Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:8]=[C:9]([O:25][CH3:26])[CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][C:22](O)=[O:23])[N:20]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN.C(Cl)CCl.C1C=CC2N(O)N=[N:39][C:37]=2C=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH:1]1([NH:6][C:7]2[CH:8]=[C:9]([O:25][CH3:26])[CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][C:22]([NH:39][CH3:37])=[O:23])[N:20]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: On1nnc2ccccc21
Reactant: COc1cc(NC2CCCC2)c2[nH]c(C3=N[C@H](CC(=O)O)CS3)cc2c1
Agent: CN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CNC(=O)C[C@@H]1CSC(c2cc3cc(OC)cc(NC4CCCC4)c3[nH]2)=N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.9 %

Procedure:
The compound (83 mg, 0.22 mmol) prepared in Example 48 was dissolved in N,N-dimethylformamide (3 ml). Methylamine (0.17 ml, 2M in THF, 0.33 mmol), EDC (72 mg, 0.38 mmol) and HOBT (60 mg, 0.44 mmol) were added thereto, and the mixture was stirred for 8 h at room temperature. After completion of the reaction, saturated sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and concentrated. The residue was purified by column chromatography to give the title compound (39 mg, Yield 46%).
Reaction SMILES: [NH2:1][C:2](=[O:29])[C@@H:3]([NH:12][C:13]([C:15]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1.[F:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.[CH:40]([S:43]([C:46]1[CH:51]=[CH:50][C:49](B(O)O)=[CH:48][CH:47]=1)(=[O:45])=[O:44])([CH3:42])[CH3:41].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[NH2:1][C:2](=[O:29])[C@@H:3]([NH:12][C:13]([C:15]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:34]2[CH:35]=[CH:36][C:31]([F:30])=[CH:32][CH:33]=2)=[CH:7][CH:6]=1.[NH2:1][C:2](=[O:29])[C@@H:3]([NH:12][C:13]([C:15]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:49]2[CH:48]=[CH:47][C:46]([S:43]([CH:40]([CH3:42])[CH3:41])(=[O:45])=[O:44])=[CH:51][CH:50]=2)=[CH:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(I)cc2)C(N)=O)CCOCC1
Reactant: CC(C)S(=O)(=O)c1ccc(B(O)O)cc1
Reactant: OB(O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(-c3ccc(F)cc3)cc2)C(N)=O)CCOCC1
Product: CC(C)S(=O)(=O)c1ccc(-c2ccc(C[C@H](NC(=O)C3(NC(=O)OC(C)(C)C)CCOCC3)C(N)=O)cc2)cc1
Temperature: 75 °C
Reaction time: 18 h

Procedure:
(S)-tert-Butyl 4-(1-amino-3-(4-iodophenyl)-1-oxopropan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 1, step (iii), 1.0 g) in acetonitrile (5 mL) under nitrogen was treated with 4-fluorophenylboronic acid (0.135 g) and 4-(isopropylsulfonyl)phenylboronic acid (0.220 g) followed by aqueous potassium carbonate (2M, 1.93 mL) and 1,1 bis(di-tert-butylphosphino)ferrocene palladium dichloride (13 mg). The mixture was stirred at 75° C. for 18 h. The reaction was evaporated, dissolved in dichloromethane, absorbed onto silica and to purified by chromatography on silica eluting with 50% ethyl acetate in isohexane and then 100% ethyl acetate to afford (S)-tert-butyl 4-(1-amino-3-(4′-fluorobiphenyl-4-yl)-1-oxopropan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate and (S)-tert-butyl 4-(1-amino-3-(4′-(isopropylsulfonyl)biphenyl-4-yl)-1-oxopropan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate as a mixture (0.620 g).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[O:10][N:9]=2)[CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35](=[O:37])[CH3:36])=[CH:31][C:30]=1[O:38][CH3:39].CN(C)C=O>O>[O:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:8]([CH:5]2[CH2:4][CH2:3][N:2]([CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:29]3[CH:34]=[CH:33][C:32]([C:35](=[O:37])[CH3:36])=[CH:31][C:30]=3[O:38][CH3:39])[CH2:7][CH2:6]2)=[N:9]1
Reactant: c1ccc2c(C3CCNCC3)noc2c1
Reactant: COc1cc(C(C)=O)ccc1OCCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(C)=O)ccc1OCCCCN1CCC(c2noc3ccccc23)CC1
Temperature: 75 °C
Yield: 94.7 %

