Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[CH:6]=[CH:5]2.[O:18]1[CH2:20][C@H:19]1[CH2:21][O:22][C:23]1[C:28]2[O:29][CH:30]=[CH:31][C:27]=2[CH:26]=[CH:25][CH:24]=1>CO>[OH2:18].[O:29]1[CH:30]=[CH:31][C:27]2[CH:26]=[CH:25][CH:24]=[C:23]([O:22][CH2:21][C@@H:19]([OH:18])[CH2:20][N:15]3[CH2:14][CH2:13][CH:12]([C:7]4[CH:6]=[CH:5][C:4]5[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=5)[CH:8]=4)[CH2:17][CH2:16]3)[C:28]1=2
Reactant: Fc1ccc2cc(C3CCNCC3)ccc2c1
Reactant: c1cc(OC[C@@H]2CO2)c2occc2c1
Solvent: CO
Product: O
Product: O[C@H](COc1cccc2ccoc12)CN1CCC(c2ccc3cc(F)ccc3c2)CC1

Procedure:
A solution 4-(2-(6-fluoro)naphthyl)piperidine (0.0692 g, 0.302 mmol, prepared in example 19) and (S)-(+)-7-(oxiranylmethoxy)-benzo[b]furan (0.0574 g, 0.302 mmol) in methanol (3 mL) was refluxed for 18 hours and then cooled and evaporated. The residue was purified using silica gel chromatography (dichloromethane/5% methanol in dichloromethane gradient elution) to give the title compound as a white amorphous solid (0.067 g, 53%). FDMS m/e=420 (M++1). [α]D=2.14 (c 0.467, methanol). C26H26NO3F.0.2H2O
Reaction SMILES: O=[C:2]1[CH2:8][C@H:7]2[N:4]([C:5](=[O:26])[C@H:6]2[C:9]([CH3:25])([O:11][C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[O:13])[CH3:10])[C@H:3]1[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=1)=[O:28].C(N(C(C)C)CC)(C)C.P(Cl)(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.[SH:66][CH2:67][CH2:68][NH:69][C:70](=[O:72])[CH3:71]>CN(C1C=CN=CC=1)C.C(#N)C.C(OCC)(=O)C>[C:70]([NH:69][CH2:68][CH2:67][S:66][C:2]1[CH2:8][C@H:7]2[N:4]([C:5](=[O:26])[C@H:6]2[C:9]([CH3:10])([O:11][C:12]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=2)=[O:13])[CH3:25])[C:3]=1[C:27]([O:29][CH2:30][C:31]1[CH:32]=[CH:33][C:34]([N+:37]([O-:39])=[O:38])=[CH:35][CH:36]=1)=[O:28])(=[O:72])[CH3:71]
Reactant: CC(C)(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)C[C@H]12
Reactant: CC(=O)NCCS
Agent: CN(C)c1ccncc1
Agent: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(=O)NCCSC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@@H](C(C)(C)OC(=O)OCc3ccc([N+](=O)[O-])cc3)[C@H]2C1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 81.4 %

Procedure:
To a solution of 4-nitrobenzyl (2R,5R,6R)-3,7-dioxo-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-1-azabicyclo[3.2.0]heptane-2-carboxylate (58 mg) and 4-(N,N-dimethylamino)pyridine (1.3 mg) in acetonitrile (3 ml) was added a solution of diisopropylethylamine (22.4 μl) in acetonitrile (0.21 ml) at 0° C. To the mixture was added a solution of diphenyl chlorophosphate (23.3 μl) in acetonitrile (0.21 ml) at 0° C. After stirring at 0° C. for 1.5 hours, the reaction mixture was cooled to -15° C., to which a solution of diisopropylethylamine (74.6 μl) in acetonitrile (0.73 ml) was added. To the mixture was added a solution of N-(2-mercaptoethyl)acetamide (13.4 mg) in acetonitrile (0.12 ml). After standing overnight at -15° C., the mixture was diluted with ethyl acetate (50 ml), washed in turn with water and saturated aqueous sodium chloride, and dried over magnesium sulfate. After evaporation of the solvent, the residue was chromatographed on silica gel (2 g) eluting with a mixture of methylene chloride and acetone (20:1 to 2:1) to give 4-nitrobenzyl (5R,6R)-3-(2-acetamidoethylthio)-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (56 mg) as an amorphous solid.
