Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:15]2[CH:14]=[CH:13][C:12]([C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=3)=[CH:11][C:10]=2[S:9](=[O:26])[C:8]2[C:3]1=[CH:4][CH:5]=[C:6]([C:27]1[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=1)[CH:7]=2.ClC1C=CC=C(C(OO)=[O:45])C=1>>[CH3:1][N:2]1[C:3]2[CH:4]=[CH:5][C:6]([C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=3)=[CH:7][C:8]=2[S:9](=[O:45])(=[O:26])[C:10]2[C:15]1=[CH:14][CH:13]=[C:12]([C:16]1[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=1)[CH:11]=2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CN1c2ccc(-c3ccc4ccccc4c3)cc2S(=O)c2cc(-c3ccc4ccccc4c3)ccc21
Product: CN1c2ccc(-c3ccc4ccccc4c3)cc2S(=O)(=O)c2cc(-c3ccc4ccccc4c3)ccc21

Procedure:
For the preparation as a by-product in the synthesis of 10-methyl-3,7-bis(2-naphthyl)phenothiazine 5-oxide, see under Example 8. For a selective preparation of the sulfone, at least two molar equivalents of m-chloroperbenzoic acid are used. Yellowish microcrystals having a melting point of 328-332° C. were obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:12]3[CH2:15][C:14](CO)([OH:16])[CH2:13]3)=[N:9][C:10]=2[I:11])[CH:5]=[CH:6][N:7]=1.I([O-])(=O)(=O)=O.[Na+]>C1COCC1.O.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:12]3[CH2:13][C:14](=[O:16])[CH2:15]3)=[N:9][C:10]=2[I:11])[CH:5]=[CH:6][N:7]=1
Reactant: OCC1(O)CC(c2nc(I)c3c(Cl)nccn23)C1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1CC(c2nc(I)c3c(Cl)nccn23)C1
Temperature: 25 °C

Procedure:
A solution of 3-(8-chloro-1-iodoimidazo[1,5-a]pyrazin-3-yl)-1-hydroxymethylcyclobutanol (4.08 g, 0.011 mol) in THF (120 mL) and water (40 mL) was charged with sodium periodate (2.8 g, 0.013 mol) at 0° C. The reaction warmed to rt and stirred for h. The reaction mixture was diluted with ethyl acetate and then washed with brine. The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo to afford the title compound as a yellow solid; 1H NMR (CDCl3, 400 MHz) δ 7.56 (1H, d, J=4.94), 7.32 (1H, d, J=4.98), 3.64 (5H, m); MS (ES+): m/z 347.82 and 349.85 [MH+]; HPLC: tR=2.89 min. (OpenLynx, polar—5 min.).
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:21])[CH2:16][CH:17]([OH:20])[CH2:18]O)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CCOC(C)=O.CCCCCCC>ClCCCl>[CH2:1]([C:9]1[CH:10]=[CH:11][C:12]([CH:15]2[O:21][CH2:18][CH:17]([OH:20])[CH2:16]2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCc1ccc(C(O)CC(O)CO)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCCCCCCCc1ccc(C2CC(O)CO2)cc1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 65.5 %

Procedure:
4-(4-octylphenyl)butane-1,2,4-triol (12 g, 40.6 mmol) was dissolved in 1,2-Dichloroethane (815 ml) under nitrogen. p-Toluenesulfonic acid monohydrate (1.55 g, 8.2 mmol) (TCI) was added and the reaction heated at about 50° C. for about 3 h. TLC in 1:1 EtOAc/heptane showed (PMA visualization) reaction complete. The solution was washed with saturated sodium bicarbonate and extract with methylene chloride (2×). The combined extracts were washed with brine, dried over sodium sulfate, filtered, and evaporated to a yellow oil. The resulting oil was chromatographed on 330 g redi-sep column eluting with 20% EtOAc in heptane for 10 min ramping to 50% over 20 min and then holding at 50% until all the product was off (monitor at 223 nm due to weak chromaphore at longer wavelengths). Removed solvent under reduced pressure to provide 5-(4-octylphenyl)tetrahydrofuran-3-ol (7.36 g, 26.6 mmol, 73.3% yield) as a colorless oil: LC/MS (method A) Rt=3.76 min.; MS m/z: 277.15 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[S:15][C:14]([CH2:16][NH:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:30])([F:29])[F:28])(=[O:20])=[O:19])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].Br[CH2:32][CH:33]1[CH2:35][CH2:34]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C>[CH:33]1([CH2:32][N:17]([CH2:16][C:14]2[S:15][C:11]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=3)=[CH:12][CH:13]=2)[S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]([F:30])([F:28])[F:29])(=[O:20])=[O:19])[CH2:35][CH2:34]1
Reactant: BrCC1CC1
Reactant: CS(=O)(=O)c1cccc(-c2ccc(CNS(=O)(=O)c3ccccc3C(F)(F)F)s2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CS(=O)(=O)c1cccc(-c2ccc(CN(CC3CC3)S(=O)(=O)c3ccccc3C(F)(F)F)s2)c1