Procedure:
A mixture of 3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride (4.3 g, 18 mmol). K2CO3 (5.5 g, 40 mmol), and 1-[4-(4-bromobutoxy)-3-methoxyphenyl]ethanone (5.5 g, 18 mmol), and dimethyl formamide (60 ml) was stirred and heated at 75° C. for 16 hours. The reaction was poured into water and was extracted with ethyl acetate. The ethyl acetate was washed (water), dried (MgSO4), and the solvent concentrated to afford 7.2 g of a beige solid. Recrystallization (twice) from ethyl alcohol yielded 3.3 g (43%) or 1-[4-[4-[4-(1,2-benzisoxazol-3-yl) )-1-piperidinyl]butoxy]-3-methoxyphenyl]ethanone, m.p.=99°-101° C.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH:24]([CH3:33])[CH2:25][NH:26][S:27]([CH:30]([CH3:32])[CH3:31])(=[O:29])=[O:28])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(Cl)[Cl:42]>C(OCC)C>[ClH:42].[NH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH:24]([CH3:33])[CH2:25][NH:26][S:27]([CH:30]([CH3:31])[CH3:32])(=[O:29])=[O:28])=[CH:19][CH:18]=2)=[CH:15][CH:16]=1
Reactant: ClCCl
Reactant: CC(CNS(=O)(=O)C(C)C)Oc1ccc(-c2ccc(CCNC(=O)OC(C)(C)C)cc2)cc1
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: CC(CNS(=O)(=O)C(C)C)Oc1ccc(-c2ccc(CCN)cc2)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
(tert-Butoxy)-N-(2-{4-[4-(1-methyl-2-{[(methylethyl)sulfonyl]amino}ethoxy)phenyl]phenyl}ethyl)carboxamide (410 mg, 0.860 mmol, prepared in example 38), trifluoroacetic acid (0.86 mL), and methylene chloride (5.75 mL) were combined and stirred, by stirbar, in a 15 mL round bottom flask, in a nitrogen system, at room temperature, for one hour. The reaction mixture was then concentrated under reduced pressure, and dissolved in excess 5N sodium hydroxide, and extracted three times with 25 mL of methylene chloride. Next the organic extracts were combined, washed with 50 mL of water, dried with potassium carbonate, filtered, and concentrated under reduced vacuum, yielding 480 mg of crude material. This crude material was dissolved in diethyl ether, and anhydrous hydrogen chloride gas was bubbled through the solution, until it was acidic. Next, the acidic solution was allowed to stir, by stirbar, for an additional hour, and then was vacuum filtered, capturing the white precipitate and drying it in a vacuum oven at 40° C. for 30 minutes, yielding the title compound (305 mg, 94%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:13]=[C:12]([CH3:21])[C:11]=2[CH:22]=[CH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1>[Pd].C(OCC)(=O)C>[Cl:8][C:6]1[CH:5]=[C:4]([S:9][C:10]2[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:13]=[C:12]([CH3:21])[C:11]=2[CH2:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: Cc1nn(-c2ccccc2)c(Sc2cc(Cl)cc(Cl)c2)c1C=Cc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1nn(-c2ccccc2)c(Sc2cc(Cl)cc(Cl)c2)c1CCc1ccccc1
Temperature: 25 °C
Reaction time: 40 h
Yield: 93.3 %

