Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([CH2:14][S:15][C:16]2[NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[N:17]=2)[CH:9]=1.C(C(C(C(OCC)=O)O)O)(OCC)=[O:28].C(N(CC)C(C)C)(C)C.OOOO.C1(C(C)C)C=CC=CC=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4].O>[F:26][C:2]([F:1])([F:25])[CH2:3][O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([CH2:14][S:15]([C:16]2[NH:17][C:18]3[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=3[N:20]=2)=[O:28])[CH:9]=1
Reactant: CCOC(=O)C(O)C(O)C(=O)OCC
Reactant: FC(F)(F)COCCOc1ccnc(CSc2nc3ccccc3[nH]2)c1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: O=C([O-])O
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=S(Cc1cc(OCCOCC(F)(F)F)ccn1)c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The thus-obtained 2-{4-[2-(2,2,2-trifluoroethoxy) ethoxy]pyridin-2-yl-methylthio}-1H-benzimidazole (6.5 g) was dissolved in toluene (160 mL). Molecular Sieve 4A (6.5 g) and water (310 μL) were added, and the mixture was stirred for 15 minutes at room temperature. Subsequently, diethyl (+)-tartrate (7.0 g) and tetraisopropyl titanate (4.8 g) were added, and the mixture was stirred for one hour at 50° C. The temperature of the mixture was returned to room temperature. N,N-Diisopropylethylamine (3.0 mL) and 88% cumene hydroxyperoxide (2.8 mL) were added, and the mixture was stirred for three hours at room temperature. A saturated sodium bicarbonate solution was added to the reaction mixture, and the mixture was stirred for 10 minutes, followed by filtration through the Celite. The filtrate was extracted with ethyl acetate. The organic layer was washed sequentially with water and brine, and brought to dryness over sodium sulfate anhydrate. The solvent was removed under reduced pressure. The residue was subjected to silica gel column chromatography (silica gel: NH-DM1020 (product of Fuji Silicia), chloroform:methanol=10:1), whereby (−)-2-{4-[2-(2,2,2-trifluoroethoxy) ethoxy]pyridin-2-yl-methanesulfinyl}-1H-benzimidazole was obtained (5.4 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][CH:12]([C:15]1[N:16]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:17](=[O:25])[C:18]2[C:23]([CH3:24])=[N:22][O:21][C:19]=2[N:20]=1)[CH2:13][CH3:14])([CH3:4])([CH3:3])[CH3:2].[C:34]1([CH3:43])[CH:39]=[CH:38][C:37]([C:40](Cl)=[O:41])=[CH:36][CH:35]=1.CCN(CC)CC>C(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:33])[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH:12]([C:15]1[N:16]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:17](=[O:25])[C:18]2[C:23]([CH3:24])=[N:22][O:21][C:19]=2[N:20]=1)[CH2:13][CH3:14])[C:40](=[O:41])[C:37]1[CH:38]=[CH:39][C:34]([CH3:43])=[CH:35][CH:36]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCC(NCCCNC(=O)OC(C)(C)C)c1nc2onc(C)c2c(=O)n1Cc1ccccc1
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCC(c1nc2onc(C)c2c(=O)n1Cc1ccccc1)N(CCCNC(=O)OC(C)(C)C)C(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.1 %

