Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[S:10][C:9]3[N:11]=[CH:12][CH:13]=[CH:14][C:8]=3[C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].C(OCCO)C>>[Cl:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH:19][C:2]1[C:3]2[S:10][C:9]3[N:11]=[CH:12][CH:13]=[CH:14][C:8]=3[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1cccc(Cl)c1
Reactant: Clc1ncnc2c1sc1ncccc12
Solvent: CCOCCO
Product: Clc1cccc(Nc2ncnc3c2sc2ncccc23)c1
Reaction time: 3 h
Yield: 29.4 %

Procedure:
A mixture of 4-chloropyrido [3',2'; 4,5]thieno[3,2-d]pyrimidine (0.12 g, 0.54 mmol), 3-chloroaniline (0.06 mL, 0.5 mmol) and 2-ethoxyethanol (5 mL) is heated under N2 with stirring at 135 C. for 3 h. Upon cooling a solid precipitates. The solid is collected by filtration, washed with acetone and dried in a vacuum oven at ~80 C. to give 4-(3-chloroanilino)pyrido[3',2'; 4,5]thieno[3,2-d]pyrimidine (46 mg, 27%). 1H NMR (DMSO) δ9.97 (1H, s), 8.88 (1H, dd, J=4.6, 1.7 Hz), 8.85 (1H, s), 8.72 (1H, dd, J=8.0, 1.7 Hz), 8.08 (2H, t, J=2.0 Hz), 7.79 (1H, ddd, J=8.3, 2.0, 0.8 Hz), 7.69 (1H, dd, J=8.0, 4.6 Hz), 7.43 (1H, t, J=8.0 Hz), 7.19 (1H, ddd, J=8.0, 2.0, 0.8 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([F:12])=[CH:7][CH:8]=2)[N:3]=1.[Li]CCCC.CON(C)[C:21](=[O:23])[CH3:22]>C1COCC1>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([C:21](=[O:23])[CH3:22])[C:6]([F:12])=[CH:7][CH:8]=2)[N:3]=1
Reactant: Fc1ccc2ccc(Cl)nc2c1
Reactant: CON(C)C(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)c1c(F)ccc2ccc(Cl)nc12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 15.1 %

Procedure:
To a solution of 2-chloro-7-fluoroquinoline (ECA International Corp, Palatine, Ill.; 300 mg, 1.652 mmol) in THF (5.0 mL) at −78° C. was added nBuLi, 1.6 M in hexanes (1.24 mL, 1.98 mmol) slowly dropwise. The solution was stirred at −78° C. for 30 min. A solution of N-methoxy-N-methylacetamide (0.25 mL, 2.48 mmol) in THF (0.5 mL) was added slowly dropwise via syringe. After 10 min, the reaction was warmed to RT. After 15 min, the reaction was quenched by addition of saturated aq. NH4Cl. The reaction was partitioned between saturated NH4Cl and EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by silica gel chromatography, using 0-50% EtOAc/hexane. The pure fractions were combined and concentrated in vacuo to give 1-(2-chloro-7-fluoroquinolin-8-yl)ethanone (56 mg, 0.250 mmol, 15.16% yield): 1H NMR (400 MHz, DMSO-d6) δ ppm 8.57 (d, J=8.6 Hz, 1H), 8.25 (dd, J=9.1, 6.2 Hz, 1H), 7.65-7.74 (m, 2H), 2.68 (s, 3H). m/z (ESI, +ve ion) 224.0 (M+H)+.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH3:12][O:13][C:14](=[O:25])[CH2:15][C:16](=O)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[N:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[F:35])=[N+:27]=[N-:28].O>CN(C=O)C>[CH2:17]([C:16]1[N:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[F:35])[N:27]=[N:28][C:15]=1[C:14]([O:13][CH3:12])=[O:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)CC(=O)Cc1ccccc1
Reactant: [N-]=[N+]=Nc1ccccc1F
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1nnn(-c2ccccc2F)c1Cc1ccccc1
Reaction time: 0.25 h