Procedure:
A suspension containing 95 mg of 5-(3,5-dichlorophenylthio)-3-methyl-1-phenyl-4-styryl-1H-pyrazole and 75 mg of 10% palladium on activated carbon in 10 ml of ethyl acetate was stirred under hydrogen (1 atm) at rt for 40 h. The suspension was filtered on Celite® and the filtrate was evaporated to leave 89 mg of 5-(3,5-dichlorophenylthio)-3-methyl-4-(2-phenylethyl)-1-phenyl-1H-pyrazole as a colourless gum. Mass spectrum (EI) m/z 438[M]+.1H NMR (DMSO-d6) 2.14 (s, 3H), 2.68 (t, 2H), 2.77 (t, 2H), 6.85 (d, 2H), 7.09 (d, 2H), 7.16 (t, 1H), 7.24 (t,2H) 7.33–7.48 (m, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:38](Cl)([O:40][C:41](=[O:47])OC(Cl)(Cl)Cl)Cl.[CH3:49][C:50]1[CH:55]=[CH:54][C:53]([CH3:56])=[CH:52][C:51]=1[S:57][CH:58](C)[CH2:59]O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:41](=[O:47])[O:40][CH2:38][CH2:59][CH2:58][S:57][C:51]2[CH:52]=[C:53]([CH3:56])[CH:54]=[CH:55][C:50]=2[CH3:49])=[CH:18][CH:17]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1ccc(C)c(SC(C)CO)c1
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2ncnc(Oc3ccc(NC(=O)OCCCSc4cc(C)ccc4C)cc3)c2cc1OC
Temperature: 25 °C
Yield: 25.1 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (66 mg) was added to toluene/triethylamine=10/1 (7 ml), and the mixture wasp heated under reflux to prepare a solution. A solution of triphosgene (100 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 2-[(2,5-dimethylphenyl)sulfanyl]-1-propanol (70 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (29 mg, yield 23%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2.Cl[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC=CC=1>[CH2:7]1[C:8]2[C:4](=[CH:3][C:2]([O:1][CH2:12][C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:14])=[CH:10][CH:9]=2)[CH:5]=[CH:6]1
Reactant: O=C(CCl)c1ccccc1
Reactant: Oc1ccc2c(c1)CCC2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: O=C(COc1ccc2c(c1)C=CC2)c1ccccc1

Procedure:
Using the method of Example 1, step A, 5-hydroxyindane is reacted with α-chloroacetophenone in benzene in the presence of sodium carbonate to provide α-(5-indenoxy) acetophenone as a yellow solid.
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH2:9][C@@H:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][C:12](=[O:20])[CH2:11]4)[C@@H:6]1[CH2:5][CH2:4][C@@H:3]2[C:21]([OH:23])=O.CC(=O)[C@@H]1[C@]2(C)[C@H]([C@H]3[C@H](CC2)[C@]2(C)[C@H](CC(=O)CC2)CC3)CC1.C(Cl)(=O)C([Cl:50])=O>C1C=CC=CC=1>[Cl:50][C:21]([C@H:3]1[CH2:4][CH2:5][C@H:6]2[C@H:7]3[C@H:17]([CH2:18][CH2:19][C@:2]12[CH3:1])[C@:15]1([CH3:16])[C@H:10]([CH2:11][C:12](=[O:20])[CH2:13][CH2:14]1)[CH2:9][CH2:8]3)=[O:23]
Reactant: O=C(Cl)C(=O)Cl
Reactant: C[C@]12CCC(=O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C(=O)O)CC[C@@H]12
Agent: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: c1ccccc1
Product: C[C@]12CCC(=O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C(=O)Cl)CC[C@@H]12