Procedure:
A solution of the compound of Example 1 Step 5 (50 mg, 0.11 mmol) in CHCl3 (10 mL) was treated with 4-toluoyl chloride (16.9 mg, 0.11 mmol) followed by Et3N (11.1 mg, 0.11 mmol). The resulting mixture was stirred at room temperature for 18 h, then concentrated under vacuum. The crude product was purified by preparative reverse-phase HPLC on a YMC S5 ODS 30×100 mm column to afford the desired product as a yellow glass (60 mg, 95%); LC/MS 100% at 4.32 min (ESI): 574 (M+H)+.
Reaction SMILES: [N:1]1([C:6]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][C:9]=2[CH3:17])=[O:7])[CH2:5][CH:4]=[CH:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:49][C:50]1[CH:63]=[CH:62][C:53]2[NH:54][C:55]([C@@H:57]([NH2:61])[CH2:58][CH2:59][CH3:60])=[N:56][C:52]=2[CH:51]=1.ClCl>O1CCCC1.ClCCl.C(O)C>[Cl:49][C:50]1[CH:63]=[CH:62][C:53]2[NH:54][C:55]([C@@H:57]([NH:61][C:12](=[O:14])[C:11]3[CH:15]=[CH:16][C:8]([C:6]([N:1]4[CH2:2][CH:3]=[CH:4][CH2:5]4)=[O:7])=[C:9]([CH3:17])[CH:10]=3)[CH2:58][CH2:59][CH3:60])=[N:56][C:52]=2[CH:51]=1
Reactant: CCC[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CC=CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC[C@H](NC(=O)c1ccc(C(=O)N2CC=CC2)c(C)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1g from 4-(2,5-dihydropyrrol-1-ylcarbonyl)-3-methylbenzoic acid, TBTU, diisopropylethylamine and (1S)-1-(5-chloro-1H-benzimidazol-2-yl)butylamine in tetrahydrofuran. Yield: quantitative; Rf value: 0.55 (silica gel: dichloromethane/ethanol=9:1); C24H25ClN4O2 (436.94); mass spectrum: (M+H)+=437/439 (chlorine isotope).
Reaction SMILES: Cl[C:2]1[CH:13]=[C:6]2[C:7]([O:9][C:10](=[O:12])[NH:11][C:5]2=[CH:4][CH:3]=1)=O.[NH:14]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:17](=O)[C:15]1=O.FC1C=C2C(=CC=1)NC(=O)C2=O>>[CH3:17][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:24]=1[N:14]=[C:15]1[C:7](=[O:9])[C:6]3[C:5]([N:11]1[C:10]2=[O:12])=[CH:4][CH:3]=[CH:2][CH:13]=3
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Reactant: O=C1Nc2ccccc2C1=O
Agent: O=C1Nc2ccc(F)cc2C1=O
Product: Cc1cccc2c(=O)n3c(nc12)C(=O)c1ccccc1-3
Yield: 31 %

Procedure:
Using the procedure in Example 12 and substituting 3-methylisatoic anhydride for 5-chloroisatoic anhydride and isatin for 5-fluoroisatin gave the title compound in 31% yield: mp 247°-248° C.; 1H NMR (300 MHz, CDCl3) δ 8.64 (d, 1H), 8.28 (d, 1H), 7.92 (d, 1H), 7.78 (dt, 1H), 7.70 (d, 1H), 7.55 (t, 1H), 7.43 (dt, 1H), 275 (s, 1H); MS (M+H)+ 263, (M+CH4CN)+ 304.
Reaction SMILES: [CH3:1][C:2]1([C:23]([O:25][CH3:26])=[O:24])[C:7](OS(C(F)(F)F)(=O)=O)=[CH:6][CH2:5][N:4]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:3]1.[F:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.[Cl-].[Li+].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C.O.C(COC)OC>[F:27][C:28]1[CH:33]=[CH:32][C:31]([C:7]2[C:2]([CH3:1])([C:23]([O:25][CH3:26])=[O:24])[CH2:3][N:4]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:5][CH:6]=2)=[CH:30][CH:29]=1
Reactant: COC(=O)C1(C)CN(C(=O)OC(C)(C)C)CC=C1OS(=O)(=O)C(F)(F)F
Reactant: OB(O)c1ccc(F)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)C1(C)CN(C(=O)OC(C)(C)C)CC=C1c1ccc(F)cc1
Yield: 79.7 %

