Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[F:9][C:10]([F:19])([F:18])[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.S(=O)(=O)(O)O>C(O)(=O)C.O>[I:1][C:13]1[CH:12]=[C:11]([C:10]([F:18])([F:19])[F:9])[CH:16]=[CH:15][C:14]=1[OH:17]
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: O=C1CCC(=O)N1I
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: Oc1ccc(C(F)(F)F)cc1I
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 63 %

Procedure:
To a suspension of N-iodosuccinimide (11.10 g, 49.5 mmol) in glacial acetic acid (40 ml) was added 4-trifluoromethyl phenol (8.02 g, 49.5 mmol) and, after 5 minutes, concentrated sulphuric acid (0.87 ml, 14.8 mmol). The pale brown/red suspension was stirred at room temperature under nitrogen for 48 hours before diluting with water and extracting with dichloromethane. The organic extract was washed with water, saturated aqueous sodium thiosulphate solution, water, dried over magnesium sulphate before decolourising charcoal added. The suspension was left to stand for 10 minutes before filtering through a short pad of silica gel eluting with dichloromethane. The solvent was evaporated in vacuo to give an oil which was purified by flash column chromatography on silica eluting with dichloromethane to give the title compound as a pale yellow oil, 9.017 g, 63% yield.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18]([NH:20][C@@H:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C@H:24]([O:31][C:32]3[CH:33]=[CH:34][C:35]4[N:36]([C:38]([CH2:41][N:42]5[CH2:47][CH2:46][N:45]([CH3:48])[CH:44]([CH2:49][O:50][Si](C(C)C)(C(C)C)C(C)C)[CH2:43]5)=[N:39][N:40]=4)[CH:37]=3)[CH2:23][CH2:22]2)=[O:19])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.O>[C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18]([NH:20][C@@H:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C@H:24]([O:31][C:32]3[CH:33]=[CH:34][C:35]4[N:36]([C:38]([CH2:41][N:42]5[CH2:47][CH2:46][N:45]([CH3:48])[CH:44]([CH2:49][OH:50])[CH2:43]5)=[N:39][N:40]=4)[CH:37]=3)[CH2:23][CH2:22]2)=[O:19])[N:8]([C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(CN5CCN(C)C(CO[Si](C(C)C)(C(C)C)C(C)C)C5)n4c3)c3ccccc32)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(CN5CCN(C)C(CO)C5)n4c3)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
A mixture of Intermediate 56f (60.0 mg, 72.0 μmol) and TBAF (1M in THF, 144 μL, 144 μmol) in THF (3 mL) was stirred at RT for 1 h. The mixture was diluted with water and extracted with EtOAc (3×). The combined organic extracts were washed with brine, and concentrated in vacuo. The residue was purified by FCC, using 0-20% MeOH in DCM, to afford the title compound as an off-white solid (24.9 mg, 51%). LCMS (Method 5): Rt 3.54 min, m/z 678 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.27 (9H, s), 1.82-2.01 (4H, m), 2.01-2.25 (7H, m), 2.53-2.88 (3H, m), 3.21 (1H, m), 3.54 (1H, m), 3.96-4.11 (2H, m), 4.37 (1H, dt, J 12.5, 5.4), 4.84 (1H, m), 5.47 (1H, m), 6.32 (1H, s), 7.10 (1H, d, J 8.4), 7.22-7.44 (9H, m), 7.72 (1H, d, J 10.3), 8.02 (1H, s), 8.30 (1H, m).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[N:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:18][CH:17]=3)=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8]C.O>C(O)(=O)C.Br>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[N:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:18][CH:17]=3)=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: CCCCCCCc1ccc(-c2cnc(-c3ccc(OC)c(F)c3)nc2)cc1
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: CCCCCCCc1ccc(-c2cnc(-c3ccc(O)c(F)c3)nc2)cc1
Temperature: 25 °C
Yield: 87.2 %

