Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]12[CH2:15][O:14][C:13]2[CH:16]=[C:17]3[C:21](=[CH:22][C:12]1=2)[CH2:20][CH2:19][O:18]3.CC1C2C=[C:30]3[C:35]4(C5C(=CC=CC=5)NC4=O)[CH2:34][O:33][C:31]3=[CH:32]C=2ON=1.CC1C=CC(S(OC[C@H]2CCCO2)(=O)=O)=CC=1.BrCC1OC(C(F)(F)F)=CC=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:32][C@H:31]1[CH2:30][CH2:35][CH2:34][O:33]1)[C:6](=[O:11])[C:5]12[CH2:15][O:14][C:13]2[CH:16]=[C:17]3[C:21](=[CH:22][C:12]1=2)[CH2:20][CH2:19][O:18]3
Reactant: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Reactant: O=C1Nc2ccc(F)cc2C12COc1cc3c(cc12)CCO3
Agent: Cc1ccc(S(=O)(=O)OC[C@H]2CCCO2)cc1
Agent: FC(F)(F)c1ccc(CBr)o1
Product: O=C1N(C[C@H]2CCCO2)c2ccc(F)cc2C12COc1cc3c(cc12)CCO3

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using 5′-fluoro-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, and (R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, 5′-fluoro-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one was obtained (60%) as a colorless solid: mp 167-169° C. (diethyl ether); 1H NMR (300 MHz, CDCl3) δ 7.06-6.85 (m, 3H), 6.47 (s, 1H), 6.39 (s, 1H), 4.76 (ABq, 2H), 4.52 (t, J=9.0 Hz, 2H), 4.28-4.20 (m, 1H), 3.89-3.69 (m, 4H), 2.98-2.95 (m, 2H), 2.10-1.63 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 178.0, 161.9, 161.2, 157.9, 138.7, 134.3, 120.0, 118.8, 115.1, 114.8, 111.7, 111.4, 110.5, 93.3, 80.5, 72.4, 68.2, 58.0, 44.8, 29.0, 28.9, 25.7; MS (ES+) m/z 382.1 (M+1).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1)=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH3:18][O:19][C:20](=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][C:25](Br)=[CH:24][CH:23]=1>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>[CH3:18][O:19][C:20](=[O:29])[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([CH:1]=[O:2])[CH:4]=2)=[CH:26][CH:27]=1
Reactant: COC(=O)Cc1ccc(Br)cc1
Reactant: O=Cc1cccc(B(O)O)c1
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: [K+]
Product: COC(=O)Cc1ccc(-c2cccc(C=O)c2)cc1
Yield: 96 %

Procedure:
3-Formylphenylboronic acid (2.25 g), potassium carbonate (4.15 g) and tetrakis(triphenylphosphine)palladium(0) (0.58 g) was added to a solution of (4-bromophenyl)-acetic acid methyl ester (2.3 g) in a nitrogen degassed mixture of toluene and methanol [9:1] (20 mL) and heated to reflux for 18 hours. On cooling the reaction was filtered through a pad of Celite, the pad was washed with ethyl acetate (2×50 mL) and the combined filtrates were concentrated. Purification on silica, eluting with iso-hexane/ethyl acetate [1:0 to 4:1], afforded the subtitle compound as yellow oil (2.45 g)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH2:9]([O:16][C:17]1[C:18]2[N:19]3[C:23](=[CH:24][CH:25]=1)[C:22]([CH2:26][CH3:27])=[C:21]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[CH:30][CH:29]=1)[C:20]3=[C:42]([CH2:44][O:45][CH2:46][CH2:47][CH2:48][CH2:49]Cl)[CH:43]=2)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(O)C>CN(C)C=O.O>[CH2:9]([O:16][C:17]1[C:18]2[N:19]3[C:23](=[CH:24][CH:25]=1)[C:22]([CH2:26][CH3:27])=[C:21]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[CH:30][CH:29]=1)[C:20]3=[C:42]([CH2:44][O:45][CH2:46][CH2:47][CH2:48][CH2:49][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH:43]=2)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C1CCNCC1
Reactant: CCc1c(-c2ccc(OCc3ccccc3)cc2)c2c(COCCCCCl)cc3c(OCc4ccccc4)ccc1n32
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: O
Product: CCc1c(-c2ccc(OCc3ccccc3)cc2)c2c(COCCCCN3CCCCC3)cc3c(OCc4ccccc4)ccc1n32
Reaction time: 0.5 h
Yield: 5.7 %