Procedure:
In analogy to example 10, step 3, N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-2-trifluoromethyl-benzenesulfonamide (example 27, step 1) was reacted with (bromomethyl)-cyclopropane and cesium carbonate in N,N-dimethylacetamide to give N-cyclopropylmethyl-N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-2-trifluoromethyl-benzenesulfonamide as a light yellow oil. MS: 546.8 ([M+NH4]+)
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([Cl:28])[CH:21]=2)[C:10]2[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([Cl:28])[CH:21]=3)[C:10]3[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc(C)c(C)c23)cc1Cl
Product: COc1ccc(CNc2nc(-n3cncn3)nc3sc(C)c(C)c23)cc1Cl

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-5,6-dimethyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-5,6-dimethyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][CH2:18][CH3:19])[C:11](=[O:20])[N:10]([CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][CH:24]=4)[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.O.NN.[H][H]>[Pd]>[NH2:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][CH2:21][N:10]2[C:9]3[N:8]=[C:7]([CH2:6][C:5]4[CH:32]=[CH:33][C:2]([F:1])=[CH:3][CH:4]=4)[NH:15][C:14]=3[C:13](=[O:16])[N:12]([CH2:17][CH2:18][CH3:19])[C:11]2=[O:20])=[CH:28][CH:27]=1
Reactant: [H][H]
Reactant: CCCn1c(=O)c2[nH]c(Cc3ccc(F)cc3)nc2n(CCc2ccc([N+](=O)[O-])cc2)c1=O
Agent: [Pd]
Agent: NN
Solvent: O
Product: CCCn1c(=O)c2[nH]c(Cc3ccc(F)cc3)nc2n(CCc2ccc(N)cc2)c1=O

Procedure:
By the method of Example 2, 4-fluorophenylacetic acid is reacted with 5,6-diamino-1-[2-(4-nitrophenyl)ethyl]-3-propyluracil (6) to yield 8-(4-fluorobenzyl)-3-[2-(4-nitrophenyl)ethyl]-1-propylxanthine. By methods well known in the art, 8-(4-fluorobenzyl)-3-[2-(4-nitrophenyl)ethyl]-1-propylxanthine is reduced with hydrazine hydrate or hydrogen gas in the presence of a palladium catalyst to yield 3-[2-(4-aminophenyl)ethyl]-8-(4-fluorobenzyl)-1-propylxanthine.
Reaction SMILES: N[C:2](N)=[S:3].BrC[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1.[OH-].[K+].Cl>C(O)C.O>[SH:3][CH2:2][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1
Reactant: BrCc1ccc2ccccc2c1
Reactant: NC(N)=S
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: SCc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 91.9 %

Procedure:
Utilizing the procedure of G. G. Urquhart, J. W. Gates and R. Conner, Org. Syn. Coll. Vol. 3, p. 363, thiourea (6.89 g, 90.5 mmol) was added to a solution of 2-(bromomethyl)naphthalene (20.6 g, 90.5 mmol) in anhydrous ethanol (100 mL) and then heated at reflux. After 17 h, the reaction solution was concentrated to an oil. The oil was dissolved in a solution of potassium hydroxide (11.2 g, 199 mmol) in water (100 mL) and heated at reflux for 2 h. The solution was then cooled to 25° C. and treated with aqueous hydrochloric acid (2.0N). The resulting aqueous mixture was extracted with ethyl acetate (3×). The combined ethyl acetate extracts were dried over magnesium sulfate, filtered and evaporated to give yellow crystals (14.5 g, 91.9% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)COc1ccc([N+](=O)[O-])cc1
Temperature: 70 °C
Reaction time: 4 h
Yield: 86.1 %