Procedure:
2.5 g of the 2-(3-fluoro-4-methoxyphenyl)-5-(4-heptylphenyl)pyrimidine obtained in Example 1 was dissolved in a mixture of 200 ml of acetic acid and 100 ml of 47% hydrobromic acid. The obtained solution was heated under reflux for 18 hours. The reaction mixture was allowed to cool to room temperature and 500 ml of water was added thereto. The crystals thus precipitated were filtered. The product thus obtained was purified by column chromatography (developing solvent: hexane: ethyl acetate 5:1) to thereby give 2.1 g of 2-(3-fluoro-4-hydroxyphenyl)-5-(4-heptylphenyl)pyrimidine. Yield: 87%.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][NH:5][CH2:6][CH2:7]Cl.[CH2:9]([O:11][C:12](=[O:20])[C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=1)[CH3:10].C(=O)([O-])[O-].[K+].[K+]>ClC1C=CC=CC=1>[CH2:9]([O:11][C:12](=[O:20])[C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]2)=[CH:15][CH:14]=1)[CH3:10]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: ClCCNCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Clc1ccccc1
Product: CCOC(=O)c1ccc(N2CCNCC2)cc1
Temperature: 25 °C
Yield: 72.9 %

Procedure:
A stirred mixture of bis-(2-chloroethyl)amine hydrochloride (5.35 g, 30.00 mmol), 4-aminobenzoic acid ethyl ester (4.13 g, 25.00 mmol), and potassium carbonate (4.40 g, 32.00 mmol) in chlorobenzene (200 mL) was refluxed for 30 hours. After cooling to ambient temperature the mixture was filtered and the filtrate was concentrated in vacuo to dryness to provide 4.27 g (73% yield) of 4-piperazin-1-yl-benzoic acid ethyl ester.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH:6]([CH3:8])[CH3:7])=[O:3].[S-:9][C:10]#[N:11].N1C2C(=CC=CC=2)C=CC=1.C([O-])([O-])=O.[Na+].[Na+]>O>[CH2:5]([O:4][C:2]([N:11]=[C:10]=[S:9])=[O:3])[CH:6]([CH3:8])[CH3:7]
Reactant: N#C[S-]
Reactant: CC(C)COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccc2ncccc2c1
Product: CC(C)COC(=O)N=C=S

Procedure:
136.58 grams (1 mole) of 99% isobutyl chloroformate are added to a 50% thiocyanate solution containing 81 grams (1 mole) of NaSCN, 81 grams of water, 4.36 grams of quinoline (catalyst) and 1.8 grams of Na2CO3 (base) while maintaining a reaction temperature of 25–30° C. with agitation. The reaction is monitored for the consumption of the chloroformate during the formation of an upper layer of isobutoxycarbonyl isothiocyanate (approximately 4 hours). The contents of the reaction vessel are filtered to remove solid sodium chloride and the isobutoxycarbonyl isothiocyanate is isolated in the form of a layer that separates from the aqueous layer.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([CH3:12])[C:10]=1[OH:11])[CH:6]=[O:7])[CH3:2].[O-:13]Cl=O.[Na+].Cl>CS(C)=O.O>[CH2:1]([C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([CH3:12])[C:10]=1[OH:11])[C:6]([OH:13])=[O:7])[CH3:2]
Reactant: [O-][Cl+][O-]
Reactant: CCc1cc(C=O)cc(C)c1O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCc1cc(C(=O)O)cc(C)c1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.8 %