Procedure:
To a dimethoxyethane solution (6.0 mL) of 3-methyl 1-tert-butyl 3-methyl-4-{[(trifluoromethyl)sulfonyl]oxy}-2,3-dihydropyridine-1,3(6H)-dicarboxylate (300 mg, 0.743 mmol) synthesized in Reference Synthesis Example 273, 4-fluorophenylboronic acid (347 mg, 2.14 mmol), tetrakis(triphenylphosphine)palladium (0) (102 mg, 0.0880 mmol), lithium chloride (321 mg, 7.57 mmol), and 2 M sodium carbonate aqueous solution (2.5 mL) were added and the resultant mixture was stirred at 90° C. for 3 hours. After completion of the reaction, water was added to the reaction solution and extraction from the resultant mixture with ethyl acetate was performed. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1) to obtain the title compound (207 mg, yield 80%).
Reaction SMILES: C(N1C2CCC(=N[OH:18])CC=2C(C2C=CC(Cl)=CC=2)=N1)C1C=CC=CC=1.[CH2:26]([N:33]1[C:42]2[CH2:41][CH2:40]N[CH2:38][CH2:37][C:36]=2[C:35]([C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][CH:44]=2)=[N:34]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Cl>C1COCC1>[CH2:26]([N:33]1[C:42]2[CH2:41][CH2:40][C:38](=[O:18])[CH2:37][C:36]=2[C:35]([C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][CH:44]=2)=[N:34]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Clc1ccc(-c2nn(Cc3ccccc3)c3c2CCNCC3)cc1
Reactant: ON=C1CCc2c(c(-c3ccc(Cl)cc3)nn2Cc2ccccc2)C1
Agent: Cl
Solvent: C1CCOC1
Product: O=C1CCc2c(c(-c3ccc(Cl)cc3)nn2Cc2ccccc2)C1

Procedure:
1-Benzyl-3-(4-chloro-phenyl)-1,4,6,7-tetrahydro-indazol-5-one oxime. A solution of 3.87 g of the compound from step G in 80 mL of THF with 5 mL of 1 M HCl was heated at reflux for 16 h. The volatiles were removed in vacuo and water was added (300 mL). The mixture was adjusted to pH 9 by the addition of 1 M NaOH and then was extracted with CH2Cl2. The combined extracts were washed with brine and the solvent was removed in vacuo to provide 1-benzyl-3-(4-chloro-phenyl)-1,4,6,7-tetrahydro-indazol-5-one. This product (3.13 g) was treated with hydroxylamine hydrochloride (3.0 g) in 20 mL of pyridine. The reaction mixture was stirred at RT for 14 h then was diluted with water (300 mL), and stirred an additional hour. The mixture was filtered on paper and the solids were washed with EtOAc and dried in vacuo to afford 2.48 g of the desired compound. 1H NMR (500 MHz, acetone-d6): 10.24 (s, 1H), 7.30-7.26 (m, 2H), 7.06-7.02 (m, 2H), 6.91-9.87 (m, 2H), 6.85-6.81 (m, 1H), 6.77-6.73 (m, 2H), 4.87 (s, 2H), 3.21 (s, 2H), 2.31 (t, J=6.6 Hz, 2H), 2.09 (t, J=6.6 Hz, 2H).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:27]([CH3:28])=[CH:26][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21](Cl)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:36][N:37]1[C:45]2[C:40](=[N:41][C:42]([Sn](CCCC)(CCCC)CCCC)=[CH:43][CH:44]=2)[CH:39]=[N:38]1.[Cl-].[Li+]>[Cu]I.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>[C:1]([O:5][C@@H:6]([C:12]1[C:27]([CH3:28])=[CH:26][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:42]4[N:41]=[C:40]5[CH:39]=[N:38][N:37]([CH3:36])[C:45]5=[CH:44][CH:43]=4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:29]1[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(Cl)c3)sc2c1-c1ccc(Cl)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc2c(cnn2C)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4ccc5c(cnn5C)n4)c3)sc2c1-c1ccc(Cl)cc1
Temperature: 120 °C