Procedure:
Piperidine (0.104 g, 1.22 mmol) was dissolved in 50 ml of dry dimethylformamide under a nitrogen atmosphere and sodium hydride (60% in oil) 47 mg, 1.16 mmol) was added. The mixture was stirred for 1/2 hour. 5-Benzyloxy-2-(4-benzyloxyphenyl)-3-((4-chlorobutoxy)methyl)-1-ethylpyrrolo[2,1,5-cd]indolizine (0.337 g, 0.583 mmol) was added and the mixture was stirred at 55-65° for 7 days. Ethanol (10 ml) was added dropwise, and the reaction mxiture was diluted with 250 ml of water. The organic material was extracted into ethyl acetate (3×100 ml), and the combined organic layers were washed with brine and dried over sodium sulfate. The solvent was eaporated and the crude product was purified by column chromatography over silica gel 60, using 5% of methanol in dichloromethane as the eluent. Fractions containing the product were collected to afford 21 mg (5%) of 5-benzyloxy-2-(4-benzyloxyphenyl)-1-ethyl-3-((4-piperidinobutoxy)methyl)pyrrolo[2,1,5-cd ]indolizine as an oil. MS(SP): m/z 640 (M+). 1H-NMR (DMSO-d6, 300 MHz) δ: 1.28-1.58 (m, 13H); 2.21-2.57 (m, 6H); 3.08 (q, 2H); 3.37-3.48 (m, 2H+H2O); 4.72 (s, 2H); 5.20 (s, 2H); 5.60 (s, 2H); 7.22 (d, 2H); 7.32-7.69 (m, 14H); 7.98 (d, 1H).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[C:13]([N:16]1[CH2:21][CH2:20][CH2:19][C:18]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)[CH2:17]1)(=[O:15])[CH3:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:56][CH2:57][CH2:58][NH:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][N+:61]=1[O-:66]>C1COCC1>[C:13]([N:16]1[CH2:21][CH2:20][CH2:19][C:18]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([O:29][CH2:56][CH2:57][CH2:58][NH:59][C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][N+:61]=3[O-:66])=[CH:27][CH:28]=2)[CH2:17]1)(=[O:15])[CH3:14]
Reactant: [O-][n+]1ccccc1NCCCO
Reactant: CCOC(=O)CC1(Cc2ccc(O)cc2)CCCN(C(C)=O)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)CC1(Cc2ccc(OCCCNc3cccc[n+]3[O-])cc2)CCCN(C(C)=O)C1
Temperature: 40 °C
Reaction time: 0.25 h

Procedure:
Diethyl azodicarboxylate (267 mg, 1.53 mmol) was added to a solution of the product from STEP 8 (348 mg, 1.09 mmol) and triphenylphosphine (437 mg, 1.66 mmol) in 3.9 ml THF at 0° C. and stirred for 15 min. 2-(3-Hydroxypropylamino)pyridine N-oxide (418 mg, 2.48 mmol) was added. The reaction was warmed to 40° C. After 15 min, the reaction was cooled to room temperature and stirred for 18 h. The reaction was concentrated and the residue was purified by chromatography (on silica gel, dichloromethane/2-propanol/acetic acid=95/5/0.5) to give a product mixture in 406 mg. The 1H NMR spectrum of the product was consistent for the proposed structure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([NH2:7])=[NH:6].[Cl:12][C:13]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:14]=1[CH:15]=[C:16]([C:19]#[N:20])[C:17]#[N:18]>>[NH2:20][CH2:19][C:16]1[C:17]([NH2:18])=[N:6][C:5]([C:4]2[CH:8]=[CH:9][C:10]([F:11])=[C:2]([F:1])[CH:3]=2)=[N:7][C:15]=1[C:14]1[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:13]=1[Cl:12]
Reactant: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Reactant: N=C(N)c1ccc(F)c(F)c1
Product: NCc1c(N)nc(-c2ccc(F)c(F)c2)nc1-c1ccc(Cl)cc1Cl