Procedure:
To a solution of 3-ethyl-4-hydroxy-5-methyl-benzaldehyde (78.8 g, 0.48 mol) in DMSO (585 mL), a solution of NaH2PO4 dihydrate (17.3 g, 0.144 mol) in water (160 mL) is added over a period of 13 min. The mixture is stirred at rt an a solution of NaClO2 (65.17 g, 0.577 mol) in water (160 mL) is added while the mixture is cooled with an ice-bath. The mixture is stirred for 1 h before a second portion of NaClO2 (43.44 g, 0.480 mol) in water (100 mL) is added while the temperature is kept between 25 and 40° C. with an ice-bath. The yellow suspension is stirred at rt for 24 h before it is acidified with 32% aq. HCl to pH 2-3. The mixture is extracted with TBME (250 mL), the org. extract is washed with water, and the washings are extracted back with TBME. The solvent of the combined org. extracts is evaporated to give crude 3-ethyl-4-hydroxy-5-methyl-benzoic acid (80.3 g) as a yellow solid.
Reaction SMILES: Cl.[CH3:2][C:3]1[N:7]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[C:6]2[CH:14]=[CH:15][C:16]([C:18](O)=O)=[CH:17][C:5]=2[N:4]=1.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[SH:28].N>>[S:28]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]=[C:18]1[C:16]1[CH:15]=[CH:14][C:6]2[N:7]([CH:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[C:3]([CH3:2])=[N:4][C:5]=2[CH:17]=1
Reactant: Nc1ccccc1S
Reactant: Cc1nc2cc(C(=O)O)ccc2n1C1CCOCC1
Agent: Cl
Agent: N
Product: Cc1nc2cc(-c3nc4ccccc4s3)ccc2n1C1CCOCC1
Temperature: 150 °C
Reaction time: 17 h
Yield: 1.9 %

Procedure:
A 4-neck flask (50 mL) equipped with reflux condenser was charged with 2-methyl-1-(tetrahydropyran-4-yl)benzimidazole-5-carboxylic acid HCl salt (see Working Example 4-3) (0.28 g, 1.08 mmol), 2-aminobenzenethiol (0.14 g, 1.08 mmol) and polyphosphoric acid (approx. 11 g), and this was heated to 150° C. and stirred for 17 hours. After being allowed to cool to room temperature, this was cooled in ice (0 to 5° C.), and concentrated aqueous ammonia (28%) was added to the liquid to give approx. pH 9. After distilling off the solvent under reduced pressure, the brown viscous residue was extracted with ethyl acetate, this was dried over anhydrous magnesium sulfate. The residue obtained after again distilling off the solvent under reduced pressure was purified by PTLC to yield the title compound (0.007 g, 1.8% yield) as greenish-pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[CH:17]([OH:19])[CH3:18].Cl[C:21]1[CH:22]=[CH:23][C:24]2[N:25]([C:27]([CH2:30][NH:31][C:32]3[C:41]4[C:36](=[CH:37][C:38]([O:42][CH3:43])=[CH:39][N:40]=4)[N:35]=[CH:34][CH:33]=3)=[N:28][N:29]=2)[N:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[Cl:1][C:2]1[CH:7]=[C:6]([C:21]2[CH:22]=[CH:23][C:24]3[N:25]([C:27]([CH2:30][NH:31][C:32]4[C:41]5[C:36](=[CH:37][C:38]([O:42][CH3:43])=[CH:39][N:40]=5)[N:35]=[CH:34][CH:33]=4)=[N:28][N:29]=3)[N:26]=2)[CH:5]=[CH:4][C:3]=1[CH:17]([OH:19])[CH3:18]
Reactant: COc1cnc2c(NCc3nnc4ccc(Cl)nn34)ccnc2c1
Reactant: CC(O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cnc2c(NCc3nnc4ccc(-c5ccc(C(C)O)c(Cl)c5)nn34)ccnc2c1
Temperature: 100 °C