Procedure:
4-Nitrophenol (13.9 g, 100 mmol) was dissolved in N,N-dimethylformamide (20 ml), and t-butyl bromoacetate (29.3 g, 150 mmol) and potassium carbonate (27.6 g, 200 mmol) were added, which was followed by stirring at 70° C. for 4 hours. The reaction mixture was diluted with ethyl acetate (100 ml), washed with water, and the aqueous layer was extracted with ethyl acetate. The extract and the previously-obtained organic layer were combined. The mixture was washed with water and dried over anhydrous magnesium sulfate. After filtration, low boiling matters were distilled away from the filtrate under reduced pressure, and the residue was purified by silica gel column chromatography. (n-hexane/ethyl acetate=5/1) and recrystallized from a mixed solvent of ethyl acetate and n-hexane to give 21.8 g of t-butyl 4-nitrophenoxyacetate as pale-yellow crystals (86%).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]([OH:10])=O)[CH3:2].C1C=CC2N(O)N=NC=2C=1.[O:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][NH:29][C:30]([C:32]2[CH:37]=[CH:36][C:35]([N:38]3[CH2:43][CH2:42][CH:41]([NH:44][C:45]([N:47]4[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]4)=[O:46])[CH2:40][CH2:39]3)=[CH:34][CH:33]=2)=[O:31])[CH2:23][CH2:22]1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[CH2:1]([N:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]([N:50]1[CH2:51][CH2:52][N:47]([C:45]([NH:44][CH:41]2[CH2:42][CH2:43][N:38]([C:35]3[CH:34]=[CH:33][C:32]([C:30](=[O:31])[NH:29][CH2:28][CH2:27][N:24]4[CH2:23][CH2:22][O:21][CH2:26][CH2:25]4)=[CH:37][CH:36]=3)[CH2:39][CH2:40]2)=[O:46])[CH2:48][CH2:49]1)=[O:10])[CH3:2]
Reactant: CCn1cccc1C(=O)O
Reactant: O=C(NCCN1CCOCC1)c1ccc(N2CCC(NC(=O)N3CCNCC3)CC2)cc1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1cccc1C(=O)N1CCN(C(=O)NC2CCN(c3ccc(C(=O)NCCN4CCOCC4)cc3)CC2)CC1
Temperature: 80 °C

Procedure:
1-ethylpyrrole-2-carboxylic acid (139 mg, 1.0 mmol) was dissolved in DMF (3.0 ml), and WSCD (230 mg, 1.2 mmol), HOBt (168 mg, 1.2 mmol), and N-(1-(4-(2-morpholinoethylcarbamoyl)phenyl)-piperidin-4-yl)-1-piperazinecarboxamide (400 mg, 0.9 mmol) obtained in Example 15(5) was added thereto, followed by stirring under heat at 80° C. for 14 hours. After the reaction mixture was allowed to cool to room temperature, a saturated sodium bicarbonate aqueous solution was added to the reaction mixture, followed by extraction with chloroform. The extract was washed with water and saturated sodium chloride, and then dried over anhydrous sodium sulfate. After the desiccant was filtered off, the residue obtained by evaporation under reduced pressure was purified using medium-pressure silica gel flash column chromatography (methanol:chloroform=1:30 to 1:10), thereby obtaining 4-((1-ethylpyrrol-2-yl)-carbonyl)-N-(1-(4-(2-morpholinoethylcarbamoyl)phenyl)-piperidin-4-yl)-1-piperazinecarboxamide (213 mg, 42%) as a milky-white solid.
Reaction SMILES: [Cl:1]C1C=CC(C([C@@:8]2([OH:33])[C@@H:12]([CH2:13][O:14]C(=O)C3C=CC(Cl)=CC=3)[O:11][C@@H:10]([N:24]3[CH:31]=[C:30]([CH3:32])[C:28]([NH2:29])=[N:27][C:25]3=[O:26])[CH2:9]2)=O)=CC=1.[OH-].[Na+].Cl>CO>[ClH:1].[CH3:32][C:30]1[C:28]([NH2:29])=[N:27][C:25](=[O:26])[N:24]([CH:31]=1)[C@@H:10]1[O:11][C@H:12]([CH2:13][OH:14])[C@@H:8]([OH:33])[CH2:9]1
Reactant: Cc1cn([C@H]2C[C@@](O)(C(=O)c3ccc(Cl)cc3)[C@@H](COC(=O)c3ccc(Cl)cc3)O2)c(=O)nc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)nc1N
Temperature: 45 °C
Reaction time: 8 h
Yield: 97.3 %

