Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:42](=[O:43])[N:13]3[C:14]([C:26]([O:28][CH:29]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:27])=[C:15]([CH2:19][S:20][C:21]4[NH:25][N:24]=[N:23][N:22]=4)[CH2:16][S:17](=[O:18])[C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:44](Br)[C:45]#[CH:46].C(N(CC)CC)C>CN(C)C=O>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:42](=[O:43])[N:13]3[C:14]([C:26]([O:28][CH:29]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)=[O:27])=[C:15]([CH2:19][S:20][C:21]4[N:22]=[N:23][N:24]([CH2:46][C:45]#[CH:44])[N:25]=4)[CH2:16][S:17](=[O:18])[C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#CCBr
Reactant: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CSc3nnn[nH]3)CS(=O)[C@H]12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C#CCn1nnc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)Cc4ccccc4)[C@H]3S(=O)C2)n1
Temperature: 0 °C
Yield: 19.7 %

Procedure:
A mixture of benzhydryl 7-(2-phenylacetamido)-3-(1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylate-1-oxide (78.0 g) in N,N-dimethylformamide (780 ml) was stirred to give a homogeneous solution and thereto were added 2-propynyl bromide (30.2 g) and triethylamine (38.5 g). The resulting solution was stirred for 22.3 hours at room temperature. The reaction mixture was added to ice-water (1.5 l) and the mixture was extracted with ethyl acetate (×2). The extract was washed with water (×4), dried over magnesium sulfate, treated with activated charcoal and then evaporated. The residue was pulverized in isopropyl ether, collected by filtration, washed with isopropyl ether and then dried. The obtained product (60.61 g) was subjected to column chromatography on silica gel (1.5 kg), using benzene and ethyl acetate (2:1) as an eluent. Fractions containing 2-(2-propynyl)-2H-tetrazolyl isomer, which were firstly eluted, were collected and then evaporated. The residue was pulverized in a mixture of isopropyl ether and n-hexane to give benzhydryl 7-(2-phenylacetamido)-3-[2-(2-propynyl)-2H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylate-1-oxide (16.34 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.Cl[C:31](=[O:38])[C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33]>>[CH3:36][CH:35]([O:34][C:32]([C:31](=[O:38])[NH:21][C@@H:19]([CH3:20])[C@H:18]([O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[N:9]=[CH:10]2)[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1)=[O:33])[CH3:37]
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Reactant: CC(C)OC(=O)C(=O)Cl
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)C(=O)OC(C)C)c1

Procedure:
Prepared as described in Example 1 using (1R,2S)-1-[1-(4-fluorophenyl)-indazol-5-yl]oxy-1-(3-methoxyphenyl)-propan-2-amine (53 mg, 0.14 mmol) and isopropyl 2-chloro-2-oxoacetate (0.035 mL, 0.27 mmol) [prepared according to G. Bucher at al, Eur J Org Chem, 545-552 (2001); b.p. 54-55° C., 30 mmHg]. Yield 54 mg (79%).
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[N:10]1[CH2:11][CH2:12][CH2:13][N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[S:16][C:15]=12.[OH-].[NH4+]>>[N+:6]([C:21]1[CH:20]=[CH:19][C:18]2[N:14]3[CH2:13][CH2:12][CH2:11][N:10]=[C:15]3[S:16][C:17]=2[CH:22]=1)([O-:9])=[O:7]
Reactant: O=[N+]([O-])O
Reactant: c1ccc2c(c1)SC1=NCCCN12
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: O=[N+]([O-])c1ccc2c(c1)SC1=NCCCN12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To 92 parts of concentrated sulfuric acid are added portionwise 18.5 parts of 3,4-dihydro-2H-pyrimido[2,1-b]benzothiazole nitrate at 0° C. Upon completion, stirring is continued for 1 hour without cooling. The reaction mixture is poured onto 200 parts of ice-water and stirred for a while. The whole is alkalized with ammonium hydroxide and the product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is stirred in 2,2'-oxybispropane. The product is filtered off and dried, yielding 16.3 parts of 3,4-dihydro-8-nitro-2H-pyrimido[2,1-b]benzothiazole; mp. 247.6° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:19][CH2:18][C:15]([C:20]([O:22]N3C4C=CC=CC=4N=N3)=O)([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:43][C:44]12[CH2:51][CH2:50][C:47]([OH:52])([CH2:48][CH2:49]1)[CH2:46][CH2:45]2>>[CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:17][CH2:16][C:15]([C:20]([NH:43][C:44]34[CH2:51][CH2:50][C:47]([OH:52])([CH2:48][CH2:49]3)[CH2:46][CH2:45]4)=[O:22])([CH2:14][CH2:13]1)[CH2:18][CH2:19]2)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)On3nnc4ccccc43)(CC1)CC2
Reactant: NC12CCC(O)(CC1)CC2
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)NC34CCC(O)(CC3)CC4)(CC1)CC2
Yield: 61.7 %