Procedure:
A suspension of 1-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethanol (228 mg, 807 μmol), N-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-7-methoxy-1,5-naphthyridin-4-amine (197 mg, 576 μmol), dichloro[1,1 bis(diphenylphoshino)ferrocene]palladium(ii)dichloromethane adduct (127 mg, 173 μmol), cesium carbonate (751 mg, 2306 μmol) in dioxane (3 mL) and water (0.6 mL) was sparged with argon for 5 min then heated to 100° C. for 6 h. Reaction cooled then partitioned between 9:1 CHCl3/IPA (20 mL) and 1M NaOH (15 mL). Aqueous further extracted with 9:1 CHCl3/IPA (2×10 mL). The combined organics dried over MgSO4. concentrated, then purified on 40 g silica eluting with an isocratic 7% 2M NH3 in MeOH/DCM. Product further purified prep HPLC eluting with water/ACN (0.1% TFA). After collected fractions were reduced to a clear the residue was dissolved in 1:1 ACN/water and pH adjusted to 9 with 1M NaOH (3-4 drops). Resulting solid collected by filtration and solid washed with water (2 mL). MS (ESI pos. ion) m/z: 462 (MH+). Calc'd exact mass for C23H20ClN7O2: 461.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)=[O:4].[S-:12][C:13]#[N:14].[K+].O>C(O)C>[Cl:11][C:7]1[CH:6]=[C:5]([C:3](=[O:4])[CH2:2][S:12][C:13]#[N:14])[CH:10]=[CH:9][CH:8]=1
Reactant: N#C[S-]
Reactant: O=C(CBr)c1cccc(Cl)c1
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#CSCC(=O)c1cccc(Cl)c1
Temperature: 25 °C
Yield: 72 %

Procedure:
A solution of 2-bromo-1-(3-chlorophenyl)ethanone (7.55 g, 32.3 mmol) and potassium thiocyanate (3.14 g, 32.3 mmol) in ethanol (70 ml) was stirred at 80° C. for 2 hours. After cooling to room temperature, water (70 ml) was poured to the reaction mixture. Crystals were collected by filtration and washed with water to give 4.92 g (69.8%) of the desired product as a solid.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20](O)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl.[F:26][C:27]1([C:31]([O:33][CH3:34])=[O:32])[CH2:30][NH:29][CH2:28]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:34][O:33][C:31]([C:27]1([F:26])[CH2:30][N:29]([C:20](=[O:21])/[CH:19]=[CH:18]\[N:15]2[CH:16]=[N:17][C:13]([C:5]3[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=[C:3]([C:2]([F:23])([F:24])[F:1])[CH:4]=3)=[N:14]2)[CH2:28]1)=[O:32]
Reactant: COC(=O)C1(F)CNC1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1(F)CN(C(=O)/C=C\n2cnc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C1
Temperature: -60 °C
Reaction time: 0.75 h
Yield: 24 %