Procedure:
To a solution of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyridin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (48 mg, 0.091 mmol) in microwave vial, was added 1-methyl-5-(tributylstannyl)-1H-pyrazolo[4,3-b]pyridine (47 mg, 0.111 mmol), copper(I) iodide (9 mg, 0.045 mmol), lithium chloride (11 mg, 0.27 mmol), Pd(PPh3)4 (10 mg, 0.009 mmol). The reaction mixture was heated at 120° C. for 4 hours. Then the mixture was washed by saturated NaHCO3, extracted by EtOAc, the organic phase was dried over MgSO4, filtered, concentrated down, purified by silica gel column, eluting by 0-60% EtOAc in hexanes to give the product. LCMS-ESI+: calc'd for C34H32ClN5O3S: 626.2 (M+H+); found: 626.3.
Reaction SMILES: [Cl:1][CH:2]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[C:3]([NH:5][CH:6]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[CH:14]=1)[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:4].[Sn](Cl)Cl>>[NH2:19][C:15]1[CH:14]=[C:13]([CH:6]([NH:5][C:3](=[O:4])[CH:2]([C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)[Cl:1])[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)CC(NC(=O)C(Cl)c1ccc(Cl)cc1)c1cccc([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Product: CCOC(=O)CC(NC(=O)C(Cl)c1ccc(Cl)cc1)c1cccc(N)c1

Procedure:
Corresponding to Example 3b, 3.1 g of (5a) were reduced using tin-(II) dichloride. A white solid was obtained (yield: 0.9 g).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8](OC(=N)C(Cl)(Cl)Cl)[O:7][CH:6]1[CH2:26][O:27][C:28](=[O:30])[CH3:29])(=[O:3])[CH3:2].[Cl:31][C:32]1[CH:33]=[N:34][CH:35]=[C:36]([Cl:53])[C:37]=1[NH:38][C:39]1[C:48]2[C:43](=[C:44]([OH:51])[C:45]([O:49][CH3:50])=[CH:46][CH:47]=2)[O:42][C:41](=[O:52])[CH:40]=1>C(#N)C>[C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([O:51][C:44]2[C:45]([O:49][CH3:50])=[CH:46][CH:47]=[C:48]3[C:43]=2[O:42][C:41](=[O:52])[CH:40]=[C:39]3[NH:38][C:37]2[C:36]([Cl:53])=[CH:35][N:34]=[CH:33][C:32]=2[Cl:31])[O:7][C@@H:6]1[CH2:26][O:27][C:28](=[O:30])[CH3:29])(=[O:3])[CH3:2]
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1O
Reactant: CC(=O)OCC1O[C@H](OC(=N)C(Cl)(Cl)Cl)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: CC#N
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1O[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Boron trifluoride•OEt2 (54 μL, 0.43 mmol) was added to a suspension of (3R,4S,5S,6R)-2-(acetoxymethyl)-6-(2,2,2-trichloro-1-iminoethoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (0.168 g, 0.341 mmol), 4-(3,5-dichloropyridin-4-ylamino)-8-hydroxy-7-methoxy-2H-chromen-2-one (60 mg, 0.17 mmol, Example 29), and anhydrous acetonitrile (2 mL) at −40° C. under N2. After 2 h at −40° C., the reaction was allowed to warm to rt and stirred overnight. The mixture was concentrated and purified by reverse-phase HPLC to give (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-(4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2-oxo-2H-chromen-8-yloxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate: 1H NMR (400 MHz, DMSO-d6): δ 9.55 (s, 1H), 8.83 (s, 2H), 8.03 (d, 1H), 7.25 (d, 1H), 5.34 (m, 2H), 5.08 (m, 1H), 4.98 (m, 1H), 4.67 (s, 1H), 4.12 (m, 1H), 3.99 (m, 2H), 3.91 (s, 3H), 2.06 (s, 3H), 1.98 (m, 6H), 1.94 (s, 3H); MS (ESI): 682.8.
Reaction SMILES: CC([Si](C1C=CC=CC=1)(C1C=CC=CC=1)[O:6][CH2:7][C@@H:8]1[CH2:14][C@H:13]2[C@H:11]([CH2:12]2)[CH2:10][N:9]1[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])(C)C.C1C=CN=CC=1.F.O.CCOC(C)=O>N1C=CC=CC=1>[OH:6][CH2:7][C@@H:8]1[CH2:14][C@H:13]2[C@H:11]([CH2:12]2)[CH2:10][N:9]1[C:15]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16]
Reactant: CC(C)(C)[Si](OC[C@@H]1C[C@@H]2C[C@@H]2CN1C(=O)OCc1ccccc1)(c1ccccc1)c1ccccc1
Agent: F
Solvent: O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C(OCc1ccccc1)N1C[C@H]2C[C@H]2C[C@H]1CO
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 91.9 %