Procedure:
The title compound, MS: m/e=381.3 (M+H+), was prepared from 3,4-difluoro-benzamidine and 2-(2,4-dichloro-benzylidene)-malononitrile in analogy to the process described in Example 11 as a solid.
Reaction SMILES: N1[NH:2][C:3](=[O:7])[CH:4]=[CH:5][CH:6]=1.Br[C:9]1[CH:14]=[CH:13][C:12]([C@H:15]2[CH2:17][C@@H:16]2[CH2:18][N:19]2[CH2:23][CH2:22][CH2:21][C@H:20]2[CH3:24])=[CH:11][CH:10]=1.N>>[CH3:24][C@@H:20]1[CH2:21][CH2:22][CH2:23][N:19]1[CH2:18][C@H:16]1[CH2:17][C@@H:15]1[C:12]1[CH:13]=[CH:14][C:9]([N:2]2[CH2:6][CH2:5][CH2:4][C:3]2=[O:7])=[CH:10][CH:11]=1
Reactant: C[C@@H]1CCCN1C[C@H]1C[C@@H]1c1ccc(Br)cc1
Reactant: O=c1cccn[nH]1
Agent: N
Product: C[C@@H]1CCCN1C[C@H]1C[C@@H]1c1ccc(N2CCCC2=O)cc1

Procedure:
The title compound was prepared using the procedure described in Example 35B substituting pyrrolidin-2-one for pyridazin-3(2H)-one and substituting the product from Example 35A for the product from Example 34F. 1H NMR (300 MHz, CD3OD) δ 0.89-0.96 (m, 1H), 1.01-0.08 (m, 1H), 1.22 (d, J=6 Hz, 3H), 1.25-1.30 (m, 1H), 1.48-1.55 (m, 1H), 1.8-1.89 (m, 4H), 2.03-2.27 (m, 4H), 2.57 (t, J=6 Hz, 2H), 2.65-2.74 (m, 1H), 3.22 (q, J=6 Hz, 1H), 3.33-3.40 (m, 1H), 3.89 (t, J=6 Hz, 2H), 7.10 (d, J=9 Hz, 2H), 7.46 (d, J=9 Hz, 2H). MS (DCl—NH3) m/z 299 (M+H)+.
Reaction SMILES: [Br:1]NC(=O)C.[CH:6]([Si:9]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[O:10][CH:11]1[C:17]2=[N:18][CH:19]=[CH:20][CH:21]=[C:16]2[CH:15]=[CH:14][CH2:13][CH2:12]1)([CH3:8])[CH3:7].[C:28]([O-:31])(=[O:30])[CH3:29].[Li+]>CC(O)=O>[C:28]([O:31][CH:15]1[C:16]2[C:17](=[N:18][CH:19]=[CH:20][CH:21]=2)[CH:11]([O:10][Si:9]([CH:6]([CH3:8])[CH3:7])([CH:22]([CH3:24])[CH3:23])[CH:25]([CH3:27])[CH3:26])[CH2:12][CH2:13][CH:14]1[Br:1])(=[O:30])[CH3:29]
Reactant: CC(=O)NBr
Reactant: CC(=O)[O-]
Reactant: CC(C)[Si](OC1CCC=Cc2cccnc21)(C(C)C)C(C)C
Agent: [Li+]
Solvent: CC(=O)O
Product: CC(=O)OC1c2cccnc2C(O[Si](C(C)C)(C(C)C)C(C)C)CCC1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-bromoacetamide (2.021 g, 14.65 mmol) was added to the AcOH (100 mL) suspension of (Z)-9-(triisopropylsilyloxy)-8,9-dihydro-7H-cyclohepta[b]pyridine (4.5597 g, 14.36 mmol) and LITHIUM ACETATE (3.79 g, 57.4 mmol) at rt under N2. The flask was wrapped with alumina foil and stirred at room temperature overnight. The reaction became a clear yellow solution. The solvent was evaporated via high vacuum. The crude was partitioned between water and ethyl acetate. Na2CO3 was added until no bubbling. The organic was separated and the aqueous was extract by ethyl acetate again. The combined organic layer was dried (Na2SO4), filtered and concentrated to give a tan oil (crude product: 6.37 g). The crude was used as it is. MS (ESI)[M+H+]=458.36.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]2[N:16]([CH3:17])[C:15]3[CH:18]=[CH:19][C:20]([C:22]([N:24]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=4)[CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:23])=[CH:21][C:14]=3[N:13]=2)=[CH:6][CH:5]=1)(=[NH:3])[NH2:2].Cl[C:39]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[O:40]>>[CH3:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][O:41][C:39](/[N:3]=[C:1](\[NH2:2])/[C:4]1[CH:5]=[CH:6][C:7]([NH:10][CH2:11][C:12]2[N:16]([CH3:17])[C:15]3[CH:18]=[CH:19][C:20]([C:22]([N:24]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=4)[CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:23])=[CH:21][C:14]=3[N:13]=2)=[CH:8][CH:9]=1)=[O:40]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Reactant: CCCCCCOC(=O)Cl
Product: CCCCCCOC(=O)/N=C(\N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OCC)c4ccccn4)ccc3n2C)cc1

