Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:10][CH:11]1[CH2:23][C:22]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:24][C:25]([F:28])([F:27])[F:26])[CH:20]=3)[N:15]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[N:31]=3)[C:14]=2[CH2:13][CH2:12]1)C1C=CC=CC=1.[H][H]>CCO.C1COCC1.[Pd]>[F:36][C:32]1[N:31]=[C:30]([CH2:29][N:15]2[C:14]3[CH2:13][CH2:12][CH:11]([NH2:10])[CH2:23][C:22]=3[C:21]3[C:16]2=[CH:17][CH:18]=[C:19]([O:24][C:25]([F:28])([F:26])[F:27])[CH:20]=3)[CH:35]=[CH:34][CH:33]=1
Reactant: O=C(NC1CCc2c(c3cc(OC(F)(F)F)ccc3n2Cc2cccc(F)n2)C1)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: NC1CCc2c(c3cc(OC(F)(F)F)ccc3n2Cc2cccc(F)n2)C1
Yield: 117.5 %

Procedure:
Dissolve [9-(6-fluoro-pyridin-2-ylmethyl)-6-trifluoromethoxy-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-carbamic acid benzyl ester (Preparation 45) (2.73 g, 5.32. mmol) in EtOH (100 mL) and THF (50 mL). Add 10% Pd/C (200 mg) and stir at room temperature under a balloon of hydrogen for 18 h. Filter the reaction through a pad of Celite®, rinse the pad with THF (50 mL), and concentrate the filtrate in vacuo to afford 2.37 g (90%) of the title compound as a dark brown oil. MS (ES): m/z 380 (M+1); HPLC (Method A): Rt=1.76 min (89%).
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[C:4]([NH2:16])[CH:3]=1.[CH3:17][C:18]([CH3:20])=O.[BH4-].S(=O)(=O)(O)O>O>[CH:18]([NH:16][C:4]1[CH:3]=[C:2]([CH3:1])[CH:15]=[CH:14][C:5]=1[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7])([CH3:20])[CH3:17]
Reactant: CC(C)=O
Reactant: Cc1ccc(C(=O)c2ccccc2)c(N)c1
Agent: O=S(=O)(O)O
Agent: [BH4-]
Solvent: O
Product: Cc1ccc(C(=O)c2ccccc2)c(NC(C)C)c1
Reaction time: 1 h

Procedure:
Examples 1-19 as recorded in the following Table I represent trials in which the amount of 4-methyl-2-aminobenzophenone (a compound III in amount of 21.1 grs. or 0.1 mol) is held constant and the amount of other reaction system components including acetone (the compound III), borohydride (sodium borohydride), acid (sulfuric acid) and water are varied. In these examples, the reaction system is maintained at 20°-25° C. throughout the reaction and the rate of addition of the borohydride is controlled accordingly, such addition requiring in most cases about 60 minutes, after which the reaction system is stirred for an additional 60 minutes, followed by filtering. The filtrate is concentrated and the residue dissolved in about 88 mls. of heptane and the resulting solution extracted first with 20 mls. of 4N. ammonium hydroxide solution, then three times each with 10 mls. of 2N. sulfuric acid, and then washed with 10 mls. of 0.5N sulfuric acid. The heptane is distilled off to obtain the desired 2-(N-isopropylamino)-4-methylbenzophenone which boils at 180° -185° C./5 mm Hg.
Reaction SMILES: [CH:1]([N-:5][CH:6]=[CH:7][N-:8][CH:9]([CH2:11][CH3:12])[CH3:10])([CH2:3][CH3:4])[CH3:2].[Li+].[Li+].[Cl:15][SiH:16](Cl)Cl>CCCCCC>[Cl:15][SiH:16]1[N:5]([CH:1]([CH2:3][CH3:4])[CH3:2])[CH:6]=[CH:7][N:8]1[CH:9]([CH2:11][CH3:12])[CH3:10]
Reactant: Cl[SiH](Cl)Cl
Reactant: CCC(C)[N-]C=C[N-]C(C)CC
Agent: [Li+]
Solvent: CCCCCC
Product: CCC(C)N1C=CN(C(C)CC)[SiH]1Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 42 %