Procedure:
To the suspension of 0.71 g of 3′,5′-O-bis(4-chlorobenzoyl)-5-methyl-2′-deoxycytidine in 4 mL of methanol was added 0.7 mL of the solution of sodium hydroxide in methanol (prepared by dissolving 100 mg of sodium hydroxide in 4 mL of methanol), and the mixture was heated at 45° C. for 5 hours with stirring. After cooling, the mixture was neutralized with a solution of hydrogen chloride in methanol, and methanol was evaporated off. After chloroform and water were added to the residue, the layers were separated, and the aqueous layer was washed with chloroform. The aqueous layer was concentrated and acidified with 6N aqueous hydrogen chloride solution, and after the addition of 5 mL of acetone, allowed to stand overnight at −14° C. The precipitated solid was filtered and dried to give 0.37 g of 5-methyl-2′-deoxycytidine hydrochloride as a light brown solid. Yield 97%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C@H:8]([CH2:13][NH:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20](Br)[CH:21]=2)[CH:16]=1)[C@@H:9]([CH3:12])[CH2:10][CH3:11])([CH3:4])([CH3:3])[CH3:2].[CH:27]1(B2OC(C)(C)C(C)(C)O2)[CH2:29][CH2:28]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].COCCOC>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[C:1]([O:5][C:6](=[O:26])[NH:7][C@H:8]([CH2:13][NH:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH:27]3[CH2:29][CH2:28]3)[CH:21]=2)[CH:16]=1)[C@@H:9]([CH3:12])[CH2:10][CH3:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC[C@H](C)[C@@H](CNc1ccc2cc(Br)ccc2c1)NC(=O)OC(C)(C)C
Reactant: CC1(C)OB(C2CC2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: CC[C@H](C)[C@@H](CNc1ccc2cc(C3CC3)ccc2c1)NC(=O)OC(C)(C)C
Temperature: 130 °C
Yield: 55.9 %

Procedure:
{(1S,2S)-1-[(6-Bromo-naphthalen-2-ylamino)-methyl]-2-methyl-butyl}-carbamic acid tert-butyl ester (210 mg, 0.5 mmol), 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (336 mg, 2.0 mmol), Pd(dppf)2Cl2 (82 mg, 0.1 mmol), K3PO4 (320 mg, 1.5 mmol) was combined in the mixture of DME (2.4 mL) and water (0.6 mL). The reaction mixture was heated at 130° C. for 10 mins under Microwave condition. The reaction mixture was cooled to r.t. and was quenched by the slow addition of 1N NaOH solution (15 mL). The reaction mixture was transferred to a separatory funnel containing water (20 mL). The aqueous layer was extracted with DCM (3×50 mL). The combined organic layers were washed with brine (50 mL), dried over MgSO4, filtered and concentrated. The residue was purified on silica gel (7%→17% ethyl acetate in hexanes) to afford {(1S,2S)-1-[(6-cyclopropyl-naphthalen-2-ylamino)-methyl]-2-methyl-butyl}-carbamic acid tert-butyl ester (107 mg, 60% yield) as a light brown solid: LC/MS (ESI) m/e 383.3 [(M+H)+, calcd for C24H34N2O2 382.6].
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH:8]([C:11]([O:13]CC)=[O:12])[S:7]1)=[O:5])[CH3:2].[OH-].[K+].C(OCC)C.Cl>C(O)C.O>[C:11]([CH:8]1[CH2:9][CH2:10][CH:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[S:7]1)([OH:13])=[O:12]
Reactant: CCOC(=O)C1CCC(C(=O)OCC)S1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Solvent: O
Product: CCOC(=O)C1CCC(C(=O)O)S1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.8 %

Procedure:
To a solution of 2,5-diethoxycarbonyltetrahydrothiophene (2.4 g) in ethanol (10 ml), potassium hydroxide (0.64 g) dissolved in ethanol (10 ml) was added dropwise and the mixture was stirred for 1 hour at room temperature. To the reaction mixture, diethyl ether and water were added. Aqueous layer was acidified with 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo to give 1.6 g (78%) of 2-carboxy-5-ethoxycarbonyltetrahydrothiophene.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[S:10][C:11]([NH:38]C(=O)OC(C)(C)C)=[C:12]([C:14](=[O:37])[NH:15][C:16]2[CH:17]=[N:18][N:19]([CH3:36])[C:20]=2[CH:21]2[CH2:27][CH2:26][CH:25]([NH:28]C(=O)C(F)(F)F)[CH:24]([F:35])[CH2:23][CH2:22]2)[N:13]=1.Cl.O1CCOCC1.C([O-])([O-])=O.[K+].[K+]>CO>[NH2:38][C:11]1[S:10][C:9]([C:3]2[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=2[F:8])=[N:13][C:12]=1[C:14]([NH:15][C:16]1[CH:17]=[N:18][N:19]([CH3:36])[C:20]=1[CH:21]1[CH2:22][CH2:23][C@@H:24]([F:35])[C@H:25]([NH2:28])[CH2:26][CH2:27]1)=[O:37]
Reactant: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1C1CCC(F)C(NC(=O)C(F)(F)F)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CO
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1C1CC[C@@H](N)[C@H](F)CC1
Temperature: 60 °C