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: Br.[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](Br)=[CH:5][C:4]=1[C:14]([O:16][CH3:17])=[O:15].[Cl-].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][Zn+])=[CH:22]N=1.O.Cl[CH2:30]Cl>C1COCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:26][C:23]2[CH:22]=[CH:30][C:20]([Cl:19])=[CH:25][CH:24]=2)=[CH:5][C:4]=1[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)c1cc(Br)c2ccccc2c1N
Reactant: Clc1ccc(C[Zn+])cn1
Reactant: ClCCl
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: Br
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc(Cc2ccc(Cl)cc2)c2ccccc2c1N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of methyl 1-amino-4-bromo-2-naphthoate hydrobromide (1.94 g, 5.37 mmol) in 10 mL of THF at 0° C. under an atmosphere of nitrogen was added (2-chloro-5-pyridyl)methylzinc chloride (41.6 mL, 0.5 M in THF, 83.2 mmol) and bis(tri-tert-butylphosphine)palladium(0) (0.177 g, 0.346 mmol). The reaction was warmed to rt, and after 16 h, treated with water (10 mL). The mixture was diluted dichloromethane and water, and a beige solid was removed via filtration. The filtrate was extracted 2× with dichloromethane and the combined organic fractions were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-20% ethyl acetate in hexanes provide methyl 1-amino-4-(4-chlorobenzyl)-2-naphthoate that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 326.1 for [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:24]12([CH2:34][NH2:35])[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]3)[CH2:25]1)[CH2:31]2>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([NH:35][CH2:34][C:24]12[CH2:33][CH:28]3[CH2:27][CH:26]([CH2:32][CH:30]([CH2:29]3)[CH2:31]1)[CH2:25]2)=[O:6]
Reactant: O=C(O)c1cc(O)ccc1Cl
Reactant: NCC12CC3CC(CC(C3)C1)C2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(O)ccc1Cl
Reaction time: 2.5 h
Yield: 2.6 %

Procedure:
To a solution of 2-chloro-5-hydroxybenzoic acid (3.12 g) in N,N-dimethylformamide (50 ml) was added 1,1′-carbonyldiimidazole (3.0 g). The resulting reaction mixture was stirred for 2.5 h and then 1-adamantanemethylamine (3.0 g) was added. Stirring was continued for 14 h. The reaction mixture was partitioned between ethyl acetate and water and the organic layer was separated, washed with water and brine and then dried over sodium sulphate (Na2SO4). The organic layer was concentrated under reduced pressure to give a residue which was purified by silica gel chromatography (eluting with 3-10% methanol in dichloromethane) to yield the subtitle compound as a white solid (0.15 g).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:16][C:17]([N:19]1[CH:23]([C:24]([OH:26])=[O:25])[CH2:22][C:21]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:20]1)=[O:18])([CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:5])[CH3:2].CN(C)C=O.Cl[CH:39]([O:45][C:46](=[O:51])[C:47]([CH3:50])([CH3:49])[CH3:48])[C:40]([O:42][CH2:43][CH3:44])=[O:41].[F-].[K+]>C(OCC)(=O)C>[CH2:1]([O:3][P:4]([CH2:16][C:17]([N:19]1[CH:23]([C:24]([O:26][CH:39]([O:45][C:46](=[O:51])[C:47]([CH3:50])([CH3:49])[CH3:48])[C:40]([O:42][CH2:43][CH3:44])=[O:41])=[O:25])[CH2:22][C:21]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[N:20]1)=[O:18])([CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:5])[CH3:2]
Reactant: CCOP(=O)(CCCCc1ccccc1)CC(=O)N1N=C(c2ccccc2)CC1C(=O)O
Reactant: CCOC(=O)C(Cl)OC(=O)C(C)(C)C
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(OC(=O)C1CC(c2ccccc2)=NN1C(=O)CP(=O)(CCCCc1ccccc1)OCC)OC(=O)C(C)(C)C
Reaction time: 48 h