Procedure:
(Z)-3-(3-(3,5-Bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.20 g, 1.0 eq.) was dissolved in DCM (4 mL). The reaction mixture was cooled to −60° C., at which temperature methyl 3-fluoroazetidine-3-carboxylate hydrochloride (0.09 g, 1.2 eq.) and T3P (50% in EtOAc) (0.427 g, 1.2 eq.) were added, followed by DIPEA (0.146 g, 2 eq.). The clear reaction mixture was stirred at −60° C. for 45 min and concentrated under reduced pressure (25° C., 20 mm Hg) to afford the crude product, which was purified by chromatography (20-30% ethyl acetate in hexane) to give (Z)-methyl-1-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)-3-fluoroazetidine-3-carboxylate. (40 mg; 24% yield). 1H NMR (400 MHz, CDCL3) δ 9.51 (S, 1H), 8.62 (s, 2H), 7.96 (s, 1H), 7.20-7.18 (d, J=10.8, 1H), 5.70-5.68 (d, J=10.8 Hz, 1H), 4.15-3.82 (m, 4H), 3.82 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:17]2[C:25]3[C:24]([NH2:26])=[N:23][CH:22]=[N:21][C:20]=3[N:19]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH2:34][CH2:35]Cl)[CH:28]=3)[CH:18]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:37]1[CH:41]=[CH:40][N:39]=[CH:38]1.[Na]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:17]2[C:25]3[C:24]([NH2:26])=[N:23][CH:22]=[N:21][C:20]=3[N:19]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH2:34][CH2:35][N:37]4[CH:41]=[CH:40][N:39]=[CH:38]4)[CH:28]=3)[CH:18]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2cn(-c3cccc(OCCCl)c3)c3ncnc(N)c23)cc1OCc1ccccc1
Reactant: c1c[nH]cn1
Agent: [Na]
Solvent: CN(C)C=O
Product: COc1ccc(-c2cn(-c3cccc(OCCn4ccnc4)c3)c3ncnc(N)c23)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.1 g of 5-(3-benzyloxy-4-methoxyphenyl)-7-[3-(2-chloro-1-ethoxy)phenyl]-4-aminopyrrolo-[2,3-d]pyrimidine and 0.3 g of sodium imidazole are heated to 85° C. in 30 ml of DMF and the mixture is stirred for 8 h. It is then cooled to RT and concentrated. After chromatography on silica gel, 5-(3-benzyloxy-4-methoxyphenyl)-7-[3-(2-(1-imidazolyl)ethoxy)phenyl]-4-amino-pyrrolo[2,3-d]pyrimidine having an m.p. of 150° C. is obtained.
Reaction SMILES: C1(OP([O-])(OC2C=CC=CC=2)=O)C=CC=CC=1.[NH2:18][C:19]1[CH:20]=[N+:21]([CH2:25][CH2:26][S:27][C:28]2[CH2:34][C@H:33]3[N:30]([C:31](=[O:38])[C@@H:32]3[C@H:35]([OH:37])[CH3:36])[C:29]=2[C:39]([O:41]CC2C=CC([N+]([O-])=O)=CC=2)=[O:40])[CH:22]=[CH:23][CH:24]=1.C1COCC1.CCOCC>P([O-])([O-])([O-])=O.[Pd]>[NH2:18][C:19]1[CH:20]=[N+:21]([CH2:25][CH2:26][S:27][C:28]2[CH2:34][C@H:33]3[N:30]([C:31](=[O:38])[C@@H:32]3[C@H:35]([OH:37])[CH3:36])[C:29]=2[C:39]([O-:41])=[O:40])[CH:22]=[CH:23][CH:24]=1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SCC[n+]3cccc(N)c3)C[C@H]12
Agent: [Pd]
Agent: O=P([O-])(Oc1ccccc1)Oc1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(SCC[n+]3cccc(N)c3)C[C@H]12
Reaction time: 1 h
Yield: 128.8 %

Procedure:
To a mixture of p-nitrobenzyl (5R, 6S)-3(2-(3-aminopyridinio)ethyl thio)-6-(1-(R)-hydroxyethyl)-7-oxo-1-azabicyclo(3.2.0)hept-2-ene-2-carboxylate diphenylphosphate (0.730 g, 1.0 mmol) and 10% palladium-on-charcoal (0.7 g) in 25 mL of a phosphate buffer (0.05 m, pH 7.4) was added 8 mL of THF and 20 mL of ether. This mixture was then hydrogenated (Parr) at 40 psi for 1 h. The resulting mixture was filtered through a pad of Celite and the filter cake was washed with H2O and ether. The aqueous phase was separated, washed with ether (2x) and then residual volatiles were removed in vacuo. The aqueous solution was immediately applied to a C18 reverse-phase column which was eluted with H2O. Lyophilization of the relevant fractions afforded 0.45 g of an off-white solid. This material was repurified by reverse-phase hplc to give the desired product (0.123 g, 35%) as an ivory-colored solid.
Reaction SMILES: [C:1]1([C@H:11]([NH:13][CH2:14][CH:15]2[CH:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:19][CH2:18][NH:17][CH2:16]2)[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[N:34]([C:37]1[CH:46]=[CH:45][CH:44]=[CH:43][C:38]=1[C:39]([O:41][CH3:42])=[O:40])=[C:35]=[O:36]>C1(C)C=CC=CC=1>[C:1]1([C@H:11]([NH:13][CH2:14][CH:15]2[CH:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:19][CH2:18][N:17]([C:35]([NH:34][C:37]3[CH:46]=[CH:45][CH:44]=[CH:43][C:38]=3[C:39]([O:41][CH3:42])=[O:40])=[O:36])[CH2:16]2)[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccccc1N=C=O
Reactant: C[C@@H](NCC1CNCCC1c1ccccc1)c1cccc2ccccc12
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)c1ccccc1NC(=O)N1CCC(c2ccccc2)C(CN[C@H](C)c2cccc3ccccc23)C1
Temperature: 90 °C
Reaction time: 8 h
Yield: 11.4 %