Procedure:
To a solution/suspension of tert-butyl 2-(2,6-difluorophenyl)-4-(5-(4-fluoro-5-(2,2,2-trifluoroacetamido)cycloheptyl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate (Diastereomer 1) (49 mg, 0.074 mmol) in MeOH (2 mL) was added a solution of HCl in dioxane (4 M, 1.9 mL, 7.42 mmol) and the mixture was heated at 60° C. for 72 hr. The solvent was removed under reduced pressure and the residue was dissolved in MeOH/water (5 mL/5 mL) and treated with K2CO3 (51 mg, 0.37 mmol). The mixture was heated at 65° C. for 18 hr. The MeOH was removed under reduced pressure and the aqueous residue was extracted with 5% MeOH/DCM (2×30 mL). The organic layers were combined, dried over MgSO4 and concentrated under reduced pressure. The residue was dissolved in MeOH and loaded onto an SCX column. The column was washed with MeOH, eluted with 3 N ammonia in MeOH and the solvent removed under reduced pressure to give 357 (Diastereomer 1) as a beige solid (10 mg, 29% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.44 (s, 1H), 7.76 (s, 1H), 7.35-7.28 (m, 1H), 7.07-6.99 (m, 2H), 6.11 (s, 2H), 4.46-4.29 (m, 1H), 3.83 (s, 3H), 3.23-3.13 (m, 1H), 2.84-2.76 (m, 1H), 2.26-1.81 (m, 6H), 1.60-1.40 (m, 2H). Alkyl NH2 not observed. LCMS (ES+) m/z 465 (M+1)
Reaction SMILES: [Cl:1][C:2]([Cl:33])([Cl:32])[CH2:3][O:4][C:5](=[O:31])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:29])[NH:21][C:22]3[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=3)=[CH:16][C:15]=2[NH2:30])=[CH:9][CH:8]=1.C([C:36]1[C:37]([N:45]=[CH:46][N:47]([CH3:49])C)=[N:38][C:39]([CH:42]([CH3:44])[CH3:43])=[CH:40][CH:41]=1)#N>C(O)(=O)C>[Cl:33][C:2]([Cl:1])([Cl:32])[CH2:3][O:4][C:5](=[O:31])[NH:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:29])[NH:21][C:22]3[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=3)=[CH:16][C:15]=2[NH:30][C:49]2[C:36]3[CH:41]=[CH:40][C:39]([CH:42]([CH3:43])[CH3:44])=[N:38][C:37]=3[N:45]=[CH:46][N:47]=2)=[CH:11][CH:12]=1
Reactant: Nc1cc(C(=O)Nc2ccc(Br)cc2)ccc1Oc1ccc(NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: CC(C)c1ccc(C#N)c(N=CN(C)C)n1
Solvent: CC(=O)O
Product: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4ccc(Br)cc4)ccc3Oc3ccc(NC(=O)OCC(Cl)(Cl)Cl)cc3)ncnc2n1
Temperature: 140 °C
Yield: 64 %