Procedure:
In an argon atmosphere, a dilithium(N,N′-di-sec-butyl-1,2-vinylenediaminide) solution prepared according to the procedure and reagent quantities described in Reference Example-8 was added to a hexane (150 mL) solution containing 25.00 g (184.6 mmol) of trichlorosilane, and the mixture was stirred at room temperature for 6 hours. Insoluble matters produced were separated by filtration, and the solvent was removed by distillation from the filtrate under atmospheric pressure. The obtained residue was distilled under reduced pressure (distillation temperature: 85° C./5×102 Pa) to obtain 2-chloro-1,3-di-sec-butyl-1,3-diaza-2-silacyclopent-4-ene (Si(sBuNCHCHNsBu)(H)Cl) as a pale yellow liquid (yielded amount: 18.10 g, yield: 42%). This product was a mixture of a plurality of isomers differing in the steric configuration from each other.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.C(N(CC)CC)C.Cl[C:17](=[O:23])[C:18]([O:20][CH2:21]C)=[O:19].C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH3:21][O:20][C:18](=[O:19])[C:17]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1)=[O:23]
Reactant: Nc1ccc(Cl)cn1
Reactant: CCOC(=O)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(=O)Nc1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
2-Amino-5-chloropyridine (1.16 g) and triethylamine (1.51 mL) were dissolved in methylene chloride (26 mL), and ethyl chlorooxoacetate (1.10 mL) was added thereto under ice cooling, followed by stirring at room temperature for 14 hours. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture to partition the mixture, and the organic layer was dried over sodium sulfate anhydrate. The solvent was distilled away under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1). The resultant pale-yellow solid was dissolved in methanol (20 mL), and the solution was stirred at 50° C. for 11 hours. The reaction mixture was concentrated under reduced pressure. The precipitated crystals were collected by filtration, and were dried, to thereby give the title compound (0.43 g).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:11][C:12]1[CH:17]=[CH:16][C:15]([C@@H:18]2[O:22][C:21](=[O:23])[CH2:20][CH2:19]2)=[CH:14][C:13]=1[CH3:24].Br[CH2:26][CH:27]=[CH:28]C.CN(P(N(C)C)(N(C)C)=O)C>C1COCC1>[CH2:28]([C@H:20]1[CH2:19][C@H:18]([C:15]2[CH:16]=[CH:17][C:12]([F:11])=[C:13]([CH3:24])[CH:14]=2)[O:22][C:21]1=[O:23])[CH:27]=[CH2:26]
Reactant: Cc1cc([C@H]2CCC(=O)O2)ccc1F
Reactant: CC=CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: C=CC[C@H]1C[C@H](c2ccc(F)c(C)c2)OC1=O
Temperature: -70 °C
Reaction time: 0.33 h

Procedure:
To a solution of lithium bis(trimethylsilyl)amide (1.2 mmol) in anhydrous THF (20 mL) was added (R)-5-(4-fluoro-3-methyl-phenyl)-dihydro-furan-2-one (194 mg) in 1 mL THF at −70° C. over a period of 15 minutes. After completing the addition, the mixture was stirred for an additional 20 min at −70° C. and then for 10 min at room temperature. The mixture was cooled down again to −70° C. and a pre-cooled solution of 200 mg 1-bromo-but-2-ene and 400 μL HMPA in 1 mL THF slowly added. The mixture was further stirred at −70° C. for 2 h and the temperature was slowly raised to room temperature over a period of 2 h. The reaction was quenched by pouring into saturated NH4Cl (20 mL) and followed extraction with ethyl acetate (3×30 mL). The combined organic layers were washed with 20 mL brine twice and dried over Na2SO4. The solvent was removed under reduced pressure and the product isolated by flash column chromatographed eluting with 0% to 50% ethyl acetate/hexane gradient solvent to give the anti/syn products (94:6 ratios).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[S:5][C:6]=1[CH2:7]O.C(N(CC)CC)C.CS([Cl:30])(=O)=O>C(Cl)Cl>[Cl:30][CH2:7][C:6]1[S:5][C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[N:3][C:2]=1[CH3:1]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCl
Reaction time: 2 h