Procedure:
In a similar manner to Example 4, (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(benzotriazol-1-yl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 4-aminobicyclo[2.2.2]octane-1-ol (13.5 mg) were used to obtain (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-[N-(4-hydroxybicyclo[2.2.2]oct-1-yl)amino]carbonylbicyclo[2.2.2)oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (31.2 mg).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:28]=[C:27]([NH:29][C:30]4[CH:35]=[CH:34][C:33]([CH:36]5[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]5)=[CH:32][N:31]=4)[C:26](=[O:42])[N:25]([CH3:43])[N:24]=3)[C:18]=1[CH2:44][OH:45])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:55][S:56](Cl)(=[O:58])=[O:57]>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:28]=[C:27]([NH:29][C:30]4[CH:35]=[CH:34][C:33]([CH:36]5[CH2:41][CH2:40][N:39]([S:56]([CH3:55])(=[O:58])=[O:57])[CH2:38][CH2:37]5)=[CH:32][N:31]=4)[C:26](=[O:42])[N:25]([CH3:43])[N:24]=3)[C:18]=1[CH2:44][OH:45])[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: Cn1nc(-c2cccc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(Nc2ccc(C3CCNCC3)cn2)c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1nc(-c2cccc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(Nc2ccc(C3CCN(S(C)(=O)=O)CC3)cn2)c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 40.5 %

Procedure:
In a 10 mL round-bottomed flask, 6-tert-butyl-8-fluoro-2-(2-(hydroxymethyl)-3-(1-methyl-6-oxo-5-(5-(piperidin-4-yl)pyridin-2-ylamino)-1,6-dihydropyridazin-3-yl)phenyl)phthalazin-1(2H)-one (35.03 mg, 57.5 μmol, Eq: 1.00) was combined with DCM (3 ml) and cooled to 0° C. DIPEA (8.91 mg, 12.0 μl, 68.9 μmol, Eq: 1.2) was added, followed by addition of methanesulfonyl chloride (6.58 mg, 4.48 μl, 57.5 μmol, Eq: 1). The reaction mixture was stirred at 0° C. to room temperature for 1 hr. The crude material was purified by flash chromatography (silica gel, 4 g, 0% to 5% of MeOH in 50% EtOAc/Hexane) to afford white solid (16 mg, 45%). (M+H)+=688.4 m/e. 1H NMR (300 MHz, CHLOROFORM-d) δ: 8.56 (s, 1H), 8.48 (br. s., 1H), 8.29 (br. s., 1H), 8.20 (br. s., 1H), 7.42-7.70 (m, 6H), 7.04 (d, J=8.2 Hz, 1H), 4.42 (br. s., 2H), 4.11 (q, J=7.0 Hz, 2H), 3.95 (d, J=11.3 Hz, 2H), 2.82 (s, 3H), 2.74-2.81 (m, 2H), 2.62 (t, J=11.5 Hz, 1H), 2.04 (s, 3H), 1.77-1.99 (m, 4H), 1.42 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[C:14]([NH:19][C:20](=[O:32])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([C:30]#[N:31])([CH3:29])[CH3:28])[CH:22]=3)[CH:15]=[CH:16][C:17]=1[Cl:18])[N:5]=2.[CH:33]1([C:36](Cl)=[O:37])[CH2:35][CH2:34]1>N1C=CC=CC=1>[Cl:18][C:17]1[CH:16]=[CH:15][C:14]([NH:19][C:20](=[O:32])[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([C:30]#[N:31])([CH3:28])[CH3:29])[CH:22]=2)=[CH:13][C:12]=1[O:11][C:6]1[N:5]=[C:4]2[S:3][C:2]([NH:1][C:36]([CH:33]3[CH2:35][CH2:34]3)=[O:37])=[N:10][C:9]2=[CH:8][CH:7]=1
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2ccc(Cl)c(Oc3ccc4nc(N)sc4n3)c2)c1
Reactant: O=C(Cl)C1CC1
Solvent: c1ccncc1
Product: CC(C)(C#N)c1cccc(C(=O)Nc2ccc(Cl)c(Oc3ccc4nc(NC(=O)C5CC5)sc4n3)c2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 46.2 %

