Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:6]=1.[Li]CCCC.[F:31][C:32]1[CH:33]=[C:34]([C:45]([C:53]2[CH:58]=[CH:57][C:56]([F:59])=[CH:55][CH:54]=2)=[N:46][S@@:47]([C:49]([CH3:52])([CH3:51])[CH3:50])=[O:48])[CH:35]=[C:36]([O:38][C:39]([F:44])([F:43])[CH:40]([F:42])[F:41])[CH:37]=1>C1COCC1>[F:31][C:32]1[CH:33]=[C:34]([C@@:45]([NH:46][S@@:47]([C:49]([CH3:52])([CH3:51])[CH3:50])=[O:48])([C:53]2[CH:54]=[CH:55][C:56]([F:59])=[CH:57][CH:58]=2)[CH2:1][C:2]2[N:3]=[N:4][N:5]([C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:6]=2)[CH:35]=[C:36]([O:38][C:39]([F:43])([F:44])[CH:40]([F:41])[F:42])[CH:37]=1.[F:31][C:32]1[CH:33]=[C:34]([C@:45]([NH:46][S@@:47]([C:49]([CH3:52])([CH3:51])[CH3:50])=[O:48])([C:53]2[CH:54]=[CH:55][C:56]([F:59])=[CH:57][CH:58]=2)[CH2:1][C:2]2[N:3]=[N:4][N:5]([C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:6]=2)[CH:35]=[C:36]([O:38][C:39]([F:43])([F:44])[CH:40]([F:41])[F:42])[CH:37]=1
Reactant: Cc1nnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: CC(C)(C)[S@@](=O)N=C(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[S@@](=O)N[C@@](Cc1nnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Product: CC(C)(C)[S@@](=O)N[C@](Cc1nnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 5-methyl-2-trityl-2H-tetrazole (0.90 g, 2.76 mmol) in dry THF (20 mL) at −78° C. under argon was added dropwise n-BuLi (2.5 M in hexane, 1.2 mL, 3 mmol). The resulting solution was stirred at −78° C. for 1 h, followed by the dropwise addition of a solution of (R)—N-((3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)(4-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide, prepared as described in Procedure 3, 4 and 5, (0.40 g, 0.91 mmol) in THF (5 mL). The reaction mixture was stirred at −78° C. to −70° C. overnight. The reaction mixture was quenched by addition of sat. NH4Cl and the aqueous layer was extracted with Et2O (2×) and the combined organic layers were washed with H2O, sat. NaCl, dried over Na2SO4, filtered and concentrated. The residue was purified by ISCO flash chromatography (silica gel, hexanes/EtOAc) to give (R)—N—((S)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-(2-trityl-2H-tetrazol-5-yl)ethyl)-2-methylpropane-2-sulfinamide as the fast eluting diastereomer (90 mg, 13% yield) and (R)—N—((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-(2-trityl-2H-tetrazol-5-yl)ethyl)-2-methylpropane-2-sulfinamide as the slow eluting diastereomer (85 mg, 12% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:18](=[CH:19][CH:20]=1)[O:17][C:11]1([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)C[C:9]2=[O:21].[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][C:33]2([C:39](=[O:40])[C:38]3[CH:41]=[C:42](Br)[CH:43]=[CH:44][C:37]=3[O:36]2)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[CH3:1][O:2][C:3](=[O:22])/[CH:4]=[CH:5]/[C:42]1[CH:43]=[CH:44][C:37]2[O:36][C:33]3([CH2:34][CH2:35][N:30]([C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:29])[CH2:31][CH2:32]3)[C:39](=[O:40])[C:38]=2[CH:41]=1.[CH3:1][O:2][C:3](=[O:22])/[CH:4]=[CH:5]/[C:6]1[CH:20]=[CH:19][C:18]2[O:17][C:11]3([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:9](=[O:21])[C:8]=2[CH:7]=1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCNCC1)O2
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)Oc1ccc(Br)cc1C2=O
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)C1(CCN(C(=O)OC(C)(C)C)CC1)O2
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)C1(CCNCC1)O2