Procedure:
A solution of [4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methanol (1.03 g, 3.75 mmol) and triethyl amine (1.05 mL, 7.5 mmol) in methylene chloride (15 mL) is cooled to 0° C., then MeSO2Cl is added dropwise. After 2 hrs, TLC indicated that the reaction is not complete, 10 mol % more of triethyl amine and MeSO2Cl are added. After additional 2 hrs, the reaction mixture is diluted with methylene chloride and washed with sodium bicarbonate, water and brine, dried over sodium sulfate. Concentration gave the crude title compound, which is used for the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](Cl)=[N:6][CH:7]=1.[CH3:12][NH2:13].CCO>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH:13][CH3:12])=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Reactant: CN
Solvent: CCO
Solvent: C1CCOC1
Product: CNc1ncc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-bromo-2-chloro-3-nitropyridine (Matrix, Columbia, USA, 9.8 g, 41.3 mmol) in 250 ml THF was added 8 M methylamine in EtOH (Aldrich, Buchs, Switzerland, 12.9 ml, 103 mmol). The reaction mixture was stirred 1 h at rt then was quenched with 300 ml water. The precipite was filtered and the filtrate concentrated before being filtered again. The yellow solids were combined and dried to give the title compound as a yellow solid (HPLC: tR 3.13 min (Method A)).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:16])[NH:10][C@H:11]([CH2:14][OH:15])[CH2:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CS(C)=O>[CH2:1]([O:8][C:9](=[O:16])[NH:10][C@H:11]([CH:14]=[O:15])[CH2:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[C@@H](CO)NC(=O)OCc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC[C@@H](C=O)NC(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 54.8 %

Procedure:
A solution of benzyl[(1S)-1-(hydroxymethyl)propyl]carbamate (30.0 g) in dimethyl sulfoxide (260 mL) was ice-cooled under a nitrogen atmosphere, and triethylamine (56.9 mL) and a solution of sulfur trioxide•pyridine complex (71.3 g) in dimethyl sulfoxide (260 mL) was successively added. The mixture was stirred at the same temperature for 1 hr, and at room temperature for 4 hr. A 1 mol/L aqueous citric acid solution (450 mL) was added to the reaction solution, and the mixture was extracted with diethyl ether. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=0→30%) to give the title compound as a colorless oil (yield: 16.3 g, 55%).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].COC1C=CC2CC([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)C3C=C(C)C=CC=3OC=2C=1.[CH2:31](Br)[C:32]#[CH:33]>C(O)CCC>[C:31]([CH:21]1[CH2:20][NH:19][CH2:24][CH2:23][NH:22]1)#[C:32][CH3:33]
Reactant: COc1ccc2c(c1)Oc1ccc(C)cc1C(N1CCNCC1)C2
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: CC#CC1CNCCN1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
3.8 G. of sodium carbonate are added to a solution of 10 g. of 1-[10,11 -dihydro-3-methoxy-8-methyl-dibenz[b,f]oxepin-10-yl]-piperazine in 55 ml. of butanol and then a solution of 2.5 ml. of propargyl bromide in 20 ml. of butanol is added dropwise. Then, the mixture is stirred for 20 hours at room temperature and the solvent is removed by distillation under reduced pressure. After working-up in an analogous manner to that described in Example 13, there is isolated crude 1-[10,11-dihydro-3-methoxy-8-methyl-dibenz[ b,f]oxepin-10-yl]-4-(2-propynylpiperazine in the form of an oil. The dihydrochloride, prepared in ethanol and recrystallized from methanol/ether, melts at 210°-212° C. (with decomposition).
Reaction SMILES: N[C:2]1[C:3]2[C:27]([CH3:29])([CH3:28])[C:26](=[O:30])[NH:25][C:4]=2[N:5]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[N:16][C:11]3=[C:10]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[N:9]=2)[N:7]=1.N(OCCC(C)C)=O.[I:39]CI>CN1C(=O)CCC1>[F:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][C:10]1[N:9]=[C:8]([C:6]2[N:7]=[C:2]([I:39])[C:3]3[C:27]([CH3:28])([CH3:29])[C:26](=[O:30])[NH:25][C:4]=3[N:5]=2)[N:12]2[CH:13]=[CH:14][CH:15]=[N:16][C:11]=12
Reactant: ICI
Reactant: CC1(C)C(=O)Nc2nc(-c3nc(Cc4ccccc4F)c4ncccn34)nc(N)c21
Agent: CC(C)CCON=O
Solvent: CN1CCCC1=O
Product: CC1(C)C(=O)Nc2nc(-c3nc(Cc4ccccc4F)c4ncccn34)nc(I)c21
Temperature: 85 °C
Reaction time: 4 h

