)c1
Temperature: 70 °C
Yield: 90 %

Procedure:
Phosphoryl chloride (500 microliters, 1.7 equivalents) was added in one portion to a stirred solution of N′-(2,6-dichloro-4-trifluoromethylphenyl)-chloroacetohydrazide (1.0 g, 3.11 mmol) in toluene (20 ml) and heated at 70° C. under an argon atmosphere for 20 hours. The cooled mixture was evaporated and the residue extracted with cyclohexane. The extracts were combined and evaporated to give the title compound (0.971 g) as an orange oil, NMR 4.4(s,2H), 7.55(s,2H), 7.7(s,1H). The yield was 90%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([F:20])([F:19])([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:5]2[N:21]=[C:22](S(C)(=O)=O)[N:23]=[C:4]2[N:3]=1.[O-:28][CH2:29][CH3:30].[Na+]>C(O)C>[CH2:29]([O:28][C:22]1[N:23]=[C:4]2[N:3]=[C:2]([CH3:1])[CH:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([S:15]([F:19])([F:18])([F:16])([F:17])[F:20])=[CH:11][CH:10]=3)[N:5]2[N:21]=1)[CH3:30]
Reactant: CC[O-]
Reactant: Cc1cc(Nc2ccc(S(F)(F)(F)(F)F)cc2)n2nc(S(C)(=O)=O)nc2n1
Agent: [Na+]
Solvent: CCO
Product: CCOc1nc2nc(C)cc(Nc3ccc(S(F)(F)(F)(F)F)cc3)n2n1
Temperature: 120 °C

Procedure:
Intermediate 10 (0.15 g, 0.349 mmol) was added to sodium ethoxide (ALDRICH, 0.071 g, 1.048 mmol) in ethanol (3 mL). The mixture was heated under microwave irradiation at 120° C. for 30 minutes. Solvent was removed under vacuum and the crude mixture was purified by flash chromatography (Si, eluting with DCM: MeOH mixtures from 100:0 to 90:10%). The title compound was obtained as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:25]#[N:26])=[C:4]([CH:22]=[CH:23][CH:24]=1)[O:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH:10]([NH:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[CH2:9][CH2:8]1.O=[C:28]([CH3:35])[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>>[NH2:26][C:25]1[C:3]2[C:2](=[CH:24][CH:23]=[CH:22][C:4]=2[O:5][CH2:6][CH:7]2[CH2:8][CH2:9][CH:10]([NH:13][C:14](=[O:21])[C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[CH2:11][CH2:12]2)[N:1]=[C:28]([CH3:35])[C:29]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: CCOC(=O)CC(C)=O
Reactant: N#Cc1c(N)cccc1OCC1CCC(NC(=O)c2ccncc2)CC1
Product: CCOC(=O)c1c(C)nc2cccc(OCC3CCC(NC(=O)c4ccncc4)CC3)c2c1N