Reaction SMILES: C([O:4][C@H:5]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:21]2[C:20](=[O:26])[CH2:19][C@@:18]2([CH3:27])[C@H:11]3[CH2:12][CH:13]=[C:14]2[C:15](=[O:17])[CH3:16])[CH2:6]1)(=O)C.[OH-].[K+]>O1CCOCC1.O>[OH:4][C@H:5]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:21]2[C:20](=[O:26])[CH2:19][C@@:18]2([CH3:27])[C@H:11]3[CH2:12][CH:13]=[C:14]2[C:15](=[O:17])[CH3:16])[CH2:6]1
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2C(=O)C[C@]2(C)C(C(C)=O)=CC[C@@H]32)C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)C1=CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Reaction time: 1 h
Yield: 77.4 %

Procedure:
A solution of 3β-acetoxy-5α-pregn-16-ene-11,20-dione (Chamberlin et al., J. Amer. Chem. Soc., 1951, 73, 2396) (25.7 g.) in dioxan (500 ml.) was treated with potassium hydroxide (10 g.) and water 250 ml. and the mixture allowed to stand at room temperature for 1 hour. After a further 1 hour at 40° the mixture was diluted with water and the product filtered off. The crude material was dissolved in chloroform and filtered through a column of grade III neutral alumina (ca. 100 g.). The material obtained was crystallised from acetone petroleum to give pure title compound (17.65 g.), as small plates, m.p. 217.5°, [α]D +82.9° (c 1.1), λmax. 234 nm. (ε 10,100).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:13]([O-])=O)[C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(O)(=O)C.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:13][C:4]1[C:5]([OH:12])=[C:6]([CH:11]=[C:2]([F:1])[CH:3]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(F)cc([N+](=O)[O-])c1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(F)cc(N)c1O
Yield: 101 %

Procedure:
A suspension of methyl 5-fluoro-2-hydroxy-3-nitrobenzoate (2.3 g, 10.7 mmol), acetic acid (2 mL) and 10% Pd/C (0.23 g) in ethyl acetate (50 mL) was stirred at 25° C. over 1 atm hydrogen for 4 hr. The mixture was filtered and the filtrate was concentrated to give crude product. The crude product was purified by chromatography (silica gel, petroleum ether/ethyl acetate=100:1 to 20:1) to give methyl 3-amino-5-fluoro-2-hydroxybenzoate (2.0 g, yield 100%) as a light yellow solid. 1H-NMR (400 MHz, CDCl3-d) δ 3.95 (s, 3H), 3.98-4.13 (s, br, 2H), 6.60-6.63 (dd, J1=9.4 Hz, J2=2.4 Hz, 1H), 6.86-6.89 (dd, J1=8.8 Hz, J2=2.8 Hz, 1H), 10.70 (s, 1H); LC-MS (ESI) m/z 186 [M+1]+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8](C3(CCC(O)=O)C4C(=CC=CC=4)N(CCCCC)C3=O)=[CH:9][C:4]=2[O:3][CH2:2]1.O1C2C=C[C:37]([C:39]3(CC(O)=O)[C:47]4[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=4)[N:41]([CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[C:40]3=[O:53])=[CH:38][C:33]=2[O:32]C1>>[CH2:48]([N:41]1[C:42]2[C:47](=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:39]2([CH2:37][CH2:38][C:33](=[O:32])[C:8]3[C:7]2=[CH:6][C:5]2[O:1][CH2:2][O:3][C:4]=2[CH:9]=3)[C:40]1=[O:53])[CH2:49][CH2:50][CH2:51][CH3:52]
Reactant: CCCCCN1C(=O)C(CC(=O)O)(c2ccc3c(c2)OCO3)c2ccccc21