Procedure:
1.500 g (3.35 mmol) of 4-amino-2-[8-(2-fluorobenzyl)imidazo[1,5-a]pyrimidin-6-yl]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one was suspended in 6.00 ml (44.56 mmol) of isopentyl nitrite and 4.00 ml (49.66 mmol) of diiodomethane and it was stirred for 2d at 85° C. 4.00 ml isopentyl nitrite and 5 ml NMP were added and the solution was stirred for 4 h at 85° C. The mixture was concentrated by evaporation in the rotary evaporator except the NMP and was purified by preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80→100:0). 928 mg (purity 69%, 37% of theor.) of the target compound was obtained.
Reaction SMILES: Br[C:2]1[C:11]2[O:10][CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][C:5]=2[S:4][CH:3]=1.[C:19](B1OC(C)(C)C(C)(C)O1)([CH3:21])=[CH2:20].C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[CH3:21][C:19]([C:2]1[C:11]2[O:10][CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][C:5]=2[S:4][CH:3]=1)=[CH2:20]
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)csc2C1
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: C=C(C)c1csc2c1OCCN(C(=O)OC(C)(C)C)C2
Temperature: 85 °C
Reaction time: 12 h
Yield: 91.5 %

Procedure:
A mixture of tert-butyl 8-bromo-2,3-dihydrothieno[2,3-f][1,4]oxazepine-4(5H)-carboxylate (334 mg) obtained in Example 1, steps 1-3, isopropenylboronic acid pinacol ester (168 mg), saturated aqueous sodium carbonate solution (6 ml), tetrakis(triphenylphosphine)palladium (32.5 mg) and DME (9 ml) was stirred at 85° C. for 12 hr under a nitrogen atmosphere, and poured into water, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 0→30% ethyl acetate/hexane) to give the title compound (270 mg, 91.5%) as an oil.
Reaction SMILES: [CH2:1]([N:8]([C:12]1[C:17]2[N:18]=[C:19](Cl)[N:20]=[C:21]([N:22]3[CH2:27][CH2:26][S:25](=[O:28])[CH2:24][CH2:23]3)[C:16]=2[N:15]=[CH:14][N:13]=1)[CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[CH2:1]([N:8]([CH2:9][CH2:10][OH:11])[C:12]1[C:17]2[N:18]=[C:19]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[N:20]=[C:21]([N:22]3[CH2:27][CH2:26][S:25](=[O:28])[CH2:24][CH2:23]3)[C:16]=2[N:15]=[CH:14][N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S1CCN(c2nc(Cl)nc3c(N(CCO)Cc4ccccc4)ncnc23)CC1
Reactant: C1CNCCN1
Product: O=S1CCN(c2nc(N3CCNCC3)nc3c(N(CCO)Cc4ccccc4)ncnc23)CC1

Procedure:
This compound was prepared analogous to Example 118 from 8-[N-benzyl-N-(2-hydroxyethyl)-amino]-2-chloro-4-(1-oxido-thiomorpholino)-pyrimido-[5,4-d]-pyrimidine (m.p.: 153°-155° C.) and piperazine.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]2[N:9]=[C:10]([N+:12]([O-])=O)[CH:11]=[C:5]2[CH2:4]1)[CH3:2].[H][H]>[Pd].CO>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]2[N:9]=[C:10]([NH2:12])[CH:11]=[C:5]2[CH2:4]1)[CH3:2]
Reactant: [H][H]
Reactant: CCN1CCn2nc([N+](=O)[O-])cc2C1
Agent: [Pd]
Solvent: CO
Product: CCN1CCn2nc(N)cc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.7 %