Procedure:
To an ice cooled solution of phenylmethyl (1S,4S,6S)-4-({[(1,1-dimethylethyl)(diphenyl)silyl]oxy}methyl)-3-azabicyclo[4.1.0]heptane-3-carboxylate D8 (0.930 g) in pyridine (14 ml) was added HF-pyridine (2.642 ml, 30.4 mmol), the resulting mixture was stirred for 20 minutes at 0° C. and then was slowly warmed to room temperature and stirred for 30 minutes. Water (200 ml) and EtOAc (30 ml) were added and stirred for 15 minutes. The organic phase was separated and the aqueous phase was extracted with EtOAc (6×5 mls). The collected organic layers were dried (Na2SO4), filtered and evaporated under reduced pressure to obtain an oil which was purified via Companion CombiFlash (Silica gel, SNAP 100 g column; eluted with 20 CV of DCM/MeOH 98/2). Collected and evaporated fractions gave the title compound D9 (0.447 g). MS: (ES/+) m/z: 262 (M+1). C15H19NO3 requires 261. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.51-7.24 (m, 5 H), 5.20-5.0 (m, 2 H), 4.73-4.48 (m, 1 H), 4.43-4.17 (m, 1 H), 3.71-3.51 (m, 1 H), 3.51-2.35 (m, 2 H), 2.46-2.24 (m, 2 H), 1.20-0.95 (m, 2 H), 0.95-0.59 (m, 2 H), 0.21-0.09 (m, 1 H).
Reaction SMILES: [CH3:1][S-:2].[Na+].[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])/[CH:9]=[CH:10]/[N+:11]([O-:13])=[O:12].C(O)(=O)C>CO>[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:9]([S:2][CH3:1])[CH2:10][N+:11]([O-:13])=[O:12])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]
Reactant: C[S-]
Reactant: COc1ccc(/C=C/[N+](=O)[O-])cc1OC
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(C(C[N+](=O)[O-])SC)cc1OC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 60.2 %

Procedure:
To a solution of sodium methanethiolate (0.62 g, 8.8 mmol) in methanol (20 ml), trans-3,4-dimethoxy-β-nitrostyrene (1.42 g, 8 mmol) was added and stirred at room temperature for 5 minutes. Further, acetic acid (0.46 ml) was added and stirred for 5 minutes. After evaporating methanol to a half amount under reduced pressure, water was added and extracted with dichloromethane and the organic layers were combined, washed with water and dried over sodium sulfate. The solvent was distilled out under reduced pressure and the residue was isolated and purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to yield 2-(3,4-dimethoxyphenyl)-2-(methylthio)nitroethane (1.24 g, 60%).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[C:4]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:5][CH:6]=[CH:7][CH:8]=1.[CH3:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[C:24](O)=[O:25].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[CH3:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[C:24]([N:12]1[CH2:11][CH2:10][N:9]([C:4]2[C:3]([C:2]([F:1])([F:15])[F:16])=[CH:8][CH:7]=[CH:6][N:5]=2)[CH2:14][CH2:13]1)=[O:25]
Reactant: CC1CCCCC1C(=O)O
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC1CCCCC1C(=O)N1CCN(c2ncccc2C(F)(F)F)CC1
Yield: 45 %