Procedure:
Prepared as in Example 2a from N-(4-((3-Amino-2-cyanophenoxy)methyl)cyclohexyl)isonicotinamide (Example 108b) and ethyl 3-oxobutanoate as a yellow solid (25%). MS 463 (MH+).
Reaction SMILES: [C:1]([O:4]C(=O)C)(=[O:3])[CH3:2].[C:8]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][C:23](=[O:25])[CH3:24])=[CH:15][N+:14]=1[O-])(=[O:10])[CH3:9].C(=O)(O)[O-].[Na+]>>[C:8]([O:11][CH:12]([O:4][C:1](=[O:3])[CH3:2])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][C:23](=[O:25])[CH3:24])=[CH:15][N:14]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)OCCOc1ccc(COC(C)=O)[n+]([O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(=O)OCCOc1ccc(C(OC(C)=O)OC(C)=O)nc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
5 ml (53.00 mmol) of acetic anhydride are added to 0.83 g of the crude product from example 26A, and without further solvent the mixture is stirred at +120° C. for 3 h. The reaction mixture is then cooled to 0° C., and 2 ml of saturated aqueous sodium bicarbonate solution are added. The aqueous phase is extracted twice with in each case 5 ml of dichloromethane, and the combined organic phases are dried over magnesium sulphate. After removal of the solvent, the crude product is used without further purification for the subsequent reaction.
Reaction SMILES: C([O:5][C:6](=[O:32])[C:7]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([CH2:19][CH:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][C:27]=3[CH3:29])[N:22]([CH3:30])[CH2:21]2)[C:11]1=[O:31])([CH3:9])[CH3:8])(C)(C)C>C(O)(C(F)(F)F)=O>[CH3:30][N:22]1[C:23]2[C:28](=[C:27]([CH3:29])[CH:26]=[CH:25][CH:24]=2)[CH:20]([CH2:19][N:12]2[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:10]([C:7]([CH3:8])([CH3:9])[C:6]([OH:32])=[O:5])[C:11]2=[O:31])[CH2:21]1
Reactant: Cc1cccc2c1C(Cn1c(=O)n(C(C)(C)C(=O)OC(C)(C)C)c3ccccc31)CN2C
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc2c1C(Cn1c(=O)n(C(C)(C)C(=O)O)c3ccccc31)CN2C
Yield: 29.6 %

Procedure:
A solution of 2-[3-(1,4-dimethyl-3H-indol-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-2-methyl-propionic acid tert-butyl ester (138 mg, 0.32 mmol) in TFA (1.0 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated. The resulting residue was purified by CombiFlash with 10% MeOH in dichloromethane as the eluent to afford the desired 2-[3-(1,4-dimethyl-3H-indol-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-2-methyl-propionic acid (36 mg, 30%). LCMS (ESMS): 378.25 (M+H+).
Reaction SMILES: C([O:5][C:6](=[O:35])[C@@H:7]([CH2:27][C:28]([O:30]C(C)(C)C)=[O:29])[NH:8][S:9]([C:12]1[CH:21]=[C:20]2[C:15]([C:16]([Cl:26])=[CH:17][N:18]=[C:19]2[NH:22][C:23]([NH2:25])=[NH:24])=[CH:14][CH:13]=1)(=[O:11])=[O:10])(C)(C)C.CCOCC>CCOC(C)=O.Cl>[ClH:26].[Cl:26][C:16]1[C:15]2[C:20](=[CH:21][C:12]([S:9]([NH:8][C@@H:7]([C:6]([OH:35])=[O:5])[CH2:27][C:28]([OH:30])=[O:29])(=[O:11])=[O:10])=[CH:13][CH:14]=2)[C:19]([NH:22][C:23]([NH2:25])=[NH:24])=[N:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)C[C@@H](NS(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: N=C(N)Nc1ncc(Cl)c2ccc(S(=O)(=O)N[C@H](CC(=O)O)C(=O)O)cc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 130.5 %