Procedure:
DBU (1.33 ml; 8.90 mmol; 1.10 eq.) was dissolved in DMF (17 ml) and put under nitrogen atmosphere. 3-Oxo-4-phenyl-butyric acid methyl ester (Chemcollect, 1.711 g; 8.90 mmol; 1.10 eq.) was added to the mixture and it was stirred for 15 min. Then a solution of 1-azido-2-fluorobenzene, prepared according to Platz, M. S. et al. J. Org. Chem. 1989, 54, 5938-5945, (1.11 g; 8.10 mmol; 1 eq.) in DMF (2 mL) was added dropwise to the solution at room temperature. The mixture was stirred at 90° C. for 2 hours. Water (30 mL) was added to the cooled reaction mixture and the aqueous layer was extracted with EtOAc (3×40 mL). Combined organics were washed with water and brine, dried over MgSO4 and concentrated under vacuum giving the title compound as a yellow oil. It was used in the next step without further purification. LC/MS (Method B): 312.1 (M+H)+.
Reaction SMILES: CCCCCC[O:7][C:8](/[N:10]=[C:11](\[NH2:46])/[C:12]1[CH:13]=[CH:14][C:15]([NH:18][CH2:19][C:20]2[N:28]([CH3:29])[C:27]3[CH:26]=[CH:25][C:24]([C:30]([N:32]([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][N:45]=4)[CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[O:31])=[CH:23][C:22]=3[N:21]=2)=[CH:16][CH:17]=1)=[O:9].NC1C=C(C=CC=1NC)C(N(C1C=CC=CN=1)CCC(OCC)=O)=O.O1C(=O)N=C(C2C=CC(NCC(O)=O)=CC=2)N1.C(Cl)(=O)C(C)(C)C>>[O:7]1[C:8](=[O:9])[N:10]=[C:11]([C:12]2[CH:13]=[CH:14][C:15]([NH:18][CH2:19][C:20]3[N:28]([CH3:29])[C:27]4[CH:26]=[CH:25][C:24]([C:30]([N:32]([C:40]5[CH:41]=[CH:42][CH:43]=[CH:44][N:45]=5)[CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[O:31])=[CH:23][C:22]=4[N:21]=3)=[CH:16][CH:17]=2)[NH:46]1
Reactant: CCCCCCOC(=O)/N=C(\N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OCC)c4ccccn4)ccc3n2C)cc1
Agent: CC(C)(C)C(=O)Cl
Agent: CCOC(=O)CCN(C(=O)c1ccc(NC)c(N)c1)c1ccccn1
Agent: O=C(O)CNc1ccc(-c2nc(=O)o[nH]2)cc1
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(-c3nc(=O)o[nH]3)cc1)n2C)c1ccccn1

Procedure:
U.S. Pat. No. 7,202,368 describes an alternative process for the synthesis of dabigatran etexilate (see Scheme 2). Example 3 describes the condensation between ethyl 3-{[3-amino-4-(methylamino)benzoyl](pyridin-2-yl)amino}propanoate (compound II) and 2-[4-(1,2,4-oxadiazol-5-on-3-yl)phenylamino]acetic acid (compound VII) in the presence of a coupling agent such as N,N′-carbonyldiimidazole (CDI), propanephosphonic anhydride (PPA), or pivaloyl chloride, to give ethyl 3-{[(2-{[(4-{1,2,4-oxadiazol-5-on-3-yl}phenyl)amino]methyl}-1-methyl-1H-benzimidazol-5-yl)carbonyl](pyridin-2-yl)amino}propanoate (compound VIII), which is subsequently hydrogenated (Example 4) in the presence of a palladium catalyst to give ethyl 3-{[(2-{[(4-carbamimidoylphenyl)amino]methyl}-1-methyl-1H-benzimidazol-5-yl)carbonyl](pyridin-2-yl)amino}propanoate (compound V). Then, Example 5 describes the acylation of compound V with n-hexyl chloroformate (compound VI) to give dabigatran etexilate. Finally, Example 6 describes the conversion of dabigatran etexilate into its mesylate salt. Although the patent describes the HPLC purities of intermediate compounds II, VII, VIII and V, no information is given neither about the purity of the isolated dabigatran etexilate nor about its mesylate salt.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([Cl:30])[CH:20]=[C:21](OS(C(F)(F)F)(=O)=O)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[S:31]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32]1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([Cl:30])[CH:20]=[C:21]([C:33]4[CH:34]=[CH:35][S:31][CH:32]=4)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(Cl)cc(OS(=O)(=O)C(F)(F)F)c3O2)cc1
Reactant: OB(O)c1ccsc1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cc(Cl)cc(-c4ccsc4)c3O2)cc1
Yield: 16.9 %