Procedure:
(E)-3-{1′-Tert-butoxycarbonyl-3-oxo-spiro[benzofuran-2(3H), 4′-piperidin]-5-yl}-acrylic acid methyl ester was synthesized according to the procedure for preparation of Intermediate 1, Step B starting from 5-bromo-3-oxo-spiro[benzofuran-2(3H), 4′-piperidin]-1′-carboxylic acid tert-butyl ester. Purification by column chromatography (eluent hexane/AcOEt:80/20 to 70/30) furnished the desired compound (780 mg).
Reaction SMILES: [CH:1]1([C:6]2[N:10]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[C:19]([C:24]([O:26]C(C)(C)C)=[O:25])=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:14][CH:13]=3)[C:9]3[CH:31]=[C:32]([CH3:36])[C:33]([CH3:35])=[CH:34][C:8]=3[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:1]1([C:6]2[N:10]([CH2:11][C:12]3[CH:13]=[CH:14][C:15]([C:18]4[C:19]([C:24]([OH:26])=[O:25])=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:16][CH:17]=3)[C:9]3[CH:31]=[C:32]([CH3:36])[C:33]([CH3:35])=[CH:34][C:8]=3[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cc2nc(C3CCCC3)n(Cc3ccc(-c4ccccc4C(=O)OC(C)(C)C)cc3)c2cc1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc2nc(C3CCCC3)n(Cc3ccc(-c4ccccc4C(=O)O)cc3)c2cc1C

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-cyclopentyl-5,6-dimethyl-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [ClH:1].C(OC([N:9]1[C@H:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:11]=[C:10]1[NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=1)=O)(C)(C)C>CCOC(C)=O>[ClH:1].[C:14]1([C@H:13]2[C@@H:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[NH:11][C:10]([NH:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=3)=[N:9]2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1C(NCc2cccc(F)c2)=N[C@@H](c2ccccc2)[C@H]1c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: Fc1cccc(CNC2=N[C@@H](c3ccccc3)[C@@H](c3ccccc3)N2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Hydrogen chloride is bubbled into a solution of 87 (1.5 g, 3.37 mmol) in EtOAc (30 mL) for 1 min, and the solution is stirred at RT overnight. The solvent is removed by rotary evaporation, and the residue crystallized from dichloromethane and Et2O to give 1.05 g of the product 88. 1H NMR (DMSO-d6) δ 9.28 (t, 1 H), 8.68 (s, 1 H), 8.15 (s, 1 H), 7.35-7.10 (m, 3 H), 7.10-6.80 (m, 7 H), 6.80-6.50 (m, 4 H), 5.03 (s, 1 H), 4.80-4.45 (m, 2 H); MS: m/z 346 (M++1).
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][NH:5][CH3:6].C(O[C:12](=[O:14])[CH3:13])(=O)C.[OH-].[Na+]>CCOCC.O>[C:12]([N:5]([CH3:6])[CH2:4][CH2:3][N:2]([CH3:7])[CH3:1])(=[O:14])[CH3:13]
Reactant: CNCCN(C)C
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: CC(=O)N(C)CCN(C)C
Temperature: 25 °C
Reaction time: 22 h