Procedure:
N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-D-aspartic acid di-t-butyl ester (50 mg, 0.095 mmol) was dissolved in a solution of EtOAc saturated with HCl (10 mL) and the mixture stirred at room temperature for 4 h. The mixture was concentrated in vacuo and the residue triturated with PhMe and then Et2O to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-D-aspartic acid hydrochloride (29 mg, 0.062 mmol) as an off-white solid.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:22][CH3:23])=[C:16]([O:19][CH2:20][CH3:21])[CH:17]=3)[CH:12]=[C:11]([CH2:24][OH:25])[C:10]=2[CH2:26][OH:27])[CH:6]=[CH:5][N:4]=1)[NH2:2].[C:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]([C:39]1[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=1)=O)(O)=[O:29].C(O)CO.C(Cl)[Cl:50]>O>[ClH:50].[N:41]1[CH:42]=[CH:43][CH:44]=[C:39]([C:37]2[C:32]3[C:31](=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:28](=[O:29])[N:1]([C:3]3[CH:8]=[C:7]([C:9]4[C:18]5[C:13](=[CH:14][C:15]([O:22][CH3:23])=[C:16]([O:19][CH2:20][CH3:21])[CH:17]=5)[CH:12]=[C:11]([CH2:24][OH:25])[C:10]=4[CH2:26][OH:27])[CH:6]=[CH:5][N:4]=3)[N:2]=2)[CH:40]=1
Reactant: O=C(O)c1ccccc1C(=O)c1cccnc1
Reactant: ClCCl
Reactant: CCOc1cc2c(-c3ccnc(NN)c3)c(CO)c(CO)cc2cc1OC
Solvent: O
Solvent: OCCO
Product: CCOc1cc2c(-c3ccnc(-n4nc(-c5cccnc5)c5ccccc5c4=O)c3)c(CO)c(CO)cc2cc1OC
Product: Cl
Temperature: 25 °C

Procedure:
A mixture of 1-(2-hydrazino-4-pyridyl)-2,3-bis(hydroxymethyl)-6-methoxy-7-ethoxynaphthalene (2.0 a), (2-carboxyphenyl)-(3-pyridyl) ketone (1.35 g) and ethylene glycol (5 ml) is refluxed for two hours. The mixture under refluxing is cooled to room temperature, and then thereto are added methylene chloride and water. The methylene chloride layer is separated, washed, dried, concentrated under reduced pressure to remove the solvent, and crystallized from chloroform. The precipitated crystals are dissolved in a mixture of chloroform and methanol, and thereto is added a 4 M solution of hydrogen chloride in dioxane (0.67 ml) to give 1-[2-{4-(3-pyridyl)-1(2H)-phthalazinon-2-yl}-4-pyridyl]-2,3-bis(hydroxymethyl)-6-methoxy-7-ethoxynaphthalene hydrochloride (1.43 g), which is listed in Table 10.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]1[CH:8]=[C:9]([CH2:13][CH2:14][CH2:15][NH:16][C:17]([C@H:19]2[CH2:24][CH2:23][C@H:22]([NH:25]C(=O)OC(C)(C)C)[CH2:21][CH2:20]2)=[O:18])[CH:10]=[N:11][CH:12]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:25][C@H:22]1[CH2:21][CH2:20][C@H:19]([C:17]([NH:16][CH2:15][CH2:14][CH2:13][C:9]2[CH:10]=[N:11][CH:12]=[C:7]([C@@H:3]3[CH2:4][CH2:5][CH2:6][N:2]3[CH3:1])[CH:8]=2)=[O:18])[CH2:24][CH2:23]1
Reactant: CN1CCC[C@H]1c1cncc(CCCNC(=O)[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCC[C@H]1c1cncc(CCCNC(=O)[C@H]2CC[C@H](N)CC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of tert-butyl {trans-4-[(3-{5-[(2S)-1-methylpyrrolidin-2-yl]pyridin-3-yl}propyl)carbamoyl]cyclohexyl}carbamate (preparation 13) (130 mg, 0.29 mmol) in DCM (3 mL) was treated with trifluoroacetic acid (1 mL). The resulting solution was stirred at ambient temperature for 2 hours after which time it was concentrated in vacuo. The residue was dissolved in MeOH and applied to an SCX-2 cartridge and eluted with MeOH followed by ammonia in MeOH (2M). The fractions containing product were concentrated in vacuo to give the title compound as a colourless gum (98 mg, 97%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:13][Si](Cl)(C)C>CO>[CH3:13][O:11][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Reactant: C[Si](C)(C)Cl
Solvent: CO
Product: COC(=O)Cc1ccc(Cl)c(Cl)c1
Reaction time: 8 h
Yield: 99.4 %