Procedure:
A 50-mL single-neck round-bottomed flask was purged with nitrogen and charged with 208a (1.4 g, 7.1 mmol), 10% palladium on carbon (50% wet, 208 mg), methanol (30 mL), and hydrogen gas. The mixture was stirred at room temperature under hydrogen atmosphere for 2 h. The catalyst was removed by filtration through a pad of CELITE® and the filtrate was concentrated under reduced pressure to afford 208b (1.0 g, 84%) as yellow oil. MS-ESI: [M+H]+ 167
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11]([OH:13])=O)[N:4]=1.[C:19]1([C:25]2[N:26]=[C:27]([C:30]3([CH2:36][NH2:37])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[S:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[C:19]1([C:25]2[N:26]=[C:27]([C:30]3([CH2:36][NH:37][C:11](=[O:13])[C:10]4[CH:14]=[CH:15][CH:16]=[C:8]([C:5]5[N:4]=[C:3]([C:2]([F:1])([F:18])[F:17])[O:7][N:6]=5)[CH:9]=4)[CH2:31][CH2:32][O:33][CH2:34][CH2:35]3)[S:28][CH:29]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: NCC1(c2nc(-c3ccccc3)cs2)CCOCC1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: O=C(NCC1(c2nc(-c3ccccc3)cs2)CCOCC1)c1cccc(-c2noc(C(F)(F)F)n2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid (52 mg, 0.202 mmole), (4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine (50 mg, 0.184 mmole), and EDCI (38.5 mg, 0.202 mmole) in CH2Cl2 (2 ml) was stirred at room temperature for 8 h. The reaction mixture was then diluted with methylene chloride (10 ml), washed with water (5 ml), dried over MgSO4 and concentrated under reduced pressure. The residue was purified by ISCO (silica gel, elute: 2% methanol in CH2Cl2) to give N-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide as a white solid product (59 mg, 62% yield): 1H NMR (CDCl3, 500 MHz): 8.49 (s, 1H), 8.22 (d, J=7.5 Hz, 1H), 7.98 (d, J=8.5 Hz, 1H), 7.88 (d, J=8 Hz, 2H), 7.56-7.53 (m, 2H), 7.52 (s, 1H), 7.369-7.31 (m, 3H), 3.97-3.93 (m, 2H), 3.91 (d, J=5.5 Hz, 2H), 3.77-3.74 (m, 2H), 2.36-2.28 (m, 2H), 2.06-2.04 (m, 2H). MS (ESI) m/z: Calculated for C25H21F3N4O3S: 514.13. found: 515.1 (M−H)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:28][CH3:29])[CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]3[CH:15]=[CH:16][C:17]([O:19][CH2:20][CH2:21][N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:18][C:13]=3[S:12][C:11]=2[CH:27]=1)[CH3:2].C1C[O:33]CC1>>[CH2:28]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]3[CH:15]=[CH:16][C:17]([O:19][CH2:20][CH2:21][N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:18][C:13]=3[S:12](=[O:33])[C:11]=2[CH:27]=1)[CH3:29]
Reactant: C1CCOC1
Reactant: CCN(CC)CCOc1ccc2c(c1)sc1cc(OCCN(CC)CC)ccc12
Product: CCN(CC)CCOc1ccc2c(c1)S(=O)c1cc(OCCN(CC)CC)ccc1-2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a cooled solution (0° C.) of the product of Example 16A (347 mg, 0.83 mmol) in dry THF (2 mL), was added a solution of CF3CO3H in THF (4 M; 0.21 mL, 0.83 mmol). The reaction was stirred 30 minutes at 0° C., then for 30 minutes at room temperature, and concentrated under vacuum. The residue was purified by flash chromatography (35 g silica gel, 1:5:94 NH4OH-MeOH—CH2Cl2) to afford the title compound (360 mg, 100%).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]([CH:24]=[O:25])=[C:11]([C:26]3[CH2:31][CH2:30][C:29]([F:33])([F:32])[CH2:28][CH:27]=3)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:35]1[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][N:36]=1>>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:19])([CH3:20])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]([C@@H:24]([C:35]3[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][N:36]=3)[OH:25])=[C:11]([C:26]3[CH2:31][CH2:30][C:29]([F:33])([F:32])[CH2:28][CH:27]=3)[C:10]1=2)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)c1nc2c(c(C3=CCC(F)(F)CC3)c1C=O)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Reactant: FC(F)(F)c1ccc(Br)nc1
Product: CC(C)c1nc2c(c(C3=CCC(F)(F)CC3)c1[C@H](O)c1ccc(C(F)(F)F)cn1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2