Procedure:
Treatment of (±)-(5-chloro-7-{[(trifluoromethyl)sulfonyl]oxy}-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.50 g, 3.10 mmol) with thiophene-3-boronic acid (0.62 g, 4.88 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (0.265 g, 0.325 mmol), and potassium carbonate (0.898 g, 6.5 mmol) generally according to the procedure described for Intermediate 35 provided 0.22 g (17%) of (±)-(5-chloro-7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a white solid. mp 115-117° C.; Anal. calcd. for C20H17ClO4S2: C, 57.07; H, 4.07. Found: C, 56.17; H, 3.85.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH2:9][CH3:10])[C:5]([NH2:6])=[C:4]([CH2:11][CH3:12])[CH:3]=1.N1C=CC=CC=1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl>[Br:1][C:2]1[CH:8]=[C:7]([CH2:9][CH3:10])[C:5]([NH:6][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:4]([CH2:11][CH3:12])[CH:3]=1
Reactant: CCc1cc(Br)cc(CC)c1N
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCc1cc(Br)cc(CC)c1NC(=O)c1ccccc1
Yield: 95.8 %

Procedure:
A solution of 4-bromo-2,6-diethylaniline (5.48 g, 24 mmol) in dichloromethane was added and stirred under nitrogen. Pyridine (5.7 g, 72.1 mmol) was added followed by benzoyl chloride (4.39 g, 31.2 mmol). The reaction was stirred for 1 h. The reaction was diluted with dichloromethane, washed with 10% sodium hydroxide solution, 1N HCl, and dried over magnesium sulfate, filtered, and evaporated. The residue was pre-absorbed onto Celite and purified by column chromatography. The column was eluted with 40 to 100% dichloromethane/hexanes. 7.64 g (96% yield) of product was obtained after purification.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:32]=[CH:31][C:6]2[NH:7][C:8]([C:13]3[C:14](=[O:30])[C:15]([CH3:29])([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:16]4[C:21]([C:22]=3[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:9][S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=1.[C:33]([NH:38][S:39](Cl)(=[O:41])=[O:40])(=[O:37])[CH2:34][CH2:35][CH3:36].C(N(CC)CC)C>ClCCl>[OH:23][C:22]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH3:29])([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:14](=[O:30])[C:13]=1[C:8]1[NH:7][C:6]2[CH:31]=[CH:32][C:3]([NH:2][S:39]([NH:38][C:33](=[O:37])[CH2:34][CH2:35][CH3:36])(=[O:41])=[O:40])=[CH:4][C:5]=2[S:10](=[O:12])(=[O:11])[N:9]=1
Reactant: CC(C)CCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Reactant: CCCC(=O)NS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(=O)NS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)c3ccccc3C(C)(CCC(C)C)C1=O)N2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 58.7 %