Procedure:
To a solution of N-{3-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-4-chlorophenyl}-3-(1-cyano-1-methylethyl)benzamide (464 mg, 1.00 mmol) in pyridine (10 mL) was added cyclopropanecarbonyl chloride (181 μL, 2.00 mmol), and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate (50 mL), washed with 5% aqueous sodium hydrogen carbonate solution (50 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=60/40→0/100), and the obtained solution was concentrated under reduced pressure. The residue was crystallized from ethyl acetate/hexane to give the title compound (246 mg, 46%) as a colorless powder.
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7](O)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].B.C1COCC1>C1COCC1.[Cl-].[Na+].O>[C:10]([NH:1][C@H:2]([CH2:7][OH:8])[CH2:3][CH:4]([CH3:5])[CH3:6])([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: B
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C[C@@H](CO)NC(=O)OC(C)(C)C
Temperature: 23 °C
Reaction time: 3 h
Yield: 89.1 %

Procedure:
To a solution of BOC-Leu-OH (15.09 g, 65 mmol, 1 equiv) in THF (150 mL) at 0° C. was added BH3•THF (163 mL of a 1.0 M solution in THF, 163 mmol, 2.51 equiv). The reaction mixture was stirred at 23° C. for 3 h and then cooled to 0° C. Brine (100 mL) was added carefully, and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography (gradient elution, 25→35% EtOAc in hexanes) to afford BOC-L-Leucinol as a colorless oil (12.59 g, 89%): IR (cm−1) 3434, 1699, 1256, 739; 1H NMR (CDCl3) δ 0.93 (dd, 6H, J=6.6, 1.5), 1.29-1.31 (m, 2H), 1.45 (s, 9H), 1.60-2.05 (m, 2H), 3.47-3.53 (m, 1H), 3.65-3.72 (m, 2H), 4.56 (s, br, 1H); Anal. (C11H23NO3) C, H, N.
Reaction SMILES: [CH2:1]([C:3]([OH:25])([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=1)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13]Br)=[CH:6][CH:5]=1)[CH3:2].[CH2:26]([NH:29][CH2:30][CH2:31][CH3:32])[CH2:27][CH3:28]>>[CH2:1]([C:3]([OH:25])([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=1)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][N:29]([CH2:30][CH2:31][CH3:32])[CH2:26][CH2:27][CH3:28])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCC(O)(c1ccc(OCCCBr)cc1)c1cccc(C(F)(F)F)c1
Reactant: CCCNCCC
Product: CCCN(CCC)CCCOc1ccc(C(O)(CC)c2cccc(C(F)(F)F)c2)cc1
Reaction time: 6 h

Procedure:
20.8 g. of α-ethyl-α-(3-trifluoromethylphenyl)-4-(3-bromopropoxy)-benzylalcohol and 41 ml. of dipropyl amine are slightly refluxed with stirring for 6 hours. After cooling, the reaction mixture is evaporated under reduced pressure. To the residue water is added and it is extracted with benzene. The benzene phase is washed with water, dried over anhydrous potassium carbonate and evaporated. The residue is fractionated in vacuo to yield 17.2 g. of the desired compound, boiling at 176° to 178° C./6.6 Pa.
Reaction SMILES: [CH3:1][C:2]([CH3:20])([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[C:18]([NH2:19])=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:9][CH2:8]1)=[O:6])[CH3:3].[CH3:21][C:22](=O)[CH2:23][CH3:24].C(O)(=O)C>CO>[CH3:3][C:2]([CH3:20])([O:4][C:5]([N:7]1[CH2:8][CH2:9][N:10]([C:13]2[C:18]([NH:19][CH:22]([CH3:21])[CH2:23][CH3:24])=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:11][CH2:12]1)=[O:6])[CH3:1]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncccc2N)CC1
Reactant: CCC(C)=O
Solvent: CC(=O)O
Solvent: CO
Product: CCC(C)Nc1cccnc1N1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Following the general procedure of PREPARATION 3 and making non-critical variations but starting with 1-[1,1-dimethylethoxycarbonyl]-4-[(3-amino)-2-pyridinyl)piperazine (International Publication No. WO 88/08424, 1.0 g), 2-butanone (0.27 g) sodium cyanoborohydride (0.23 g), acetic acid (5.1 ml) and methanol, the title compound is obtained, NMR (300 MHz, CDCl3) 7.68, 6.94, 6.86, 4.18, 3.56, 3.33, 3.05, 1.53, 1.47, 1.18 and 0.96 δ.
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([C:12]#[N:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:15][OH:16].[OH-].[K+]>C(O)C>[C:1]1([C:7]2[O:11][C:10]([C:12](=[N:15][OH:16])[NH2:13])=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#Cc1ccc(-c2ccccc2)o1
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: NC(=NO)c1ccc(-c2ccccc2)o1
Temperature: 25 °C