Procedure:
N-Acetyl-N,N',N'-trimethylethylenediamine intermediate was prepared in the following manner. N,N,N'-Trimethylethylenediamine (24.5 g, 0.24 mol) was added to acetic anhydride (38 mL, 0.40 mol) over 1.5 hours with cooling in an ice-water bath. After stirring another 22 hours at ambient temperature, the reaction mixture was diluted with 50 mL of ether and 25 mL of water, and then cooled in an ice-water bath. A solution of 25 percent aqueous NaOH was added until the pH was approximately 10 and the phases were separated. The aqueous phase was extracted two more times with ether and the combined organic phase was concentrated on the rotary evaporator (50°,>100 mm Hg). Yield=2.4 g. The aqueous phase was saturated with NaCl and extracted again with methylene chloride (3×25 mL). After evaporation, it gave a total of 33.4 g of yellow liquid. Distillation through a 1×8 cm Vigreux column afforded 23.53 g of colorless liquid, bp 90°-1°/7 mm Hg (68 percent yield).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:19]3[C:24]([Cl:25])=[CH:23][N:22]=[C:21](Cl)[N:20]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:39][O:40][C:41]1[CH:47]=[C:46]([C:48]2[CH2:49][CH2:50][N:51]([CH3:54])[CH2:52][CH:53]=2)[C:45]([N+:55]([O-:57])=[O:56])=[CH:44][C:42]=1[NH2:43]>CC(O)CCC>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:19]3[C:24]([Cl:25])=[CH:23][N:22]=[C:21]([NH:43][C:42]4[CH:44]=[C:45]([N+:55]([O-:57])=[O:56])[C:46]([C:48]5[CH2:53][CH2:52][N:51]([CH3:54])[CH2:50][CH:49]=5)=[CH:47][C:41]=4[O:40][CH3:39])[N:20]=3)=[CH:11]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2nc(Cl)ncc2Cl)c2ccccc21
Reactant: COc1cc(C2=CCN(C)CC2)c([N+](=O)[O-])cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCC(C)O
Solvent: O
Product: COc1cc(C2=CCN(C)CC2)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cn(S(=O)(=O)c3ccccc3)c3ccccc23)n1
Yield: 69.2 %

Procedure:
A mixture of 1-(benzenesulfonyl)-3-(2,5-dichloropyrimidin-4-yl)indole (Intermediate 10, 384 mg, 0.95 mmol), p-toluene sulphonic acid monohydrate (271 mg, 1.43 mmol) and 2-s methoxy-4-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-5-nitroaniline (Intermediate 3, 250 mg, 0.95 mmol) was heated in 2-pentanol (12 mL) at reflux under N2 for 24 h. Further p-toluene sulphonic acid monohydrate (0.090 g, 0.48 mmol) was then added and the mixture was heated at reflux for a further 6 h. The mixture was then concentrated in vacuo and the resulting reside was dissolved into a mixture of CH2Cl2, CH3OH and EtOAc (10 mL, 3 mL and 3 mL). This solution was concentrated in vacuo onto silica. Purification by FCC, eluting with 4-10% CH3OH in CH2Cl2 gave the title compound (415 mg, 56%) as a yellow foam; 1H NMR: 2.29 (1.95H, s), 2.52 (0.7H, m), 2.73 (2.6H, s), 3.18 (1.4H, m), 3.57 (2H, s), 3.96 (3H, s), 5.68 (1H, s), 7.00 (1H, s), 7.11 (1.3H, d), 7.26 (1H, m), 7.44 (1H, m), 7.49 (1.3H, d), 7.64 (2H, t), 7.73 (1H, m), 8.01 (1H, d), 8.07-8.15 (2H, m), 8.19 (1H, d), 8.64 (2H, d), 8.70 (1H, s), 8.97 (1H, s); (the spectrum seems to appear to show a mixture of rotamers, arising due to restricted rotation of bonds within the molecule) m/z: ES+ MH+ 631.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]1[C:14](C)=[N:15][N:16]=[C:9]1[CH:8]=[C:7]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24])([O-:3])=[O:2].I([O-])(=O)(=O)=[O:26].[Na+]>[Ru](=O)=O>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:7](=[O:26])[C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:13]=[CH:12][C:11]=1[N:10]1[CH:14]=[N:15][N:16]=[C:9]1[CH3:8]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: Cc1nnc2cc(-c3ccccc3Cl)c3cc([N+](=O)[O-])ccc3n12
Agent: O=[Ru]=O
Agent: [Na+]
Product: Cc1nncn1-c1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1Cl