Procedure:
A mixture of the products of Example 361E (2.39 g, 4.2 mmol) and Example 8E (N′-(3-cyano-6-isopropyl-pyridin-2-yl)-N,N-dimethyl-formamidine) (0.91 g, 4.2 mmol) in 10 mL of glacial acetic acid was heated in a 140° C. preheated oil bath for 45 minutes. The reaction mixture was cooled, evaporated in vacuo and the residue partitioned between ethyl acetate (250 mL) and water (100 mL). The organic phase was then washed with saturated aqueous sodium bicarbonate and then brine, dried over anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure. The resulting residue was triturated with methanol, filtered, and dried in vacuo to provide the title compound (2.0 g, 64%) as a beige solid. MS (ESI+) m/z 743/745 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ ppm: 1.31 (d, J=6.62 Hz, 6 H), 3.10-3.27 (m, 1 H), 4.93 (s, 2 H), 6.93-7.05 (m, 3 H), 7.39-7.62 (m, 5 H), 7.77 (d, J=8.82 Hz, 2 H), 8.17 (s, 1 H), 8.60 (s, 1 H), 8.78 (d, J=8.09 Hz, 1 H), 10.08 (s, 1 H), 10.16 (s, 1 H), 10.35 (s, 2 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH2:13][CH2:14][OH:15])=[CH:5][CH:4]=1.C(N(CC)CC)C.[S:23](Cl)([CH3:26])(=[O:25])=[O:24].O>ClCCl>[CH3:26][S:23]([O:15][CH2:14][CH2:13][C:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[CH:7]=[CH:8][CH:9]=1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc2cccc(CCO)c2c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2cccc(CCOS(C)(=O)=O)c2c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
2-(7-Methoxy-1-naphthyl)ethanol (25 mmol) and triethylamine (30 mmol) are dissolved in 50 ml of dichloromethane and the reaction mixture is cooled to 0° C. using an ice bath. Mesyl chloride (30 mmol) is added dropwise and the reaction mixture is stirred at ambient temperature for 2 hours and then poured into 100 ml of water. The organic phase is washed with 1M hydrochloric acid solution and then with water, dried over magnesium sulphate and evaporated. The oil obtained is precipitated from a mixture of diethyl ether/petroleum ether (1/1). The title product is filtered off under suction and then recrystallised from to diisopropyl ether.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](/[CH:11]=[CH:12]\[C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)[CH:7]=[CH:8][C:9]=1[CH3:10])([O-])=O>C(O)(=O)C.ClCCl.[Zn]>[NH2:1][C:4]1[CH:5]=[C:6](/[CH:11]=[CH:12]\[C:13]2[CH:14]=[C:15]([O:23][CH3:24])[C:16]([O:21][CH3:22])=[C:17]([O:19][CH3:20])[CH:18]=2)[CH:7]=[CH:8][C:9]=1[CH3:10]
Reactant: COc1cc(/C=C\c2ccc(C)c([N+](=O)[O-])c2)cc(OC)c1OC
Agent: [Zn]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cc(/C=C\c2ccc(C)c(N)c2)cc(OC)c1OC
Reaction time: 1 h
Yield: 49.1 %

Procedure:
65 mg of (Z)-1-(3-nitro-4-methylphenyl)-2-(3,4,5-trimethoxyphenyl) ethene were dissolved in 4 ml of acetic acid and 4 ml of dichloromethane, and 300 mg of zinc were added thereto and stirred for one hour. The reaction liquid was filtered, concentrated and purified by silica gel column chromatography (dichloromethane:hexane=2.1 by volume) to obtain 29 mg of the intended compound. The yield was 46.5%.
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8](=[O:12])(=[O:11])[NH:9][CH3:10])=[CH:6][C:5]([C:13]2[N:14]([C:32](Cl)=[O:33])[CH:15]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[CH:16]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[N:17]=2)=[C:4]([O:35][CH2:36][CH3:37])[CH:3]=1.O.[OH:39][N:40]1[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=2[N:42]=[N:41]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[N:40]1([O:39][C:32]([N:14]2[C@H:15]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[C@H:16]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)[N:17]=[C:13]2[C:5]2[CH:6]=[C:7]([S:8](=[O:12])(=[O:11])[NH:9][CH3:10])[C:2]([Cl:1])=[CH:3][C:4]=2[O:35][CH2:36][CH3:37])=[O:33])[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=2[N:42]=[N:41]1
Reactant: On1nnc2ccccc21
Reactant: CCOc1cc(Cl)c(S(=O)(=O)NC)cc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(Cl)c(S(=O)(=O)NC)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)On1nnc2ccccc21

Procedure:
In an analogous manner as described in example 29, 5-[4,5-bis-(4-chloro-phenyl)-4,5-dihydro-1H-imidazol-2-yl]-2-chloro-4-ethoxy-N-methyl-benzenesulfonamide was treated with phosgene and diisopropylethylamine in methylene chloride to give 2-(4-chloro-2-ethoxy-5-methylsulfamoyl-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride. The crude carbamoyl chloride was then reacted with 1-hydroxybenzotriazole hydrate and diisopropylethylamine in methylene chloride to give the racemic 2-(4-chloro-2-ethoxy-5-methylsulfamoyl-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carboxylic acid benzotriazol-1-yl ester after purification by flash column chromatography (silica gel, eluting with a gradient of ethyl acetate in hexanes).