Reactant: CCCCCN1C(=O)C(CCC(=O)O)(c2ccc3c(c2)OCO3)c2ccccc21
Product: CCCCCN1C(=O)C2(CCC(=O)c3cc4c(cc32)OCO4)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 21, and making non-critical variations using 3-[3-(1,3-benzodioxol-5-yl)-2-oxo-1-pentyl-2,3-dihydro-1H-indol-3-yl]propanoic acid to replace [3-(1,3-benzodioxol-5-yl)-2-oxo-1-pentyl-2,3-dihydro-1H-indol-3-yl]acetic acid, the title compound was obtained (32%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.57 (s, 1H), 7.37-7.28 (m, 1H), 7.08-7.03 (m, 2H), 6.95 (d, 1H), 6.02 (s, 1H), 5.95-5.91 (m, 2H), 3.73 (t, 2H), 3.37-3.24 (m, 1H), 2.79-2.67 (m, 1H), 2.41-2.32 (m, 2H), 1.76-1.64 (m, 2H), 1.38-1.28 (m, 4H), 0.87 (t, 3H); 13C NMR (75 MHz, CDCl3) δ 195.4, 177.4, 152.3, 148.0, 142.7, 138.9, 133.6, 128.8, 128.4, 124.1, 122.9, 108.9, 106.9, 106.6, 101.9, 51.7, 40.2, 33.1, 32.8, 29.0, 27.1, 22.3, 14.0; MS (ES+) m/z 400.1 (M+23), 378.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]=[S:13].[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl[CH2:23][C:24](O)=[O:25]>>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[N:21]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:24](=[O:25])[CH2:23][S:13]1
Reactant: O=C(O)CCl
Reactant: NCc1ccccc1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SCC(=O)N1Cc1ccccc1

Procedure:
2-Methyl-4-nitrophenyl isothiocyanate was reacted with benzylamine followed by chloroacetic acid according to Method C8a to afford 2-(2-methyl-4-nitrophenylimino)-3-(phenylmethyl)-1,3-thiazolidin-4-one.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2(C3C=CN=CC=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([NH2:18])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:25][C:26]([S:29](N)=[O:30])([CH3:28])[CH3:27].CO.C(=O)(O)[O-].[Na+]>CCO.CCO.CCO.CCO.[Ti].C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:9]([C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:11]#[N:18])=[N:10][S:29]([C:26]([CH3:28])([CH3:27])[CH3:25])=[O:30])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(C)S(N)=O
Reactant: NC1=NC(c2ccncc2)(c2ccc(F)c(Br)c2)c2ccccc21
Agent: [Ti]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)S(=O)N=C(c1ccc(F)c(Br)c1)c1ccccc1C#N
Reaction time: 0.08 h
Yield: 30 %

Procedure:
A mixture of 2-(3-bromo-4-fluorobenzoyl)benzonitrile (Scheme #11, E) and tetraethyl orthotitanate (1 M solution in tetrahydrofuran, 18.3 mL, 18.3 mmol) was stirred for 5 minutes, then 2-methyl-2-propanesulfinamide (1.11 g, 9.13 mmol) was added and the resulting mixture was heated to reflux over night. When the reaction had cooled to room temperature methanol, aqueous saturated sodium bicarbonate and ethyl acetate was added. After filtering the reaction mixture through a pad of sodium sulfate, the filtrate was concentrated. Purification of the residue by column chromatography using chloroform as the eluent gave the title compound (1.22 g, 30% over 2 steps). 1H NMR (CDCl3) δ 7.90-7.69 (m, 3 H), 7.68-7.39 (m, 3 H), 7.18 (t, J=8.21 Hz, 1 H), 1.38 (br s, 9 H); MS (AP) m/z 407, 409 [M+1]+.