Procedure:
In the manner given in Example 3, 7-nitro-1-methyl-5-(o-chlorophenyl)-s-triazolo[4,3-a]quinoline is oxidized at low temperature with sodium periodate with ruthenium dioxide to give 2'-chloro-5-nitro-2-(3-methyl-4H-1,2,4-triazol-4-yl)benzophenone.
Reaction SMILES: [CH2:1]([C:5]1[CH2:6][C@@H:7]2[C@H:10]([CH:11]=1)[C:9](=[CH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]2)[CH2:2][CH2:3]C.O[CH:21](CCC=C)C(CC(C)C)C(O)=O>>[CH2:1]([C:5]1[CH2:6][C@@H:7]2[C@H:10]([CH:11]=1)[C:9](=[CH:12][C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:8]2)[CH:2]([CH3:3])[CH3:21]
Reactant: CCCCC1=C[C@@H]2C(=CC(=O)OC(C)(C)C)C[C@@H]2C1
Reactant: C=CCCC(O)C(CC(C)C)C(=O)O
Product: CC(C)CC1=C[C@@H]2C(=CC(=O)OC(C)(C)C)C[C@@H]2C1

Procedure:
The compound of interest (3.7 g, 67%) was obtained as an oil substance (E/Z mixture) in the same way as in paragraph (10-c) using 3-hydroxy-2-isobutyl-6-heptenoic acid (4.3 g).
Reaction SMILES: [C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[NH2:18][C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1.I([O-])(=O)(=O)=O.[Na+].CO>O>[OH:3][CH:2]1[C@H:1]([N:10]2[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[CH:4]([OH:5])[N:18]1[C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)n1
Reactant: Nc1ncccn1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CO
Product: Nc1ccn([C@@H]2O[C@H](CO)C(O)N(c3ncccn3)C2O)c(=O)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.3 %

Procedure:
To a solution of cytidine (2.43 g) and 2-aminopyrimidine (0.95 g) in water (15 ml) was added sodium metaperiodate (2.13 g) at 15° C. The solution was stirred at ambient temperature for four hours. To the reaction mixture was added methanol (20 ml). A precipitate was filtered off and the filtrate was condenced in vacuo. The condenced solution was lyophilized to give white powder of 1-[(2R, 6R)-3,5-dihydroxy-6-hydroxymethyl-4-(2-pyrimidinyl)morpholin-2-yl]cytosine (3.20 g).
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:8][S:9]([C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[O:25][CH:26]=[CH:27][N:28]=4)=[CH:20][C:19]=3[CH2:29][NH:30][CH3:31])=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:10])=[N:4][O:5][C:6]=1[CH3:7].C(N(CC)CC)C.[C:39]([CH2:43][C:44](Cl)=[O:45])([CH3:42])([CH3:41])[CH3:40].OS([O-])(=O)=O.[Na+]>C(Cl)Cl>[CH3:1][C:2]1[C:3]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[CH:23]=[CH:22][C:21]([C:24]3[O:25][CH:26]=[CH:27][N:28]=3)=[CH:20][C:19]=2[CH2:29][N:30]([CH3:31])[C:44](=[O:45])[CH2:43][C:39]([CH3:42])([CH3:41])[CH3:40])(=[O:11])=[O:10])=[N:4][O:5][C:6]=1[CH3:7]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: CNCc1cc(-c2ncco2)ccc1-c1ccccc1S(=O)(=O)Nc1noc(C)c1C
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1onc(NS(=O)(=O)c2ccccc2-c2ccc(-c3ncco3)cc2CN(C)C(=O)CC(C)(C)C)c1C
Reaction time: 0.08 h

Procedure:
To the title product of Step F in 300 ml of CH2Cl2 at 0° C., triethylamine (6.17 g, 60.96 mmol) was added and stirred for 5 minutes. To the mixture, t-butylacetyl chloride (3.98 g, 29.57 mmol) was added dropwise over 10 minutes. The reaction mixture was stirred at 0° C. for 10 minutes and at room temperature for 1 hr. 100 ml 10% aqueous NaHSO4 was added. The aqueous layer was extracted with 100 ml CH2Cl2. The combined organic extracts were washed with 100 ml H2O, 50 ml brine, dried and concentrated. The residue was chromatographed on silica gel using 60:40:1 hexane/EtOAc/AcOH to provide the title product of this Example (13.10 g, 80% for two steps) as a white solid. melting point=120-128° C. (amorphous).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([S:12]([Cl:15])(=[O:14])=[O:13])[CH:9]=[CH:8][C:4]=1[C:5](O)=O.[NH3:16].[NH2:17][C:18]1[C:23]([NH2:24])=[CH:22][CH:21]=[CH:20][N:19]=1>>[ClH:15].[CH3:1][O:2][C:3]1[CH:11]=[C:10]([S:12]([NH2:16])(=[O:14])=[O:13])[CH:9]=[CH:8][C:4]=1[C:5]1[NH:24][C:23]2[C:18]([N:17]=1)=[N:19][CH:20]=[CH:21][CH:22]=2
Reactant: COc1cc(S(=O)(=O)Cl)ccc1C(=O)O
Reactant: Nc1cccnc1N
Reactant: N
Product: COc1cc(S(N)(=O)=O)ccc1-c1nc2ncccc2[nH]1
Product: Cl