Procedure:
A solution of 5α-androstan-3-one 17β-carboxylic acid (2.1 g., corrected for the presence of 15% 5α-pregnan-3,20 -dione) and oxalyl chloride (4 ml.) in dry benzene (125 ml.) was refluxed for 1.5 hours before evaporation to dryness to afford crude 17β-chlorocarbonyl-5α-androstan-3-one. Morpholinoethanol (5 ml.) was added to a stirred solution of the acid chloride in dry ether (125 ml.) and pyridine (3 ml.) at room temperature. After 1 hour the mixture was diluted with ether (100 ml.) and washed with aqueous 10% sodium hydroxide and water, dried (MgSO4), filtered and evaporated to give a gum (3.275 g.). A sample (2.0 g.) gave, after purification by preparative t.l.c. (ethanol/chloroform 1:19) title compound (900 mg.) as a white froth; [α]D + 54.5°, (c. 0.9).
Reaction SMILES: ClC1C=CC([CH:8]([N:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11]2=[O:21])[CH3:9])=CC=1.[I-].[CH3:23][N:24]1[C:32]2[C:27](=[C:28]([CH3:33])[CH:29]=[CH:30][CH:31]=2)[C:26]([CH2:34][N+](C)(C)C)=[CH:25]1.[C:39]([O-:42])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:23][N:24]1[C:32]2[C:27](=[C:28]([CH3:33])[CH:29]=[CH:30][CH:31]=2)[C:26]([CH2:34][N:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:19](=[O:20])[N:10]([CH2:8][CH2:9][N:10]3[CH2:11][CH2:39][O:42][CH2:9][CH2:8]3)[C:11]2=[O:21])=[CH:25]1
Reactant: O=C([O-])[O-]
Reactant: Cc1cccc2c1c(C[N+](C)(C)C)cn2C
Reactant: CC(c1ccc(Cl)cc1)n1c(=O)[nH]c2ccccc2c1=O
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc2c1c(Cn1c(=O)n(CCN3CCOCC3)c(=O)c3ccccc31)cn2C
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a mixture of 3-[1-(4-chloro-phenyl)-ethyl]-1H-quinazoline-2,4-dione (175 mg, 0.58 mmol) and (1,4-dimethyl-1H-indol-3-ylmethyl)-trimethylammonium iodide (210 mg, 0.61 mmol) in DMF (2.5 mL) is added K2CO3 (100 mg, 0.72 mmol). The mixture is stirred at 60° C. for 4 hours.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][CH:11]([F:41])[C:12]1[N:16]([C:17]2[N:22]=[C:21]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:20]=[C:19]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[N:18]=2)[C:15]2[CH:35]=[CH:36][CH:37]=[C:38]([O:39][CH3:40])[C:14]=2[N:13]=1.[Cl-].Cl[S:44]([CH2:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][NH+:50]=1)(=[O:46])=[O:45].O>C(Cl)Cl>[F:41][CH:11]([F:10])[C:12]1[N:16]([C:17]2[N:22]=[C:21]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[N:20]=[C:19]([N:29]3[CH2:34][CH2:33][N:32]([S:44]([CH2:47][CH2:48][C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][N:50]=4)(=[O:45])=[O:46])[CH2:31][CH2:30]3)[N:18]=2)[C:15]2[CH:35]=[CH:36][CH:37]=[C:38]([O:39][CH3:40])[C:14]=2[N:13]=1
Reactant: O=S(=O)(Cl)CCc1cccc[nH+]1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCNCC2)nc(N2CCOCC2)n1
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCN(S(=O)(=O)CCc3ccccn3)CC2)n1
Reaction time: 4 h
Yield: 71.5 %