Procedure:
A mixture of the product of Example 34B (52.2 mg, 0.110 mmol) and the product of Example 99A (102 mg, 0.55 mmol) in dichloromethane (5 mL) was treated with triethylamine (66.5 mg, 0.658 mmol). The mixture was stirred at r.t. for 15 minutes. The reaction mixture was partitioned between dichloromethane and 1N hydrochloric acid, and the aqueous phase extracted with additional dichloromethane. The organic phase was dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by HPLC to give the title compound (38 mg, 59%). 1H NMR (300 MHz, DMSO-d6) δ 0.41 m, 1 H) 0.69 (m, 8 H) 0.79 m, 1 H) 1.37 m, 4 H) 1.56 (s, 3 H) 2.04 m, 1 H) 2.11 (t, J=7.35 Hz, 2 H) 2.22 m, 1 H) 7.48 (dd, J=8.82, 2.21 Hz, 1 H) 7.53 m, 1 H) 7.59 (d, J=2.21 Hz, 1 H) 7.71 (d, J=8.82 Hz, 1H) 7.76 (d, J=4.04 Hz, 2 H) 8.15 (d, J=7.72 Hz, 1 H) 10.95 (s, 1 H) 11.99 (s, 1H) 13.81 (s, 1H). MS (ESI+) m/z 589.1 (M+H)+, 606.1 (M+NH4)+, (ESI−) 587.2 (M−H).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:7][CH2:6][C:5]([C:8]2[C:9]([NH:14][C:15]([NH:17]C(OCC)=O)=S)=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH2:3]1.Cl.[NH2:25]O.CO>C(O)C>[CH3:23][C:2]1([CH3:1])[CH2:7][CH2:6][C:5]([C:8]2[C:9]3[N:10]([N:25]=[C:15]([NH2:17])[N:14]=3)[CH:11]=[CH:12][CH:13]=2)=[CH:4][CH2:3]1
Reactant: NO
Reactant: CCOC(=O)NC(=S)Nc1ncccc1C1=CCC(C)(C)CC1
Agent: Cl
Solvent: CCO
Solvent: CO
Product: CC1(C)CC=C(c2cccn3nc(N)nc23)CC1
Temperature: 70 °C
Yield: 62.4 %

Procedure:
To a solution of N-[3-(4,4-dimethyl-cyclohex-1-enyl)-pyridin-2-yl]-N′-carboethoxy-thiourea (1.42 g, 3.48 mmol) in ethanol (4.3 mL) was added at room temperature hydroxylamine hydrochloride (1.50 g, 21.4 mmol) and methanol (4.3 mL). The yellow suspension was heated to 70° C. over night. The solvent was evaporated under reduced pressure and the residue was partitionated between ethyl acetate and water. The aqueous layer was extracted twice with ethyl acetate and the organic layers were combined, washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The crude material was purified by column chromatography on silica gel first with ethyl acetate as the eluent and then once again with a mixture of heptane/ethyl acetate (1:1 v/v) as the eluent to yield the title compound as a yellow solid (526 mg, 51%).
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][C:15]([N:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][C:29](=[O:36])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:19][CH2:18]2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[CH:5]1[C:6]2[C:15]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][C:29](=[O:36])[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH2:19][CH2:18]3)=[N:14][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[S:7][C:1]=2[CH:2]=[CH:3][CH:4]=1
Reactant: O=C(OCCOCCN1CCN(C(=O)Nc2ccccc2Sc2ccccc2)CC1)c1ccccc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O=P(Cl)(Cl)Cl
Product: O=C(OCCOCCN1CCN(C2=Nc3ccccc3Sc3ccccc32)CC1)c1ccccc1
Temperature: 90 °C
Reaction time: 19 h

Procedure:
Benzoic acid 2-{2-[4-(2-phenylsulfanyl-phenylcarbamoyl)piperazin-1-yl]-ethoxy}-ethyl ester (2 g, 3.96 mmol), phosphorus oxychloride (15 ml) and phosphorus pentoxide (2 g) were charged into a reaction flask. Then the mixture was stirred at 90° C. for 19 h. Phosphorus oxychloride was evaporated in vacuo. Dichloromethane (20 ml) and ice-water (20 ml) were added to the residue. NaHCO3 was added until the pH was 7-8. The organic phase was separated, washed with saturated NaCl-water (10 ml), dried with Na2SO4 and evaporated. Yield of benzoic acid 2-[2-(4-dibenzo[b,f][1,4]-thiazepin-11-yl-piperazin-1-yl]-ethoxy]-ethyl ester 1.53 g.
Reaction SMILES: [CH2:1]([O:5][CH:6]=[CH2:7])[CH2:2][CH2:3][CH3:4].[C:8]([OH:13])(=[O:12])[C:9]([CH3:11])=[CH2:10]>>[C:8]([O:13][CH:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH3:7])(=[O:12])[C:9]([CH3:11])=[CH2:10]
Reactant: C=C(C)C(=O)O
Reactant: C=COCCCC
Product: C=C(C)C(=O)OC(C)OCCCC