Procedure:
Prepared analogously to Example 47 starting from 2-methoxy-4-chlorosulfonyl-benzoic acid, ammonia, and 2,3-diamino-pyridine.
Reaction SMILES: [OH:1][C@H:2]([CH3:6])[C:3]([NH2:5])=O.F[B-](F)(F)F.C([O+](CC)CC)C.N[C:20]1[C:21]([NH:29][C@H:30]2[CH2:35][CH2:34][C@H:33]([OH:36])[CH2:32][CH2:31]2)=[C:22]2[S:28][CH:27]=[CH:26][C:23]2=[N:24][CH:25]=1>O1CCCC1.C(O)C>[OH:1][C@@H:2]([C:3]1[N:29]([C@H:30]2[CH2:31][CH2:32][C@H:33]([OH:36])[CH2:34][CH2:35]2)[C:21]2=[C:22]3[S:28][CH:27]=[CH:26][C:23]3=[N:24][CH:25]=[C:20]2[N:5]=1)[CH3:6]
Reactant: C[C@@H](O)C(N)=O
Reactant: Nc1cnc2ccsc2c1N[C@H]1CC[C@H](O)CC1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCO
Product: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](O)CC1
Reaction time: 0.25 h

Procedure:
A mixture of (2R)-2-hydroxypropanamide (96 mg, 1.1 mmol) and triethyloxonium tetrafluoroborate (0.20 g, 1.1 mmol) in tetrahydrofuran (2 mL) became a solution after stirred for 15 min. After another 45 min, this solution was added to a mixture of trans-4-[(6-aminothieno[3,2-b]pyridin-7-yl)amino]cyclohexanol (95 mg, 0.36 mmol) in ethanol (2.9 mL) and heated at reflux for 2 h. The resulting mixture was purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (0.9 mg, 0.8%). LCMS calculated for C16H20N3O2S (M+H)+: m/z=318.1. Found: 318.0.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)=O.[CH3:12][C:13]1([CH3:26])[C@@H:15]2[CH2:16][C:17]3[C:21]([C@H:14]12)=[C:20]([CH3:22])[S:19][C:18]=3[C:23](=[O:25])[CH3:24].C[O-].[Na+]>CO.C(OCC)C>[O:25]=[C:23]([C:18]1[S:19][C:20]([CH3:22])=[C:21]2[C:17]=1[CH2:16][C@H:15]1[C:13]([CH3:26])([CH3:12])[C@H:14]12)[CH:24]=[CH:1][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1
Reactant: CC(=O)c1sc(C)c2c1C[C@@H]1[C@H]2C1(C)C
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: Cc1sc(C(=O)C=Cc2ccc(C(=O)O)cc2)c2c1[C@H]1[C@@H](C2)C1(C)C
Reaction time: 2 h
Yield: 57.3 %