Procedure:
Coupling of 1-(3-(trifluoromethyl)pyridin-2-yl)piperazine (271 mg, 1.17 mmol) with 2-methylcyclohexanecarboxylic acid (100 mg, 0.70 mmol) was carried out according to a similar procedure described for example 19A using N,N-dimethylformamide (1 mL) as solvent and benzotriazole-1 yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (700 mg, 1.56 mmol) as coupling agent. 1-[(2-methylcyclohexyl)carbonyl]-4-[3-(trifluoromethyl)pyridin-2-yl]piperazine was obtained in 45% yield (112 mg) as colorless oil.
Reaction SMILES: [C:1]1([N:7]2[C:11]3([CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[CH2:13][CH2:12]3)[C:10](=[O:29])[NH:9]C2)C=[CH:5][CH:4]=[CH:3][CH:2]=1.FC1C=CC(C(C2CCN(CCN3C(=O)C4C(=CC=CC=4)NC3=O)CC2)=O)=CC=1.CC1N=C2N(C=CS2)C(=O)C=1CCN1CCC(=C(C2C=CC(F)=CC=2)C2C=CC(F)=CC=2)CC1.C1C=CC(N2CCN(CCCN3C(=O)NC4C=CC=CC=4C3=O)CC2)=CC=1>>[F:27][C:24]1[CH:25]=[CH:26][C:21]([C:20](=[O:28])[CH2:19][CH2:18][CH2:17][N:14]2[CH2:15][CH2:16][C:11]([N:7]3[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5]3)([C:10](=[O:29])[NH2:9])[CH2:12][CH2:13]2)=[CH:22][CH:23]=1
Reactant: O=C(CCCN1CCC2(CC1)C(=O)NCN2c1ccccc1)c1ccc(F)cc1
Agent: Cc1nc2sccn2c(=O)c1CCN1CCC(=C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Agent: O=C(c1ccc(F)cc1)C1CCN(CCn2c(=O)[nH]c3ccccc3c2=O)CC1
Agent: O=c1[nH]c2ccccc2c(=O)n1CCCN1CCN(c2ccccc2)CC1
Product: NC(=O)C1(N2CCCCC2)CCN(CCCC(=O)c2ccc(F)cc2)CC1

Procedure:
4-phenyl-8-[3-(4-fluorobenzoyl)propyl]-1-oxo-2,4,8-triazaspiro[4,5]decane (INN:spiperone), 3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]-ethyl]-2,4-[1H, 3H]-quinazolinedione (INN: ketanserin), pirenperin (INN), ritanserin (INN) and pelanserin (INN).
Reaction SMILES: [F:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].[CH2:24](Br)[CH:25]=[CH2:26].Cl>C(#N)C>[CH2:26]([N:15]1[CH2:16][CH2:17][CH:12]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])[C:2]=2[F:1])[CH2:13][CH2:14]1)[CH:25]=[CH2:24]
Reactant: CS(=O)(=O)c1cccc(C2CCNCC2)c1F
Reactant: C=CCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCN1CCC(c2cccc(S(C)(=O)=O)c2F)CC1

Procedure:
Preparation according to Example 1: 4-[2-fluoro-3-(methylsulfonyl)phenyl]piperidine (0.34 g, 1.32 mmol), acetonitrile (4 ml), potassium carbonate (0.34 g, 2.6 mmol) and allyl bromide (0.12 ml, 1.38 mmol). Yield: 0.2 g (51%). The amine was converted to the hydrochloric acid salt and recrystallized from ethanol/diethyl ether: M.p. 259-261° C. MS m/z (relative intensity, 70 eV) 297 (M+, 87), 296 (82), 270 (bp, 268 (41), 133 (57).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)([CH:10]2[CH2:15][CH2:14][N:13](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:12][CH2:11]2)O)=[CH:4][CH:3]=1.[ClH:42]>>[ClH:42].[F:41][C:38]1[CH:39]=[CH:40][C:35]([C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[C:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:36][CH:37]=1
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Agent: Cl
Product: Fc1ccc(C(=C2CCNCC2)c2ccc(F)cc2)cc1
Reaction time: 1 h