Procedure:
A solution of 2.0 g. of (+)-4,5-dihydro-1-[[ethoxy(4-phenylbutyl)phosphinyl]acetyl]-3-phenyl-1H-pyrazole-5-carboxylic acid, from Example 1(c), in 30 ml. of dry dimethylformamide under argon at room temperature is treated with 1.2 g. of ethyl 2-chloro-2-pivaloyloxyacetate, from part (a), and 0.58 g. of anhydrous potassium fluoride. After stirring for 48 hours the mixture is diluted with ethyl acetate and washed with water (3×). The organic fraction is dried (MgSO4) and concentrated in vacuo to give crude product. Flash chromatography on silica gel and elution with acetone/hexane (2:1) gives homogeneous (+)-4,5-dihydro-1-[[ethoxy(4-phenylbutyl)phosphinyl]acetyl]-3-phenyl-1H-pyrazole-5-carboxylic acid, 1-(2,2-dimethyl-1-oxopropoxy)-2-ethoxy-2-oxoethyl ester as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([C:13]2[N:14]=[C:15]([C:18]3[CH:19]=[N:20][C:21]([CH3:24])=[CH:22][CH:23]=3)[S:16][CH:17]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:32](Cl)(Cl)=[O:33].[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>O1CCOCC1.O>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:32]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[O:33])[S:11][C:7]=2[C:6]([C:13]2[N:14]=[C:15]([C:18]3[CH:19]=[N:20][C:21]([CH3:24])=[CH:22][CH:23]=3)[S:16][CH:17]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2csc(-c3ccc(C)nc3)n2)c2sc(N)nc12
Reactant: C1COCCN1
Reactant: O=C(Cl)Cl
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COc1ccc(-c2csc(-c3ccc(C)nc3)n2)c2sc(NC(=O)N3CCOCC3)nc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.1 g of 4-methoxy-7-[2-(6-methyl-pyridin-3-yl)-thiazol-4-yl]-benzothiazol-2-ylamine (0.00028 Mol) were dissolved in dioxane (2 ml) and treated with 0.047 ml triethylamine (0.00034 Mol) and 0.164 ml of phosgene (20% in toluene) (0.00031 Mol). After stirring for 2 hrs. at room temperature 0.122 ml of morpholine (0.0014 Mol) were added and the whole mixture was stirred for 16 hrs. at ambient temperature. Upon addition of water (5 ml) a precipitation formed, which was filtered, washed with water and dried. This crude material was triturated with hot MeOH and after cooling to room temperature filtered. The filtrate was evaporated and the residue subjected to column chromatography (silicagel, CH2Cl2/MeOH+1% NH4OH). The title compound was obtained as a light yellow solid (7%); MS (ISP): m/e=468 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]([C:6]1[CH:11]=[CH:10][C:9](SC)=[C:8]([Cl:14])[CH:7]=1)=[O:5].O[O:17][S:18]([O-:20])=O.[K+].[CH3:22]O>O>[CH3:1][O:2][C:3](=[O:15])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([S:18]([CH3:22])(=[O:20])=[O:17])=[C:8]([Cl:14])[CH:7]=1)=[O:5]
Reactant: O=S([O-])OO
Reactant: COC(=O)C(=O)c1ccc(SC)c(Cl)c1
Reactant: CO
Agent: [K+]
Solvent: O
Product: COC(=O)C(=O)c1ccc(S(C)(=O)=O)c(Cl)c1
Reaction time: 4 h
Yield: 60 %