Procedure:
A solution of 4-formyl-benzoic acid (1.04 g mg, 6.93 mmol), (1aS,5aR)-1-(1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-ethanone (850 mg, 3.86 mmol), NaOMe (4.17 g, 77.2 mmol) in methanol (30 mL) is stirred at 65° C. for 2 h. Another portion of 4-formyl-benzoic acid (400 mg, 2.66 mmol) is added and stirring is continued at 65° C. for 2 h. The reaction mixture is diluted with diethyl ether (200 mL) and washed with 5% aq. citric acid solution followed by water. The organic phase is dried over MgSO4 and evaporated. The crude product is purified by CC on silica gel eluting with DCM containing 2-7% methanol, followed by crystallisation from methanol:water 1:1 to give 4-[3-oxo-3-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propenyl]-benzoic acid (780 mg) as beige yellow powder; LC-MS: tR=1.06 min, [M+1]+=353.03; 1H NMR (CDCl3): δ 8.13 (d, J=8.2 Hz, 2H), 7.76 (d, J=15.2 Hz, 1H), 7.68 (d, J=8.2 Hz, 2H), 7.29 8d, J=15.8 Hz, 1H), 3.14 (dd, J=5.9, 18.8 Hz, 1H), 2.96 (d, J=18.8 Hz, 1H), 2.44 (s, 3H), 2.00-1.91 (m, 2H), 1.15 (s, 3H), 0.75 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([S:34][CH3:35])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([NH:26][C:27]([C:29]4[CH:33]=[CH:32][S:31][CH:30]=4)=[O:28])[CH:22]=[CH:23][C:24]=3[CH3:25])[C:13]=2[CH2:12][NH:11][C:10]1=[O:36].ClC1C=C(C=CC=1)C(OO)=[O:42]>C(Cl)Cl.CN(C=O)C>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([S:34]([CH3:35])=[O:42])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([NH:26][C:27]([C:29]4[CH:33]=[CH:32][S:31][CH:30]=4)=[O:28])[CH:22]=[CH:23][C:24]=3[CH3:25])[C:13]=2[CH2:12][NH:11][C:10]1=[O:36]
Reactant: CSc1nc(-c2cc(NC(=O)c3ccsc3)ccc2C)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2ccsc2)cc1-c1nc(S(C)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
N-{3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-thiophene-carboxamide (0.052 g, 0.1 mmol) was dissolved in a mixture of CH2Cl2 (10 mL) and DMF (0.5 mL). Then 3-chloroperoxybenzoic acid (50-60%) (0.03 g, ˜0.1 mmol) was added and the mixture stirred for 45 min at room temperature. Solvent was pumped off in vacuo to give the title compound plus a small amount of the corresponding sulfone. The mixture was used without further purification. LC-MS m/z 540 (M+H)+, 1.76 min (ret. time).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9]2[CH:17]=[CH:16][C:12]3=[N:13][O:14][N:15]=[C:11]3[CH:10]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[O:18]1[CH2:20][CH:19]1[C:21]1[CH:30]=[CH:29][C:24]2[C:25](=[O:28])[O:26][CH2:27][C:23]=2[CH:22]=1>>[N:13]1[O:14][N:15]=[C:11]2[CH:10]=[C:9]([CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][N:4]([CH2:20][CH:19]([C:21]4[CH:30]=[CH:29][C:24]5[C:25](=[O:28])[O:26][CH2:27][C:23]=5[CH:22]=4)[OH:18])[CH2:3][CH2:2]3)[CH:17]=[CH:16][C:12]=12
Reactant: c1cc2nonc2cc1CCN1CCNCC1
Reactant: O=C1OCc2cc(C3CO3)ccc21
Product: O=C1OCc2cc(C(O)CN3CCN(CCc4ccc5nonc5c4)CC3)ccc21