Procedure:
α,α-Bis-(4-fluorophenyl)-1-(triphenylmethyl)-4-piperidinemethanol (67 g; 0.123 mol) was dissolved in hydrochloric acid (1 l; 2 mol/l) and the solution was heated under reflux for 2 h. The solution was cooled, the precipitated solid was collected by filtration and suspended in anhydrous diethyl ether. The mixture was stirred for 1 h, filtered and the solid was crystallised from methanol/ether to give the product (28.3 g) as white crystals; m.p. 83° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([O:8][CH2:9][C:10]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:11]=2[C:12]([O:14]C)=[O:13])[CH2:3]1.[CH3:21][C:22]1[CH:23]=[C:24]([C:28]2[O:29][C:30]([CH3:35])=[C:31]([CH2:33]I)[N:32]=2)[CH:25]=[CH:26][CH:27]=1>>[CH3:21][C:22]1[CH:23]=[C:24]([C:28]2[O:29][C:30]([CH3:35])=[C:31]([CH2:33][O:1][CH:2]3[CH2:7][CH2:6][CH2:5][CH:4]([O:8][CH2:9][C:10]4[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:11]=4[C:12]([OH:14])=[O:13])[CH2:3]3)[N:32]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)c1c(C)cccc1COC1CCCC(O)C1
Reactant: Cc1cccc(-c2nc(CI)c(C)o2)c1
Product: Cc1cccc(-c2nc(COC3CCCC(OCc4cccc(C)c4C(=O)O)C3)c(C)o2)c1

Procedure:
Using methyl 2-(3-hydroxycyclohexyloxymethyl)-6-methylbenzoate and 2-(3-methylphenyl)-4-iodomethyl-5-methyloxazole as starting materials in the procedure of Example XXXI, gave the product 59 of molecular weight 449.55 (C27H31NO5), MS(ESI): 450.53 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[CH:8][N:9]([CH2:11][CH2:12][S:13][C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:10]=[C:6]2[C:5](=[O:33])[N:4]([CH3:34])[C:3]1=[O:35].[Li+].CC([N-]C(C)C)C.[B:44](OC(C)C)([O:49]C(C)C)[O:45]C(C)C>C1COCC1>[CH3:1][N:2]1[C:7]2=[CH:8][N:9]([CH2:11][CH2:12][S:13][C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:10]([B:44]([OH:49])[OH:45])=[C:6]2[C:5](=[O:33])[N:4]([CH3:34])[C:3]1=[O:35]
Reactant: Cn1c(=O)c2cn(CCSC(c3ccccc3)(c3ccccc3)c3ccccc3)cc2n(C)c1=O
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1c(=O)c2c(B(O)O)n(CCSC(c3ccccc3)(c3ccccc3)c3ccccc3)cc2n(C)c1=O
Temperature: -78 °C
Reaction time: 2 h

Procedure:
1,3-Dimethyl-6-(2-(tritylthio)ethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (step 2)(3.6 g, 7.47 mmol) was dissolved in anhydrous THF (67.3 mL) at room temperature in an oven dried flask. The flask was evacuated and backfilled with nitrogen (×3) and cooled to −78° C. LDA (0.719 M, 16.63 mL, 11.96 mmol) was added over 10 mins followed by triisopropyl borate (2.76 mL, 11.96 mmol) and the reaction aged for 2 hr at −78° C. The reaction was quenched with saturated NH4Cl solution (60 mL) added via syringe under nitrogen and the mixture was warmed to room temperature and stirred overnight under nitrogen. The mixture was then diluted DCM (400 mL). The layers were separated and the aqueous extracted with DCM (2×100 mL). The combined organics were passed through a hydrophobic frit and the solvent was reduced to ˜20 mL under reduced pressure and EtOAc (100 mL) added to the resulting red oil. Reduction of solvent volume under reduced pressure to ˜25 mL afforded precipitation of a white solid. The solid was collected by reduced pressure filtration, washed with EtOAc (10 mL) and dried under vacuum 50° C. for 16 h to afford the title compound;