Procedure:
A mixture of 10 g (0.059 mole) of 5-phenyl-2-furonitrile, 4.1 g (0.060 mole) of hydroxylamine hydrochloride, 4.0 g (0.060 mole) of potassium hydroxide, and 150 ml of absolute ethanol was refluxed for 21/2 hours, cooled to room temperature, and then added to 750 ml of ice/H2O. the resulting solid was washed in water and dried at 60° to yield 10 g (84%), m.p. 118°-120°.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][CH:12]([C:23]([O:26][CH2:27][CH3:28])([CH3:25])[CH3:24])[C:13]([O:15]CC2C=CC=CC=2)=[O:14])[N:4]=1.[H][H]>C(O)C.[C].[Pd]>[CH3:10][O:9][C:7]1[N:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([O:11][CH:12]([C:23]([O:26][CH2:27][CH3:28])([CH3:24])[CH3:25])[C:13]([OH:15])=[O:14])[N:6]=1
Reactant: CCOC(C)(C)C(Oc1nc(OC)nc(OC)n1)C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(C)(C)C(Oc1nc(OC)nc(OC)n1)C(=O)O
Temperature: 20 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
That is, in 200 ml of ethanol were dissolved 39.2 g (0.1 mol) of Compound 155 prepared in the above (6), and 0.5 g of palladium carbon was added thereto as a catalyst. The mixture was stirred at room temperature (20° C.) for 1 hour while blowing hydrogen therein. Subsequently, the catalyst was removed by filtration, and the mother liquor was concentrated to obtain 28.6 g (yield: 95%) of the title compound as a colorless oily product.
Reaction SMILES: Cl.[OH2:2].N=[C:4]1[C:8]([CH3:15])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[S:7][C:6](=[S:16])[N:5]1[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CO>[CH3:15][C:8]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[S:7][C:6](=[S:16])[N:5]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:4]1=[O:2]
Reactant: O
Reactant: CC1(c2ccccc2)SC(=S)N(Nc2ccccc2)C1=N
Agent: Cl
Solvent: CO
Product: CC1(c2ccccc2)SC(=S)N(Nc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
37% hydrochloric acid (5 ml) and water (1 ml) was added at room temperature with stirring to a solution of 4-imino-5-methyl-5-phenyl-3-phenylaminothiazolidine-2-thione (9.38 g) in methanol (50 ml). The solution was stirred for 24 hrs at room temperature. The solvent was then evaporated under reduced pressure. The residue was purified by column chromatography (ethyl acetate-n-hexane, 1/3) to yield an oily 5-methyl-5-phenyl-3-phenylamino-2-thioxothiazolidin-4-one (7.02 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH3:16])([CH3:4])([CH3:3])[CH3:2].[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[N:30]=[CH:29][C:28]([C:31]2[S:32][C:33]([CH3:39])=[C:34]([CH2:36][CH2:37]O)[N:35]=2)=[CH:27][CH:26]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:17])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:37][CH2:36][C:34]2[N:35]=[C:31]([C:28]3[CH:29]=[N:30][C:25]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[F:18])=[CH:26][CH:27]=3)[S:32][C:33]=2[CH3:39])=[CH:11][C:10]=1[CH3:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(O)ccc1CCC(=O)OC(C)(C)C
Reactant: Cc1sc(-c2ccc(-c3ccccc3F)nc2)nc1CCO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: Cc1cc(OCCc2nc(-c3ccc(-c4ccccc4F)nc3)sc2C)ccc1CCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.6 %