Procedure:
Obtained by starting from (S)-5-(tert-butyldimethylsilyloxy)-4-(4,4-difluorocyclohex-1-enyl)-2-isopropyl-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-3-carbaldehyde and 2-bromo-5-(trifluoromethyl)pyridine.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][S:11][C:10](=S)[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1[O:17]C1C.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([C@H:8]1[CH2:12][S:11][C:10](=[O:17])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: S=C1N[C@@H](Cc2ccccc2)CS1
Reactant: CC1CO1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1N[C@@H](Cc2ccccc2)CS1
Reaction time: 2 h

Procedure:
To a solution (4S)-4-benzyl-1,3-thiazolidine-2-thione (38 g) in dichloromethane (350 mL), cooled to 0° C. was added propylene oxide (12.7 mL) and trifluoroacetic acid (14 mL). After stirring the reaction mixture for 2 hours, the solvents were evaporated under reduced pressure to obtain a residue which was purified by column chromatography over silica gel using 20% ethylacetate in hexane as eluant to afford the title compound (0.9 g). Mass (m/z): 194.18
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][N:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[Br:11][C:12]1[CH:13]=[N:14][C:15](Cl)=[N:16][CH:17]=1.O>C1COCC1>[Br:11][C:12]1[CH:13]=[N:14][C:15]([O:3][CH2:4][CH2:5][N:6]2[CH2:10][CH2:9][CH2:8][CH2:7]2)=[N:16][CH:17]=1
Reactant: OCCN1CCCC1
Reactant: Clc1ncc(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Brc1cnc(OCCN2CCCC2)nc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
50 mg (1.15 mmol, 60%) NaH are added to a solution of 0.17 mL (1.38 mmol) N-(2-hydroxyethyl)pyrrolidine in 10 mL THF at RT. The reaction solution is stirred for 15 min at RT and then 200 mg (1.03 mmol) 5-bromo-2-chloropyrimidine are added. The solution is stirred for 16 h at RT. 10 mL water are added and the aqueous phase is extracted with 20 mL EtOAc. The organic phase is dried over Na2SO4 and the solvent is eliminated i.vac. Further purification is carried out by column chromatography on silica gel (DCM/MeOH/NH3 9:1:0.1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(N(CC)CC)C.[C:24](Cl)(=[O:26])[CH3:25]>C(Cl)Cl>[C:24]([N:14]1[CH2:15][CH2:16][N:11]([C:3]2[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=2[F:1])[CH2:12][CH2:13]1)(=[O:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)c(F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A stirred solution of 1-(2-fluoro-4-nitrophenyl)piperazine (15 g, 66.6 mmol) in DCM (160 ml) was cooled to 0° C. Triethylamine was then added (11.23 ml, 79.92 mmol) followed by dropwise addition of acetyl chloride (5.68 ml, 79.92 mmol). The solution was allowed to warm to ambient temperature and stir for 1.5 hour. The reaction mixture was diluted with DCM, washed with water, sat. sodium hydrogen carbonate and brine. It was dried and the solvent was evaporated to give the title compound as a solid which was dried in vac oven overnight at 50° C. (17.46 g, 98%). NMR (400 MHz) 2.05 (s, 3H), 3.30 (dt, 4H, under H2O signal), 3.61 (m, 4H), 7.18 (t, 1H), 8.02 (d, 1H), 8.02 (dd, 1H); m/z 268.