Procedure:
The reaction procedure of Example 1 was repeated using equimolar amounts of n-butylvinyl ether and methacrylic acid. The structure of the product, 1-n-butoxyethyl methacrylate (Compound C) was obtained in 88% yield. Compound C is an example of a mono-functional alpha-alkoxyalkyl(meth)acrylate which may optionally be included with multi-functional alpha-alkoxyalkyl(meth)acrylate compounds in compositions of the present invention. The structure of Compound C was confirmed by 1H NMR and infrared analysis.
Reaction SMILES: C[O:2][C:3](=[O:39])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:38])[CH:12]([N:19]2[C:24](=[O:25])[CH:23]=[C:22]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[CH:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)[CH:21]=[N:20]2)[CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[N:6][CH:5]=1.[OH-].[Li+].CO>O1CCCC1>[CH:14]1([CH2:13][CH:12]([N:19]2[C:24](=[O:25])[CH:23]=[C:22]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[CH:33]3[CH2:34][CH2:35][CH2:36][CH2:37]3)[CH:21]=[N:20]2)[C:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:39])=[O:2])=[CH:5][N:6]=2)=[O:38])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COC(=O)c1ccc(NC(=O)C(CC2CCCC2)n2ncc(Oc3ccccc3C3CCCC3)cc2=O)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(NC(=O)C(CC2CCCC2)n2ncc(Oc3ccccc3C3CCCC3)cc2=O)nc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 30.6 %

Procedure:
A solution of 6-{3-cyclopentyl-2-[4-(2-cyclopentyl-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionylamino}-nicotinic acid methyl ester (Example 66, 130 mg, 0.24 mmol) in tetrahydrofuran (5.0 mL) at 25° C. was treated with a 0.5N aqueous lithium hydroxide solution (1.0 mL) and methanol (1.0 mL). The resulting solution was stirred at 25° C. for 5 h. After this time, the solution was concentrated in vacuo. The residue was treated with a 1N aqueous hydrochloric acid solution (0.6 mL). The mixture was extracted with ethyl acetate. The organics were then washed with a saturated aqueous sodium chloride solution and then concentrated in vacuo. The resulting solids were triturated with hexanes and diethyl ether. The resulting solids were collected by filtration and dried in vacuo to afford 6-{3-cyclopentyl-2-[4-(2-cyclopentyl-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionylamino}-nicotinic acid (38 mg) as a solid; ES+-HRMS m/e calcd for C29H32N4O5 [M+H+] 517.2446 found 517.2443. 1H-NMR (300 MHz, DMSO-d6) δ ppm 1.03-2.05 (m, 18H), 2.31 (m, 1H), 3.04 (m, 1H), 5.57 (dd, J=4.2, J=10.6 Hz, 1H), 5.61 (d, J=2.7 Hz, 1H), 7.20 (m, 1H), 7.27-7.38 (m, 2H), 7.49 (m, 1H), 8.08 (d, Jo=8.8 Hz, 1H), 8.20 (d, J=2.7 Hz, 1H), 8.24 (dd, Jo=8.8 Hz, Jm=2.2 Hz, 1H), 8.84 (d, Jm=2.2 Hz, 1H), 11.33 (s, 1H), 13.18 (br.s., 1H).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12](Br)[CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([Si](C)(C)Cl)(C)(C)C.BrC1C=C(C=CC=1)CO.C([Li])CCC.[OH:39][CH2:40][C@@H:41]1[C@:49]2([CH3:50])[C@@:44]([OH:52])([CH2:45][C:46](=[O:51])[CH2:47][CH2:48]2)[CH2:43][CH2:42]1>C1COCC1.CCCCCC>[OH:39][CH2:40][C@@H:41]1[C@:49]2([CH3:50])[C@@:44]([OH:52])([CH2:45][C@:46]([C:12]3[CH:13]=[CH:14][CH:15]=[C:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH:11]=3)([OH:51])[CH2:47][CH2:48]2)[CH2:43][CH2:42]1
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(Br)c1
Reactant: C[C@]12CCC(=O)C[C@@]1(O)CC[C@@H]2CO
Agent: CC(C)(C)[Si](C)(C)Cl
Agent: OCc1cccc(Br)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1cccc([C@@]2(O)CC[C@]3(C)[C@@H](CO)CC[C@]3(O)C2)c1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 72 %