Procedure:
5-(2-{4-[2-(2,1,3-benzoxadiazol-5-yl)ethyl]piperazin-1-yl}-1-hydroxyethyl)-2-benzofuran-1(3H)-one was prepared in a similar fashion as to the synthesis described in EXAMPLE 12 starting from 5-[2-(piperazin-1-yl)ethyl]-2,1,3-benzoxadiazole and 5-oxiran-2-yl-2-benzofuran-1(3H)-one. LC/MS: [(M+1)]+=409.
Reaction SMILES: [CH3:1][I:2].[CH3:3][O:4][C:5]1[C:6]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[N:7][S:8][N:9]=1>CC(C)=O>[I-:2].[CH3:3][O:4][C:5]1[C:6]([C:10]2[CH:11]=[N+:12]([CH3:1])[CH:13]=[CH:14][CH:15]=2)=[N:7][S:8][N:9]=1
Reactant: CI
Reactant: COc1nsnc1-c1cccnc1
Solvent: CC(C)=O
Product: COc1nsnc1-c1ccc[n+](C)c1
Product: [I-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of methyl iodide (0.37 ml, 6 mmol) and 3-(4-methoxy-1,2,5-thiadiazol-3-yl)pyridine (500 mg, 2.5 mmol) in acetone (10 ml) was stirred at room temperature for 18 h. The title compound precipitated from the solution and was collected by filtration. Yield: 1.0 g (100%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:6][C:3]=1[C:4]#[N:5].[O-:20][C:21]#[N:22].[Na+].FC(F)(F)C(O)=O>ClCCl>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][C:8]([O:10][CH3:11])=[C:7]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:6]=2)[N:1]=[C:21]([OH:20])[N:22]=1
Reactant: N#C[O-]
Reactant: COc1cc(N)c(C#N)cc1OCc1ccccc1
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2nc(O)nc(N)c2cc1OCc1ccccc1
Reaction time: 0.75 h
Yield: 60.5 %

Procedure:
A solution of 2-amino-5-benzyloxy-4-methoxybenzonitrile (26.7 g, 0.10 mol) in dichloromethane was treated with sodium cyanate (17.1 g, 0.26 mol) and then trifluoroacetic acid (20.9 ml, 0.26 mol) was added dropwise to the resulting mixture at room temperature. After 45 minutes, the mixture was diluted with dichloromethane (11) and stirred for a further 18 hours. The mixture was then concentrated under reduced pressure and partitioned between methanol and 2N aqueous sodium hydroxide and stirred for 2 hours. The methanol was then removed under reduced pressure and the yellow solid isolated by filtration, washing sequentially with water, acetone and diethyl ether to afford the subtitle compound as a yellow solid (18.0 g, 54%). A further quantity of product was obtained by concentration of the filtrate, acidification with concentrated hydrochloric acid (95 ml), warming on a steam bath for 5 minutes, cooling and neutralisation with solid potassium carbonate. The solid obtained was isolated by filtration, washing sequentially with water, ethanol and diethyl ether to afford the subtitle compound as a yellow solid (12.11 g, 93% combined yield). Rf 0.23 (0.880 aqueous ammonia:methanol:dichloromethane 2:14:84, v/v). MS m/z 298 (MH)+.
Reaction SMILES: C([O:3][C:4](=[O:32])/[CH:5]=[C:6](\[CH3:31])/[CH:7]=[CH:8]/[C@@H:9]1[CH2:11][C@@:10]1([C:13]1[CH:14]=[C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[C:16]2[O:20][CH2:19][C:18]([CH3:22])([CH3:21])[C:17]=2[CH:23]=1)[CH3:12])C.C(O)C.[OH-].[Na+].O>C(#N)C>[CH3:21][C:18]1([CH3:22])[C:17]2[CH:23]=[C:13]([C@@:10]3([CH3:12])[CH2:11][C@H:9]3/[CH:8]=[CH:7]/[C:6](/[CH3:31])=[CH:5]/[C:4]([OH:32])=[O:3])[CH:14]=[C:15]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH3:30])[C:16]=2[O:20][CH2:19]1
Reactant: CCOC(=O)/C=C(C)/C=C/[C@@H]1C[C@]1(C)c1cc(-c2ccccc2C)c2c(c1)C(C)(C)CO2
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Solvent: CCO
Product: CC(/C=C/[C@@H]1C[C@]1(C)c1cc(-c2ccccc2C)c2c(c1)C(C)(C)CO2)=C\C(=O)O

Procedure:
Following General Procedure H and using 5-[(1S, 2S)-2-(3,3-dimethyl-7-o-tolyl-2,3-dihydro-benzofuran-5-yl)-2-methyl-cyclopropyl]-3-methyl-penta-2E,4E-dienoic acid ethyl ester (Compound 25, 0.096 g, 0.22 mmol), ethanol (20 mL), and 5M aqueous sodium hydroxide (5 mL) followed by preparative reverse phase HPLC using 10% water in acetonitrile as the mobile phase, the title compound was obtained (0.044 g, 45%) as a white solid.