Procedure:
To a solution of (3,4-dichloro-phenyl)-acetic acid (90.5 mmol) in methanol (200 mL) was added trimethylsilylchloride (181 mmol) and the mixture was stirred overnight before it was concentrated. The residue was diluted with ether (200 mL) and the solution was washed with 1 N NaOH, brine, dried over MgSO4, and concentrated in vacuo to give (3,4-dichloro-phenyl)-acetic acid methyl ester (90 mmol) as a colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]=[C:10]=[S:11].[CH2:12]([NH:14][CH2:15][C:16](O)=[O:17])[CH3:13].C(N(CC)CC)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:16](=[O:17])[CH2:15][N:14]([CH2:12][CH3:13])[C:10]1=[S:11]
Reactant: CCNCC(=O)O
Reactant: Cc1ccc(N=C=S)c(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCN1CC(=O)N(c2ccc(C)cc2Cl)C1=S
Yield: 21.7 %

Procedure:
The title compound was prepared by the procedure described in Example 28 using 18.3 g of 2-chloro-4-methylphenyl-isothiocyanate, 18.4 g of N-ethyl glycine, 20.2 g of triethyl amine, and 300 mL of chloroform. Crystallization from ethyl acetate afforded the title compound (5.8 g) as a peach solid, m.p. 126°-128° C. Anal. Calcd. for. C12H13Cl N2O S: C, 53.63; H, 4.88; N, 10.42. Found: C, 53.50; H, 4.76; N, 10.28. Mass spectrum (+FAB, IM+H]+) m/z 269/271.
Reaction SMILES: CO.C[O:4][C:5](=[O:33])[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([CH3:13])[C:7]=1[N:14]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[S:15]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16]>CCOCC>[CH2:26]([N:14]([S:15]([C:18]1[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)(=[O:17])=[O:16])[C:7]1[C:8]([CH3:13])=[C:9]([Cl:12])[CH:10]=[CH:11][C:6]=1[C:5]([OH:33])=[O:4])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COC(=O)c1ccc(Cl)c(C)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Solvent: CCOCC
Solvent: CO
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2)c2c(C(=O)O)ccc(Cl)c2C)cc1
Yield: 92.6 %

Procedure:
In the same manner as described in Example 19, except a mixture of MeOH and ThF was used instead of MeOH, 0.506 g (1.1 mmol) of the product of Example 98 provided 0.454 g (93%) of the desired carboxylic acid as a white solid after triion with ether. Electrospray Mass Spec 446.1(M+H).
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:6]=[C:5]([S:14](Cl)(=[O:16])=[O:15])[N:4]=1)[CH3:2].[Cl:18][C:19]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:20]=1[NH2:21]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Cl:18][C:19]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:20]=1[NH:21][S:14]([C:5]1[N:4]=[C:3]([CH2:1][CH3:2])[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:6]=1)(=[O:16])=[O:15]
Reactant: CCc1nc(S(=O)(=O)Cl)nn1-c1ccccc1
Reactant: Nc1c(Cl)cccc1Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CCc1nc(S(=O)(=O)Nc2c(Cl)cccc2Cl)nn1-c1ccccc1
Yield: 30.4 %

Procedure:
5-Ethyl-1-phenyl-1,2,4-triazole-3-sulphonyl chloride (2.7 g), prepared by a method analogous to that of Example A, was added to a stirred solution of 2,6-dichloroaniline (1.8 g), and 4-dimethylaminopyridine (0.1 g) in dry pyridine (15 ml). After 48 hours at 25° C. most of the pyridine was removed in vacuo, and the residue was dissolved in dichloromethane. The solution was extracted with dilute hydrochloric acid and then re-evaporated. The residue was treated with 4M sodium hydroxide solution (25 ml) at 80° C. for 1 hour and then filtered. The filtered solid was washed with warm water, the filtrate was acidified with concentrated hydrochloric acid, and the product was recrystallised from ethanol to give 1.2 g of desired product, mp 185°-187° C.