Procedure:
To a suspension of 60.0 g of 3-(tert-butyldimethylsilyloxymethyl)bromobenzene (prepared from tert-butyldimethylchlorosilane and 3-bromobenzyl alcohol according to the procedure described by Kendall P. M. et al., J. Org. Chem., 1979, 44, 1421) in 500 ml of anhydrous THF cooled to -78° C., 131 ml of 1.6M n-butyllithium in n-hexane were added under a nitrogen atmosphere and the resulting mixture was stirred for 2.5 hrs. A solution of 6.30 g of (1S,3aS,7aR)-1-hydroxymethyl-3a-hydroxy-7a-methyl-5-perhydroindenone in 60 ml of anhydrous THF was added. After 1 hr the reaction mixture was allowed to warm to 0° C., and cautiously quenched with 300 ml of 5% aqueous NaH2PO4.H2O and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by flash-chromatography (SiO2) with n-hexane/acetone/chloroform 6:2:2 as the eluant to give 9.62 g of (1S,3aS,5R,7aR)-1-hydroxymethyl-5-(3-tert-butyldimethylsilyloxymethylphenyl)-7a-methylperhydroinden-3a,5-diol as a white foam.
Reaction SMILES: [C:1]([C:4]1(C(OC)=O)[CH2:9][CH2:8][CH:7]([C:10]([O:12][CH3:13])=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].Cl.O>C(O)C>[C:1]([CH:4]1[CH2:9][CH2:8][CH:7]([C:10]([O:12][CH3:13])=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: COC(=O)C1CCC(C(C)=O)(C(=O)OC)CC1
Agent: Cl
Solvent: O
Solvent: CCO
Product: COC(=O)C1CCC(C(C)=O)CC1

Procedure:
Dimethyl 1-acetylcyclohexane-1,4-dicarboxylate (23.3 g) was added to a solution of concentrated hydrochloric acid (253 ml) in ethanol (126 ml). After refluxing for 10 hours the reaction mixture was poured into water and then extracted with dichloromethane. The organic phase was then washed with saturate sodium bicarbonate solution and brine. After drying over anhydrous magnesium sulphate the solvent was removed under reduced pressure to give methyl 4-acetylcyclohexanecarboxylate as a colourless oil. This was purified by distillation (b.pt 138°-145° C. at 14 mmHg).
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([NH2:10])(=[O:9])=[O:8].C(N=[C:22]=[O:23])CCC.N12CCN(CC1)CC2.C(Cl)(Cl)=O>ClC1C=CC=CC=1>[C:1]1([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([N:10]=[C:22]=[O:23])(=[O:9])=[O:8]
Reactant: NS(=O)(=O)c1ccccc1-c1ccccc1
Reactant: CCCCN=C=O
Agent: C1CN2CCN1CC2
Agent: O=C(Cl)Cl
Solvent: Clc1ccccc1
Product: O=C=NS(=O)(=O)c1ccccc1-c1ccccc1
Reaction time: 2 h