Reaction SMILES: [CH2:1]([C:4]1([S:7]([NH:10][C:11]2[C:19]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][C:22]=3[Cl:28])=[C:18]([F:29])[C:14]3[N:15]=[CH:16][O:17][C:13]=3[CH:12]=2)(=[O:9])=[O:8])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].C[N+]1([O-])CC[O:34]CC1.[OH2:38]>C1COCC1.[Os](=O)(=O)(=O)=O>[OH:38][CH:2]([CH2:3][OH:34])[CH2:1][C:4]1([S:7]([NH:10][C:11]2[C:19]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][C:22]=3[Cl:28])=[C:18]([F:29])[C:14]3[N:15]=[CH:16][O:17][C:13]=3[CH:12]=2)(=[O:9])=[O:8])[CH2:6][CH2:5]1
Reactant: C[N+]1([O-])CCOCC1
Reactant: O
Reactant: C=CCC1(S(=O)(=O)Nc2cc3ocnc3c(F)c2Nc2ccc(Br)cc2Cl)CC1
Agent: O=[Os](=O)(=O)=O
Solvent: C1CCOC1
Product: O=S(=O)(Nc1cc2ocnc2c(F)c1Nc1ccc(Br)cc1Cl)C1(CC(O)CO)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.2 %

Procedure:
To a solution of 1-allyl-N-(4-fluoro-5-((4-bromo-2-chlorophenyl)amino)benzo[d]oxazol-6-yl)cyclopropane-1-sulfonamide (100 mg, 0.38 mmol) in THF (10 mL) was added N-methylmorpholine-N-oxide (44 mg, 0.38 mmol) followed by osmium tetraoxide (10 mg, 0.04 mmol) and water (0.5 mL). After stirring at room temperature overnight, the mixture was concentrated and then diluted with EA. The organic layer was washed with water, saturated NaHCO3 (aq.) and brine sequentially, dried over Na2SO4, filtered and concentrated to give a residue, which was purified by flash chromatography to give the product as white solid (30 mg, 28.2% yield). 1H NMR (400 MHz, CDCl3): δ 8.10 (s, 1H), 7.98 (s, 1H), 7.45-7.34 (m, 2H), 7.32-7.21 (m, 1H), 6.83 (s, 1H), 6.44-6.30 (m, 1H), 4.41-4.25 (m, 2H), 4.21-4.12 (m, 1H), 3.72-3.62 (m, 1H), 2.85-2.78 (m, 1H), 1.32-1.26 (m, 2H), 1.16-1.21 (m, 4H). MS APCI (+) m/z: 535.8, [M+H].
Reaction SMILES: C(O[C:9](=O)[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=1)C1C=CC=CC=1.C([Li])CCC.[C:24]([O:29][CH2:30][C@@H:31]1[O:33]C1)(=[O:28])CCC>C1COCC1>[F:17][C:13]1[CH:12]=[C:11]([N:10]2[CH2:9][CH:30]([CH2:31][OH:33])[O:29][C:24]2=[O:28])[CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Nc1cccc(F)c1)OCc1ccccc1
Reactant: CCCC(=O)OC[C@H]1CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C1OC(CO)CN1c1cccc(F)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 72.2 %

Procedure:
A solution of amine 91 (39.2 g, 160.0 mmol) in anhydrous THF (300 mL) was cooled to −78° C. in a dry-ice/acetone bath before a solution of n-butyl lithium (n-BuLi, 2.5 M solution in hexane, 70.4 mL, 176 mmol, 1.1 equiv) was dropwise added under N2. The resulting reaction mixture was subsequently stirred at −78° C. for 1 h before a solution of (R)-(−)-glycidyl butyrate (25.37 g, 24.6 mL, 176 mmol, 1.1 equiv) in anhydrous THF (100 mL) was dropwise added into the reaction mixture at −78° C. under N2. The resulting reaction mixture was stirred at −78° C. for 30 minutes (min) before being gradually warmed to room temperature for 12 h under N2. When TLC and high performance liquid chromatography/mass spectrometry (HPLC/MS) showed the reaction was complete, the reaction mixture was quenched with H2O (200 mL), and the resulting mixture was stirred at room temperature for 1 h before EtOAc (200 mL) was added. The two layers were separated, and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organic extracts were washed with H2O (2×100 mL) and saturated aqueous NaCl (100 