Procedure:
A solution of 3-(4-Hydroxy-2-methyl-phenyl)-propionic acid tert-butyl ester (120 mg, 0.5 mmol) and 2-{2-[6-(2-Fluoro-phenyl)-pyridin-3-yl]-5-methyl-thiazol-4-yl}-ethanol (101 mg, 0.323 mmol) in toluene (3.0 mL) is degassed and filled with nitrogen for 3 times. Tributylphosphine (0.124 mL, 0.5 mmol) is added to the reaction mixture under nitrogen at 0° C., followed by addition of of 1,1′-(azodicarbonyl)-dipiperidine (120 mg, 0.5 mmol). The reaction mixture is allowed to warm to room temperature and stirred overnight, the mixture is loaded on silica gel column. Chromatography gave the title compound (130 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=O.[N:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1.C(O)(C)C>C(OC(=O)C)(=O)C>[N+:11]([C:8]1[CH:7]=[C:4]([CH:5]=[CH:20][C:17]2[CH:18]=[CH:19][N:14]=[CH:15][CH:16]=2)[CH:3]=[C:2]([OH:1])[C:9]=1[OH:10])([O-:13])=[O:12]
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Reactant: Cc1ccncc1
Solvent: CC(C)O
Solvent: CC(=O)OC(C)=O
Product: O=[N+]([O-])c1cc(C=Cc2ccncc2)cc(O)c1O

Procedure:
A solution containing 2.0 g (0.011 mole) of 3,4-dihydroxy-5-nitrobenzaldehyde and 2.23 g (0.024 mole) of 4-picoline in 9.0 ml of acetic anhydride was refluxed for 1 h. About 15 ml of isopropanol was then added and the solution was cooled to 0° C. where upon the diacetyl-derivative of the desired product crystallized. After filtration the product was suspended in 100 ml of 0.5N hydrochloric acid and refluxed for 1.5 h. After cooling the precipitate was filtered, washed with water and acetone and dried. Yield 1.89 g (67%), m.p. above 350° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1([CH2:12][CH2:11][CH2:10][O:9][CH2:8]1)[CH2:6][C:5]2=[O:17].[Br-].[CH:19]1([Zn+])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C1COCC1.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.[Cu]I>[CH:19]1([C:2]2[CH:3]=[C:4]3[C:14](=[CH:15][CH:16]=2)[O:13][C:7]2([CH2:12][CH2:11][CH2:10][O:9][CH2:8]2)[CH2:6][C:5]3=[O:17])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: [Zn+]C1CCCCC1
Reactant: O=C1CC2(CCCOC2)Oc2ccc(Br)cc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [Br-]
Solvent: C1CCOC1
Product: O=C1CC2(CCCOC2)Oc2ccc(C3CCCCC3)cc21
Temperature: 160 °C
Yield: 33.1 %

Procedure:
Pd(PPh3)2Cl2 (60 mg) in a 40 mL tube under Ar was treated sequentially with 6-bromo-2′,4′,5′,6′-tetrahydrospiro[chroman-2,3′-pyran]-4-one (600 mg, 2.01 mmol) in THF (20 mL*3), CuI (600 mg) and cyclohexylzinc(II) bromide (8.1 mL, 4.02 mmol). The mixture was heated under microwave at 160° C. for 10 min. The reaction mixture was concentrated in vacuo to give the residue, which was purified by column chromatography to give 6-cyclohexyl-2′,4′,5′,6′-tetrahydrospiro[chroman-2,3′-pyran]-4-one (200 mg, 30%). 1H-NMR (CDCl3): 1.31 (t, 4H), 1.48 (m, 1H), 1.62 (m, 5H), 1.76 (d, 4H), 1.89 (m, 1H), 2.06 (d, 1H), 2.49 (s, 1H), 2.61 (m, 2H), 3.49 (m, 2H), 3.79 (m, 2H), 6.88 (d, 1H), 7.29 (d, 2H), 7.61 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([N:12]2[CH2:16][CH2:15][CH:14]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]2)=[C:7]([F:25])[C:6]=1F)[CH3:2].[CH:28]1([NH2:31])[CH2:30][CH2:29]1>CN(C)C(=O)C>[CH2:1]([O:3][C:4](=[O:27])[C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([N:12]2[CH2:16][CH2:15][CH:14]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]2)=[C:7]([F:25])[C:6]=1[NH:31][CH:28]1[CH2:30][CH2:29]1)[CH3:2]
Reactant: CCOC(=O)c1cc(Cl)c(N2CCC(NC(=O)OC(C)(C)C)C2)c(F)c1F
Reactant: NC1CC1
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1cc(Cl)c(N2CCC(NC(=O)OC(C)(C)C)C2)c(F)c1NC1CC1
Yield: 48.7 %