Procedure:
DIPEA (0.29 mL, 1.66 mmol) was added to a suspension of 2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (Example 2) (150 mg, 0.336 mmol) and 2-[2-(chlorosulfonyl)ethyl]pyridinium chloride (122 mg, 0.504 mmol) in CH2Cl2 (10 mL) at room temperature under nitrogen, and the mixture was stirred for 4 hrs. Additional 2-[2-(chlorosulfonyl)ethyl]pyridinium chloride (41 mg, 0.169 mmol) was added and the reaction mixture was stirred for another 20 hrs. Water was added and the phases were separated. The aqueous phase was extracted with CH2Cl2, the combined organic extracts were dried (Na2SO4), and the solvent was removed under vacuum. Chromatography on silica, eluting with CH2Cl2/MeOH (100:0 to 98.5:1.5), gave 2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(4-{[2-(2-pyridinyl)ethyl]sulfonyl}-1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (148 mg, 71%).
Reaction SMILES: S(C)C.[CH3:4][Li].[C:6]([NH:25][C@@H:26]([CH2:29][CH3:30])[CH:27]=[O:28])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH4+].[Cl-]>CCOCC.CCCCCC>[C:6]([NH:25][C@@H:26]([CH2:29][CH3:30])[C@H:27]([OH:28])[CH3:4])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC[C@@H](C=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [Li]C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CSC
Solvent: CCOCC
Product: CC[C@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)[C@@H](C)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred suspension of CuBr.SMe2 (2.74 g, 2.2 eq, 13.33 mmol) in ether (100 mL) under an argon atmosphere at −70° C., was added methyl lithium (1.6 M in ether, 15.13 mL, 4.0 eq, 24.21 mmol) dropwise and the solution allowed to warm to room temperature. The mixture was recooled to −70° C., to which was added a solution of (S)-2-(trityl-amino)-butyraldehyde (2 g, 1 eq, 6.05 mmol) in Et2O (25 mL) dropwise with stirring. The reaction mixture was stirred at this temperature for 2 h and then at −55° C. for 4 h, when TLC (hexane:Et2O; 80:20) indicated that the reaction had gone to completion. To the reaction mixture was added a saturated aqueous solution of NH4Cl (100 mL) and allowed to warm to room temperature over 16 h. The reaction mixture was extracted with Et2O (2×200 mL), and the combined organic phase washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by silica gel column chromatography, eluted with hexane:Et2O (80:20) to afford the title compound as a light yellow oil. Yield: 1.37 g (66%). (80% de 2R,3S: 20% de 2S,3S). 1H-NMR (d6-DMSO, 250 MHz): δ 0.0.47 & 0.55 (2×t, J=7.50 & 7.26 Hz —NHCH(CH2CH3)CH(CH3)OH), 0.99-1.12 (m, 5H, —NHCH(CH2CH3)CH(CH3OH), 2.01 (m, 1H, —NHCH(CH2CH3)CH(CH3)OH), 3.22-3.43 (m, 1H, —NHCH(CH2CH3) CH(CH3)OH), 4.41 (d, 1H, J=3.31 Hz, —NHCH(CH2CH3)CH(CH3)OH), 7.14-7.56 (m, 15H, 3×Ph).
Reaction SMILES: [OH-].[Li+].[C:3]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]1[N:11]([CH3:22])[C:12](=[O:21])[C:13]([OH:20])=[C:14]([C:16]([O:18]C)=[O:17])[N:15]=1>O.C1COCC1>[C:3]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]1[N:11]([CH3:22])[C:12](=[O:21])[C:13]([OH:20])=[C:14]([C:16]([OH:18])=[O:17])[N:15]=1
Reactant: COC(=O)c1nc(Cc2ccccc2-c2ccccc2)n(C)c(=O)c1O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(Cc2ccccc2-c2ccccc2)nc(C(=O)O)c(O)c1=O
Reaction time: 24 h
Yield: 10.4 %

Procedure:
A solution of lithium hydroxide (8.2 mg, 342 μmol) in water was added to a stirred solution of methyl 2-(biphenyl-2-ylmethyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate (0.1 g, 285 μmol) in THF. After 24 h, the reaction was quenched by addition of 1M HCl, extracted into EtOAc, washed with brine, dried (MgSO4) and evaporated. Purification by preparative HPLC gave the desired product as a white solid (0.010 g; 10%). LCMS: m/z=337 (MH+).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:23])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])[CH2:10][CH2:9]1)C1C=CC=CC=1>ClCCCl.ClC(OC(Cl)C)=O>[ClH:22].[Cl:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:15][C:14]([CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)=[O:23]
Reactant: O=C(Cc1ccccc1Cl)C1CCN(Cc2ccccc2)CC1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Product: Cl
Product: O=C(Cc1ccccc1Cl)C1CCNCC1
Reaction time: 0.5 h
Yield: 162.3 %