mL), dried over MgSO4, and concentrated in vacuo. White crystals precipitated from the concentrated solution when most of the solvent was evaporated. The residue was then treated with 20% EtOAc/hexane (100 mL) and the resulting slurry was stirred at room temperature for 30 min. The solids were collected by filtration and washed with 20% EtOAc/hexane (2×50 mL) to afford the desired (5R)-(3-(3-fluoro-phenyl)-5-hydroxymethyl-oxazolidin-2-one (alcohol 92, 24.4 g, 72.3% yield) as white crystals. This product was directly used in subsequent reactions without further purification. 1H NMR (300 MHz, DMSO-d6) δ 3.34–3.72 (m, 2H), 3.83 (dd, 1H, J=6.2, 9.0 Hz), 4.09 (t, 1H, J=12.0 Hz), 4.68–4.75 (m, 1H), 5.23 (t, 1H, J=5.6 Hz, OH), 6.96 (m, 1H), 7.32–7.56 (m, 3H). C10H10FNO3, LCMS (EI) m/e 212 (M++H).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:29][C:30]([OH:33])([CH3:32])[CH3:31])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([N:17]3[C:25](=[O:26])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18]3=[O:27])[C:8]=2[N:28]=1)[CH3:2].[O:34]=[C:35]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:37](=[O:44])[N:36]1[CH2:45][C:46](O)=[O:47].N1(C2C=CN=CC=2)CCCC1.C(N=C=NC(C)C)(C)C>C(Cl)Cl>[O:34]=[C:35]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:37](=[O:44])[N:36]1[CH2:45][C:46]([O:33][C:30]([CH3:32])([CH3:31])[CH2:29][N:6]1[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([N:17]3[C:18](=[O:27])[C:19]4[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:25]3=[O:26])[C:8]=2[N:28]=[C:5]1[CH2:4][O:3][CH2:1][CH3:2])=[O:47]
Reactant: CCOCc1nc2c(N3C(=O)c4ccccc4C3=O)nc3ccccc3c2n1CC(C)(C)O
Reactant: O=C(O)CN1C(=O)c2ccccc2C1=O
Agent: CC(C)N=C=NC(C)C
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Product: CCOCc1nc2c(N3C(=O)c4ccccc4C3=O)nc3ccccc3c2n1CC(C)(C)OC(=O)CN1C(=O)c2ccccc2C1=O
Temperature: 50 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
2-(2-(Ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-yl)isoindoline-1,3-dione (1600 mg, 3.6 mmol), 1,3-dihydro-1,3-dioxo-2H-isoindole-2-acetic acid (CAN 4702-13-0, 2.22 g, 10.8 mmol) and 4-(1-pyrrolidinyl)-pyridine (800 mg, 5.4 mmol) were combined with DCM (36 mL) to give a white suspension. N,N′-diisopropylcarbodiimide (1.68 mL, 10.8 mmol) and molecular sieves were added. The reaction mixture was heated to 50° C. and stirred for 2 hours and was, after cooling, filtered. The filtrate was diluted with DCM (150 mL) and washed with 1 N hydrochloric acid and water. Water phases were extracted with DCM, organic phases were combined, dried over MgSO4, filtered and concentrated in vacuo. Diisopropylurea was removed after trituration with DCM/methanol by filtration, the filtrate was concentrated and the residue was purified by flash chromatography (silica gel, 0% to 100% ethyl acetate in heptane) to give a light yellow solid. Crystallization from DMSO yielded a first crop of product (1.95 g), and the mother liquor after concentration and preparative HPLC another 0.13 g of product. In total 2.08 g (91%) of the title compound was isolated as white solid; LC-MS (UV peak area, ESI) 95.9%, 632.2157 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:35])([CH2:29][N:30]1[CH:34]=[N:33][CH:32]=[N:31]1)[C@H:10]([N:12]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH:27]=[N:26][N:25]=[N:24]3)=[CH:19][CH:18]=2)[C:13]1=[O:28])[CH3:11].[C:36](=[O:44])([O:40][CH2:41][CH2:42][CH3:43])[O:37][CH2:38][Cl:39].C(#N)C>C(OC(C)C)(C)C>[Cl-:39].[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:35])([C@H:10]([N:12]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH:27]=[N:26][N:25]=[N:24]3)=[CH:19][CH:18]=2)[C:13]1=[O:28])[CH3:11])[CH2:29][NH+:30]1[CH2:34][N:33]([CH2:38][O:37][C:36]([O:40][CH2:41][CH2:42][CH3:43])=[O:44])[CH:32]=[N:31]1