Procedure:
To a solution of 158 mg of (1R)-1-(1-naphthyl)-N-[(4-phenylpiperidin-3-yl)methyl]ethaneamine and 0.100 mL of triethylamine in 3.0 mL of toluene was added 83 mg of methyl 2-isocyanatobenzoate at room temperature. It was stirred at 90° C. overnight, and then cooled to room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform-methanol) to obtain 27.3 mg of methyl 2-({[3-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpiperidin-1-yl]carbonyl}amino)benzoate as a colorless foamy substance.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([I:15])=[CH:11][CH:10]=2)[CH2:4]1.C(N(C(C)C)CC)(C)C.Cl[CH:26](Cl)[C:27](=[N:29][NH:30]S(C1C(C)=CC=CC=1)(=O)=O)[CH3:28]>CO>[I:15][C:12]1[CH:13]=[CH:14][C:9]([N:5]2[CH2:4][C@H:3]([CH2:2][N:1]3[CH:26]=[C:27]([CH3:28])[N:29]=[N:30]3)[O:7][C:6]2=[O:8])=[CH:10][CH:11]=1
Reactant: NC[C@H]1CN(c2ccc(I)cc2)C(=O)O1
Reactant: CC(=NNS(=O)(=O)c1ccccc1C)C(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: Cc1cn(C[C@H]2CN(c3ccc(I)cc3)C(=O)O2)nn1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
(5S)-5-(Aminomethyl)-3-(4-iodophenyl)-1,3-oxazolidin-2-one (6.0 g, 18.9 mmol) was dissolved in methanol (150 ml, c=0.1M) and cooled to 0° C. Diisopropylethylamine (13.1 ml, 75.4 mmol) was added and the reaction stirred at 0° C. for 5 min; toluenesulfonic acid 2-(2,2-dichloro-1-methylethylidene)hydrazide was then added and the reaction stirred overnight. The volatiles were concentrated in vacuo, dichloromethane was added and some product crystallized from solution; the remaining residue was purified by flash chromatography on silica gel using 0-5% methanol in dichloromethane as the eluent. The relevant fractions were combined giving 5.5 g of the desired product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][CH2:10][CH2:11][SH:12])=[CH:4][CH:3]=1.[C:13](=O)(OC1C=CC=CC=1)[O:14]C1C=CC=CC=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[CH2:10][CH2:11][S:12][C:13]2=[O:14])=[CH:6][CH:7]=1
Reactant: Cc1ccc(CNCCS)cc1
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Product: Cc1ccc(CN2CCSC2=O)cc1
Yield: 29.8 %

Procedure:
The procedure of Example 2 is followed, 4.0 g (0.022 mol) of N-(4-methylphenylmethyl)cysteamine are reacted with 4.71 g (0.022 mol) of diphenyl carbonate then the reaction mixture is worked up to give 1.36 g (29.8%) of the title compound, m.p.: 49°-50° C.
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:11]([NH2:19])(=[S:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCOCC>C(O)C>[C:12]1([C:11]2[S:18][CH:2]=[C:3]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:19]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NC(=S)c1ccccc1
Reactant: CCOC(=O)CC(=O)CBr
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)Cc1csc(-c2ccccc2)n1