Procedure:
A solution of 4-[3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-5-chloro-2,3-difluorobenzoic acid ethyl ester (Example 21, 3.75 g, 9.3 mmol) and cyclopropylamine (14.0 mL, 201 mmol) in N,N-dimethylacetamide (5 mL) is heated in a sealed glass tube for 48 hours at 100° C. The solution is then concentrated under high vacuum and purified by column chromatography (1:9 ethyl acetate/hexanes) to afford the title compound (2.0 g). 1H NMR (CDCl3): δ 7.64 (d, 1H), 7.56 (bs, 1H), 4.98–4.90 (bd, 1H), 4.40–4.20 (m, 3H), 3.78–3.63 (m, 4H), 2.97–2.83 (m, 1H), 2.35–2.21 (m, 1H), 1.93–1.81 (m, 1H), 1.46 (s, 9H), 1.38 (t, 3H), 0.75–0.61 (m, 2H), 0.57–0.50 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[O:8][CH:7]=[C:6]([OH:9])[C:4](=[O:5])[CH:3]=1.CN(C)C.[C:14](Cl)(=[O:22])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>C1COCC1>[C:14]([O:9][C:6]1[C:4](=[O:5])[CH:3]=[C:2]([CH3:1])[O:8][CH:7]=1)(=[O:22])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: Cc1cc(=O)c(O)co1
Reactant: CCCCCCCC(=O)Cl
Agent: CN(C)C
Solvent: C1CCOC1
Product: CCCCCCCC(=O)Oc1coc(C)cc1=O
Reaction time: 0.08 h
Yield: 89.9 %

Procedure:
Allomaltol (600 mg; 4.76 mmol) was weighed out into a round bottom flask (100 ml) containing a stir-bar. The contents were diluted with anhydrous THF (˜20 ml) and stirred (˜5 min) to afford a solution. Next, trimethyl amine (833 μl; 6.33 mmol; 1.33 equiv.) was added drop-wise and the contents stirred (˜5 min). Octanoyl chloride (770 μl; 724 mg; 4.45 mmol) was then added drop-wise, capped and stirred at room temperature. The reaction was monitored via silica gel TLC. Once complete, the reaction mixture was concentrated under reduced pressure and the contents purified by silica gel chromatography to afford 1.01 g of light yellow crystalline product (4.00 mmol; 90% yield). This compound was found to have an EC50 of 532 μM. 1H NMR (DMSO-d6) δ 8.39 (s, 1H; 2-H); 6.35 (s, 1H; 5-H); 2.54-2.52 (t, 2H); 2.29 (s, 3H; 6-CH3); 1.60-1.58 (p, 2H); 1.34-1.31 (m, 2H), 1.31-1.24 (m, 6H); 0.87-0.85 (t, 3H; —CH3).
Reaction SMILES: [ClH:1].[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.[F:19][C:20]1[CH:29]=[CH:28][C:23]([O:24][CH2:25][CH2:26]Br)=[CH:22][CH:21]=1.C([O-])([O-])=O.[K+].[K+]>>[ClH:1].[F:19][C:20]1[CH:29]=[CH:28][C:23]([O:24][CH2:25][CH2:26][N:16]2[CH2:17][CH2:18][CH:13]([CH2:12][C:3]3[CH:4]=[CH:5][C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[CH:2]=3)[CH2:14][CH2:15]2)=[CH:22][CH:21]=1
Reactant: Fc1ccc(OCCBr)cc1
Reactant: c1ccc2cc(CC3CCNCC3)ccc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Fc1ccc(OCCN2CCC(Cc3ccc4ccccc4c3)CC2)cc1

Procedure:
The title compound was prepared from 4-((2-naphthyl)methyl)piperidine hydrochloride (150 mg, 573 μmol), 2-(4-fluorophenoxy)ethyl bromide (132 mg, 602 μmol) and K2CO3 (162 mg, 1.17 mmol) as a colorless solid (126 mg): mp 170-172° C.; 1H NMR (CDCl3) 1.60-1.92 (m, 3H), 2.02-2.41 (m, 2H), 2.65-2.90 (m, 4H), 3.45-3.55 (m, 2H), 3.60-3.71 (m, 2H), 4.51 (t, J=4.2 Hz, 2H), 6.77-7.01 (m, 4H), 7.25 (d, J=6.0 Hz, 1H), 7.40-7.51 (m, 2H), 7.57 (s, 1H), 7.72-7.84 (m, 3H) 12.64 (bs, 1H). Anal. Calcd for C24H27ClFNO: C, 72.08; H, 6.80; N, 3.50. Found: C, 71.73; H, 6.64; N, 3.34.