Reactant: C[C@@H](N1CCN(c2ccc(-n3cnnn3)cc2)C1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: CCCOC(=O)OCCl
Solvent: CC(C)OC(C)C
Solvent: CC#N
Product: CCCOC(=O)OCN1C=N[NH+](C[C@](O)(c2ccc(F)cc2F)[C@@H](C)N2CCN(c3ccc(-n4cnnn4)cc3)C2=O)C1
Product: [Cl-]
Temperature: 100 °C
Reaction time: 12 h
Yield: 3 %

Procedure:
A mixture of 1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-tetrazol-1-yl)phenyl]-2-imidazolidinone (0.5 g), chloromethyl propyl carbonate (3.2 g) and acetonitrile (1 ml) was stirred for 12 hours at 100° C. After having been cooled, the mixture was diluted with diisopropyl ether (10 ml), and the resulting powder was collected by filtration. The powder was subjected to silica gel chromatography (eluent: ethyl acetate→acetone→acetone/ethanol=10/1→acetone/ethanol=5/1). The solvent was distilled off, and the residue was subjected to ODS column chromatography (eluent: methanol/water=3/2) to give 1-[(2R,3R)-2-(2,4-difluorophenyl)-2-hydroxy-3-[2-oxo-3-[4-(1H-tetrazol-1-yl)phenyl]-1-imidazolidinyl]butyl]-4-propoxycarbonyloxymethyl-1H-1,2,4-triazolium chloride (Compound 19, 0.02 g) as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH:5]=[O:6].[CH3:11][Mg]Cl.[NH4+].[Cl-]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]([OH:6])[CH3:11])[CH:7]=[C:8]([F:10])[CH:9]=1
Reactant: C[Mg]Cl
Reactant: O=Cc1cc(F)cc(Br)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)c1cc(F)cc(Br)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 45 %

Procedure:
To a solution of 3-bromo-5-fluorobenzaldehyde (6.0 g, 29.6 mmol, prepared according to patent WO 0066556) in THF (100 ml) was added dropwise at 0° C. methylmagnesiumchloride (3N in THF, 12 ml). The reaction mixture was stirred for 3 hours at room temperature and then sat. NH4Cl solution was added. The aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed with water, dried over MgSO4, filtered and the solvent was removed in vacuo. The crude product was purified by chromatography over silica gel to yield 1-(3-bromo-5-fluoro-phenyl)-ethanol (2.9 g, 45%), 1H-NMR (300 MHz, CDCl3): δ=7.31 (s, 1H), 7.14 (d, 1H), 7.04 (d, 1H), 4.82-4.94 (m, 1H), 1.51 (d, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][C:6]2([CH3:15])[CH3:14])#[CH:2].[O:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1>C(N(CC)CC)C.C(OCC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:9]([O:13][C:20](=[O:16])[C:19]1[CH:3]=[CH:1][C:2]([C:2]#[C:1][C:3]2[CH:12]=[CH:11][C:10]3[C:9](=[O:13])[CH2:8][CH2:7][C:6]([CH3:15])([CH3:14])[C:5]=3[CH:4]=2)=[CH:17][CH:18]=1)[CH3:8]
Reactant: C1CCOC1
Reactant: C#Cc1ccc2c(c1)C(C)(C)CCC2=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