Procedure:
After dissolving 252 mg of 1-(1-benzylpiperidin-4-yl)-2-(2-chlorophenyl)ethanone in 3 ml of 1,2-dichloroethane, 0.1 ml of 1-chloroethyl chloroformate was added while stirring on ice, and the mixture was heated to reflux for 1 hour. The reaction solution was concentrated under reduced pressure, 3 ml of methanol was added to the residue, and heating to reflux was continued for 30 minutes. The reaction solution was concentrated under reduced pressure, ethyl acetate was added to the residue and the precipitate was filtered out to obtain 171 mg of 4-(2-chlorophenylacetyl)piperidine hydrochloride. After then suspending 98 mg of the 4-(2-chlorophenylacetyl)piperidine hydrochloride in 3 ml of dichloromethane, 77 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and 114 mg of sodium triacetoxyborohydride were added while stirring on ice, and the stirring was continued overnight at room temperature. A 1N sodium hydroxide solution was added to the reaction mixture to render it alkaline, and then extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (112 mg, 78% yield).
Reaction SMILES: O[CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][S:15][CH2:16][CH2:17][N:18]2[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][N:20]=[C:19]2[CH3:26])[CH:6]=[CH:5][N:4]=1.S(Cl)([Cl:29])=O.C(=O)([O-])O.[Na+]>ClCCl>[Cl:29][CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][S:15][CH2:16][CH2:17][N:18]2[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][N:20]=[C:19]2[CH3:26])[CH:6]=[CH:5][N:4]=1
Reactant: Cc1c(SCCCCSCCn2c([N+](=O)[O-])cnc2C)ccnc1CO
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1c(SCCCCSCCn2c([N+](=O)[O-])cnc2C)ccnc1CCl
Temperature: 0 °C

Procedure:
4 g (10 mmol) of 2-hydroxymethyl-3-methyl-4-{4-[2-(2-methyl-5-nitroimidazol-1-yl)ethylthio]butylthio}-pyridine are dissolved in 40 ml of dichloromethane. 1.56 g (13.11 mmol) of thionyl chloride in 5 ml of dichloromethane are added dropwise with ice-cooling. The mixture is stirred at 0C for 2 h. It is then added to 250 ml of ice-water and neutralized with saturated sodium hydrogen carbonate solution. The dichloromethane phase is separated off and the aqueous phase is extracted again with dichloromethane. The combined organic phases are washed with water, dried over magnesium sulfate, filtered and concentrated. The title compound is obtained as a yellow oil which is reacted without further purification. Yield 4.15 g (100% of theory).
Reaction SMILES: S(Cl)([Cl:3])=O.[ClH:5].[CH2:6]([N:13]([CH2:17][CH2:18]O)[CH2:14][CH2:15]O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>ClCCl>[ClH:3].[CH2:6]([N:13]([CH2:17][CH2:18][Cl:3])[CH2:14][CH2:15][Cl:5])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: OCCN(CCO)Cc1ccccc1
Agent: Cl
Solvent: ClCCl
Product: ClCCN(CCCl)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
7.70 g (64.7 mmol) of thionyl chloride were added dropwise to a stirred solution of 5.00 g (21.6 mmol) of (2-[benzyl-(2-hydroxyethyl)amino]ethanol hydrochloride (XIX) in 100 ml of dry dichloromethane at 0° C., and the resulting reaction solution was then stirred at room temperature for 1 h. The solvent and excess thionyl chloride were removed in vacuo, and the reaction product was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:12]2[CH2:15][CH:14]([N:16]([CH3:25])[C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[CH3:24])[CH2:13]2)=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8]>O1CCOCC1.O>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:12]2[CH2:13][CH:14]([N:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[CH3:24])[CH3:25])[CH2:15]2)=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(Cl)cnc1N1CC(N(C)c2ccc(F)cc2C)C1
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(F)ccc1N(C)C1CN(c2ncc(Cl)cc2C(=O)O)C1
Temperature: 60 °C
Reaction time: 2 h
Yield: 95.5 %

Procedure:
To a solution of methyl 5-chloro-2-(3-(methyl(2-methyl-4-fluoro-phenyl)amino)azetidin-1-yl)nicotinate (D87) (170 mg, 0.467 mmol) in 1,4 dioxane (3 ml) and water (1 ml) 1M NaOH (0.7 ml) was added. The mixture was stirred at 60° C. for 2 h. Organic solvent was evaporated and remaining aqueous were acidified 2N HCl and extracted with ethylacetate (3×5 ml). The combined organic phases after solvent evaporation afforded the title compound (D120) (156 mg)