Procedure:
(3-Chloro-4-methylsulfanyl-phenyl)-oxo-acetic acid methyl ester (prepared as in PCT WO 2004/052869 A1, Example 1, 1.89 g, 7.72 mmol) and oxone (14.26 g, 23.3 mmol) were combined in a mixture of water (4 mL) and methanol (40 mL) and stirred for 4 h. The methanol was evaporated in vacuo and the remaining mixture was treated with water (30 mL) and extracted with ethyl acetate (3×40 mL). The combined organic phases were dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 50% ethyl acetate/hexanes) to afford (3-chloro-4-methanesulfonyl-phenyl)-oxo-acetic acid methyl ester (1.27 g, 60%) as a white solid: H1-NMR (400 MHz, CDCI3) δ=3.32 (3H, s), 4.03 (3H, s), 8.14 (1H, dd, J=8.0 Hz, J=1.6 Hz), 8.23 (1H, d, J=1.6 Hz), 8.30 (1H, d, J=8.0 Hz).
Reaction SMILES: [NH2:1][N:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[CH2:4][CH2:3]1.C([N:16]1[CH2:20][CH2:19][NH:18][C:17]1=O)(=O)C>>[NH:18]1[CH2:19][CH2:20][N:16]=[C:17]1[NH:1][N:2]1[CH2:3][CH2:4][C:5]2[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=2[CH2:7][CH2:8]1
Reactant: NN1CCc2ccccc2CC1
Reactant: CC(=O)N1CCNC1=O
Product: c1ccc2c(c1)CCN(NC1=NCCN1)CC2
Reaction time: 1 h

Procedure:
5 g of (0.03 M) 3-amino-2,3,4,5-tetrahydro-1H-3-benzazepin and 4.3 g of (0.034 M) 1-acetyl-imidazolidin-2-one are stirred in 50 ml POCL3 for 1 hour at 100° C. The remaining process steps are analogous to those set forth in Example 5.
Reaction SMILES: Cl[SiH:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]1[C:11]([CH3:14])([CH3:13])[CH3:12].O1C[CH2:18][CH2:17][CH2:16]1.C=C([Mg]Br)C>CCCCCC>[C:11]([N:3]1[CH:4]=[CH:5][N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[SiH:2]1[C:17]([CH3:18])=[CH2:16])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)N1C=CN(C(C)(C)C)[SiH]1Cl
Reactant: C1CCOC1
Agent: C=C(C)[Mg]Br
Solvent: CCCCCC
Product: C=C(C)[SiH]1N(C(C)(C)C)C=CN1C(C)(C)C
Yield: 47 %

Procedure:
In an argon atmosphere, 8.71 g (37.4 mmol) of Si(tBuNCHCHNtBu)(H)Cl was dissolved in 20 mL of hexane and after adding a (prop-1-en-2-yl)magnesium bromide tetrahydrofuran solution (0.57 mol/L, 69.0 mL, 39.3 mmol), the resulting solution was refluxed for 14 hours. Insoluble matters produced were separated by filtration, and the solvent was removed by distillation from the filtrate under atmospheric pressure. The obtained residue was distilled under reduced pressure (distillation temperature: 80° C./4.3×102 Pa) to obtain 1,3-di-tert-butyl-2-(prop-1-en-2-yl)-1,3-diaza-2-silacyclopent-4-ene (Si(tBuNCHCHNtBu)(H)C(CH3)CH2) as a yellow liquid (yielded amount: 4.18 g, yield: 47%).
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:12][CH:11]2[C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=3[CH3:28])[CH2:17][CH2:16]2)=[O:14])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-].[Na+].[C:31]1([N:37]=[C:38]=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCCC1.C(OCC)(=O)C>[C:1]1([S:7]([N:10]2[CH2:12][CH:11]([C:13]([N:15]3[CH2:16][CH2:17][N:18]([C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=4[CH3:28])[CH2:19][CH2:20]3)=[O:14])[N:37]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:38]2=[O:39])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C=Nc1ccccc1
Reactant: Cc1ccc(C)c(N2CCN(C(=O)C3CN3S(=O)(=O)c3ccccc3)CC2)c1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(C)c(N2CCN(C(=O)C3CN(S(=O)(=O)c4ccccc4)C(=O)N3c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.1 %

Procedure:
To a solution of (RS)-(1-benzenesulfonyl-aziridin-2-yl)-[4-(2,5-dimethyl-phenyl)-piperazin-1-yl]-methanone (0.084 g) in tetrahydrofuran (2 ml) were added sodium iodide (0.035 g) and phenylisocyanate (0.038 g). The mixture was stirred for 3 h at room temperature. The mixture was diluted with ethyl acetate and washed with water, 1% aqueous Na2S2O3 solution and again with water. The organic phase was dried, filtered and evaporated. The product was purified by chromatography (SiO2, cyclohexane/ethyl acetate 4:1=>1:1) to give (RS)-1-benzenesulfonyl-4-[4-(2,5-dimethyl-phenyl)-piperazine-1-carbonyl]-3-phenyl-imidazolidin-2-one (0.071 g) as a colorless solid. MS: 519.3 ([M+H]+)