A solution of 6-ethynyl-4,4-dimethyl-1,2,3,4-tetrahydronaphthalene-1-one (Intermediate 13, 0.23 g, 1.1 mmol) and ethyl-4-iodo benzoate (Reagent A, 0.36 g, 1.3 mmol) in triethyl amine (7 mL) and anhydrous tetrahydrofuran (3 mL) was treated with copper(I)iodide (0.114 g, 0.6 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (0.23 g, 0.33 mmol) was added and the reaction mixture was stirred overnight at room temperature. It was diluted with diethyl ether and filtered over a bed of celite. The filtrate was evaporated in vacuo to a brown oil that was subjected to flash column chromatography over silica gel (230-400 mesh) using 6-7% ethyl acetate in hexane as the eluent to afford the title compound (0.29 g, 72%) as a pale brown solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[F:9][C:10]([F:21])([F:20])[C:11]1[N:16]=[C:15]([C:17](Cl)=[O:18])[CH:14]=[CH:13][CH:12]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:1][C:17]([C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:10]([F:21])([F:9])[F:20])[N:16]=2)=[O:18])[CH:7]=1
Reactant: Nc1cc(Cl)ncn1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1cc(Cl)ncn1)c1cccc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-amino-6-chloropyrimidine (230 mg, 1.78 mmol) in DCM (15 mL) is added 6-(trifluoromethyl)picolinoyl chloride (276 mg, 1.78 mmol) and DIPEA (0.912 ml, 5.33 mmol). The mixture is stirred overnight at RT. The mixture is diluted with DCM (10 mL), washed with saturated NaHCO3 solution (25 mL). The organic layer is dried over MgSO4 and evaporated under reduced pressure. The residue is purified by prep HPLC E, delivering the title compound as a yellowish solid (102 mg, 19%); LC-MS A: tR=0.89 min; [M+H]+=302.92.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[C:9]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:15]=4[S:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:3][CH2:2]1.[F:21][C:22]1[CH:23]=[C:24]([CH2:28][C:29](C2C=CC=CC=2)=O)[CH:25]=[CH:26][CH:27]=1.[C-:37]#[N:38].C([Al+]CC)C.C1(C)C=CC=CC=1>C(Cl)Cl.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[F:21][C:22]1[CH:23]=[C:24]([C:28]([N:1]2[CH2:2][CH2:3][CH:4]([NH:7][C:8]3[C:9]4[C:16]5[CH2:17][CH2:18][CH2:19][CH2:20][C:15]=5[S:14][C:10]=4[N:11]=[CH:12][N:13]=3)[CH2:5][CH2:6]2)([CH3:29])[C:37]#[N:38])[CH:25]=[CH:26][CH:27]=1
Reactant: [C-]#N
Reactant: O=C(Cc1cccc(F)c1)c1ccccc1
Reactant: c1nc(NC2CCNCC2)c2c3c(sc2n1)CCCC3
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: CC[Al+]CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C#N)(c1cccc(F)c1)N1CCC(Nc2ncnc3sc4c(c23)CCCC4)CC1
Reaction time: 24 h
Yield: 100 %

Procedure:
To a mixture of N-(piperidin-4-yl)-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-amine (2.86 g, 10 mmol) and 3-fluorophenylacetophenone (1.38 g, 10 mmol) in dry DCM (25 mL) was added titanium isopropoxide (2.85 g, 10 m.mol) at room temperature and stirred for 24 h. 1 M solution of diethylaluminumcyanide in toluene (1.2 mL, 10 mmol) was added to the above solution and the mixture was allowed to stir for 24 h. The reaction was quenched by the addition of saturated aq. NaHCO3 solution (15 mL) and the organic layer was separated, dried and concentrated under reduced pressure to get the title compound (4.3 g, 100%) as pale yellow powder. 1H NMR (400 MHz, CDCl3): δ 8.01 (s, 1H), 7.35-7.24 (m, 2H), 6.99 (t, 1H), 6.78 (t, 1H), 4.21 (brs, 1H, NH), 3.91-3.86 (m, 1H), 3.11-3.03 (m, 2H), 2.91 (t, 2H), 2.49-2.27 (m, 4H), 2.00-1.92 (m, 4H), 1.42 (s, 3H). MS (ESI) m/z: Calculated: 435.56; Observed: 436.2 (M++1).