Procedure:
Ethyl γ-bromoacetoacetate [2.62 g, 0.9-1.0 mole, described by A. Burger and G. E. Ullyot, J. Org. Chem., 12, 346 (1947)]is added in one portion to a suspension of thiobenzamide [117.5 g, 0.857 mole, described by A. Silberg et al., Ber., 94, 2887 (1961)] in ethanol. The clear solution is refluxed on a steam bath for 2 hr, cooled and slowly added with stirring to ether (3500 ml). The white crystalline precipitate is collected, washed with ether and partitioned between water and ether. Sodium bicarbonate is added in portions until the mixture is alkaline. The mixture is extracted with ether, the ether solution is washed with saturated sodium chloride solution, dried, and evaporated to give ethyl 2-phenylthiazole-4-acetate (VII; R1 = H, R9 = CH2CH3), γmaxCHCl3 1725 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][NH2:14].N1C(C)=CC=CC=1C.Cl/[C:24](=[CH:27]/[C:28]#[N:29])/[C:25]#[N:26].Cl/C(=C\C#N)/C#N>CO>[NH2:29][C:28]1[N:13]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:9])([F:11])[F:10])=[CH:5][C:4]=2[Cl:12])[N:14]=[C:24]([C:25]#[N:26])[CH:27]=1
Reactant: N#C/C=C(/Cl)C#N
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: N#C/C=C(\Cl)C#N
Solvent: Cc1cccc(C)n1
Solvent: CO
Product: N#Cc1cc(N)n(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Reaction time: 16 h
Yield: 71 %

Procedure:
A 50 mL round-bottom flask was charged with (2,6-dichloro-4-trifluoromethyl-phenyl)-hydrazine (1.2 g, 4.84 mmol), 2,6-lutidine (0.57 g, 5.32 mmol, 1.1 equiv.) and methanol (10 mL). A mixture of chloromaleonitrile and chlorofumaronitrile (0.82 g, 7.29 mmol) was slowly added at 20-25° C. Stirring was continued for about 16 hours at that temperature. The solution was then concentrated at a pressure of 50 mbar. The residue was purified by flash column chromatography (silica, hexanes/EtOAc 100:0→70:30) to give the product as a off-white solid (1.1 g, 3.43 mmol, 71%), melting point: 117-118° C., 1H-NMR (360 MHz, CDCl3): δ [ppm]=7.78 (d, 2H, J=0.4 Hz); 6.04 (s, 1H); 3.83 (bs, 2H), 13C-NMR (125 MHz, DMSO-d6): δ [ppm]=150.0; 136.0; 135.9; 132.7 (q, J=34 Hz); 126.43; 126.42; 122.4 (q, J=273 Hz); 114.6; 90.8.
Reaction SMILES: [C:1]1([C:7]2[C:11]3=[N:12][C:13](=[O:16])[C:14](=[O:15])[C:10]3=[N:9][C:8]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:23]([N:12]1[C:11]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[C:8]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:9]([CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:10]=2[C:14](=[O:15])[C:13]1=[O:16])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: O=c1nc2c(-c3ccccc3)c(-c3ccccc3)nc-2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1C(=O)N(Cc2ccccc2)c2c(-c3ccccc3)c(-c3ccccc3)n(Cc3ccccc3)c21
Temperature: 100 °C
Yield: 101.3 %

Procedure:
A 100 ml round-bottom flask equipped with a stirrer and reflux condenser is charged with 1.47 g (5.1 mmol) of diphenyl-diketopyrrolopyrrole (hereinafter referred to DPP), 3.44 g (20.1 mmol) of benzyl bromide, 1.38 g (10.0 mmol) of K2CO3 and 50 ml of DMF. Under nitrogen atmosphere, the mixture is stirred and heated at 100° C. for 42.5 hours. The slurry is cooled and the orange solid is isolated by filtration. The solid is washed with water and MeOH, followed by dissolving in hot CHCl3. This CHCl3 solution is applied to silica gel column using CH2Cl2 as eluent. After condensation, 1.21 g of an orange solid is obtained (51%).