Procedure:
23.3 g of 2-biphenylylsulfonamide, 10.9. g of n-butyl isocyanate, a catalytic amount of 1,4-diazabicyclo[2,2,2]-octane and 180 ml of chlorobenzene were refluxed with stirring for 2 hours. Then, phosgene in a slight excess of the theroretical amount was blown through the reaction mixture over 2 hours while maintaining the internal temperature at 115°-120° C. At this time, any unreacted phosgene escaping from the reaction system was trapped in a dry ice trap and returned to the reactor. After addition of the phosgene, the reaction mixture was further stirred at the reflux temperature for a short time to complete the reaction. The mixture was cooled, and if necessary, it was filtered under reduced pressure to remove the insoluble matter. It was then concentrated under reduced pressure, to obtain 20.0 g of 2-biphenylylsulfonylisocyanate. B.p. 135°-137° C./0.7-0.8 mmHg.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][C:8]1[N:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][CH:9]=1>C1COCC1>[CH3:7][C:8]1[N:13]=[C:12]([CH2:14][NH2:15])[CH:11]=[CH:10][CH:9]=1
Reactant: Cc1cccc(C#N)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cccc(CN)n1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a cooled solution of 1.0 M LiAlH4 in THF (35.6 mL, 35.6 mmol) at 0° C. was added dropwise a solution of 6-methyl-pyridine-2-carbonitrile I-4h (2.0 g, 16.9 mmol) in THF (34 mL). The reaction mixture was stirred at 0° C. for 5 minutes after the addition was complete and then quenched with the addition of 1N NaOH (20 mL). The resulting reaction mixture was stirred for 1 h and filtered through celite washing well with ether. The filtrate was diluted with 1N NaOH (20 mL) and the organic layer separated. The organic layer was then washed with brine, dried (Na2SO4), and concentrated in vacuo to give the desired product I-4i (1.02 g).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([S:7](=[O:10])(=[O:9])[NH2:8])=[C:4]([C:11]([OH:13])=O)[CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[S:6][C:5]2[S:7](=[O:10])(=[O:9])[NH:8][C:11](=[O:13])[C:4]=2[CH:3]=1
Reactant: Cc1cc(C(=O)O)c(S(N)(=O)=O)s1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1cc2c(s1)S(=O)(=O)NC2=O
Yield: 49 %

Procedure:
A mixture of 0.1 gm (0.45 millimols) of 5-methyl-2-sulfamoyl-thiophene-3-carboxylic acid, 50 ml of anhydrous toluene and 5 mgm of p-toluene-sulfonic acid was heated for 10 hours in a vessel equipped with a water trap. The reaction mixture was evaporated to dryness in vacuo and separated by column chromatography. 0.40 mgm (49% of theory) of 5-methyl-thieno[3,2-d]isothiazole-3(2H)-one-1, 1-dioxide were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[Br:12]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OCC)C.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:12][CH2:11][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[C:3]([O:2][CH3:1])[CH:10]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc(C)ccc1C#N
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(CBr)ccc1C#N
Temperature: 25 °C
Yield: 68.3 %

Procedure:
To a solution of 2-methoxy-4-methylbenzonitrile (0.438 g, 2.98 mmol) in CCl4 (6 mL) was added recrystallized N-bromosuccinimide (0.544 g, 3.05 mmol) followed by benzoyl peroxide (47 mg, 0.19 mmol). The resultant mixture was heated to reflux for 45 minutes then cooled to room temperature. The mixture was diluted with diethyl ether (30 mL), filtered through filter paper, and the filtrate was concentrated. Purification of the crude material by column chromatography (6:1 hexanes-EtOAc) provided 0.46 g (68%) of 4-(bromomethyl)-2-methoxybenzonitrile as a white solid. 1H NMR (CDCl3) δ3.96 (s, 3H), 4.45 (s, 2H), 6.99 (s, 1H), 7.03 (d, 1H, J=9 Hz), 7.53 (d, 1H, J=9 Hz).