Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C@:22]2([CH3:28])[CH2:26][O:25]C(=O)[NH:23]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].[OH-].[Li+].C(O)C.O>>[NH2:23][C@@:22]([C:17]1[CH:16]=[CH:15][C:14]2[C:19](=[CH:20][CH:21]=[C:12]([O:11][C@H:8]3[CH2:7][CH2:6][C@@H:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:10][CH2:9]3)[CH:13]=2)[CH:18]=1)([CH3:28])[CH2:26][OH:25]
Reactant: CCCC[C@H]1CC[C@@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCC[C@H]1CC[C@@H](Oc2ccc3cc([C@@](C)(N)CO)ccc3c2)CC1

Procedure:
The mixture of (R)-4-(6-(cis-4-butylcyclohexyloxy)naphthalen-2-yl)-4-methyloxazolidin-2-one (294.3 mg, 0.7714 mmol) and lithium hydroxide (203 mg, 8.48 mmol) in Ethanol (4.9 mL, 0.084 mol) and water (1.6 mL, 9.1 mmol) was heated to reflux for overnight. LCMS showed reaction completed. The solvent was removed under vacuum and the residue was partitioned between water and CH2Cl2. The aqueous was extensively extracted with CH2Cl2. And the combined organic phase was dried over Na2SO4. The concentrated residue was taken up into CH2Cl2 and subjected to chromatography purification with CH2Cl2/MeOH (10:90 to 80:20) to give the product. LCMS 339.53 ([M−NH2]+, 100%). 1H NMR (400 MHz, CD3OD) δ ppm 0.92 (t, J=7.0 Hz, 3H), 1.21-1.50 (m, 9H), 1.54 (s, 3H), 1.56-1.71 (m, 4H), 2.05 (brd, J=13.3 Hz, 2H), 3.71 (AB, J=10.8 Hz, 2H), 4.69 (brs, 1H), 7.14 (dd, J=8.8, 3.3 Hz, 1H), 7.19 (s, 1H), 7.53 (d, J=8.7 Hz, 1H), 7.72 (d, J=8.7 Hz, 1H), 7.76 (d, J=8.7 Hz, 1H), 7.83 (s, 1H).
Reaction SMILES: C[O:2][C:3](=[O:34])[C@@H:4]([O:6][C:7]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]2[C:8]=1[C:9]([CH3:33])=[C:10]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]3[CH:32]=[CH:31][CH:30]=[N:29]3)=[CH:24][CH:23]=1)[C:11]([CH:18]1[CH2:20][CH2:19]1)=[N:12]2)[CH3:5].[OH-].[Li+].Cl>O1CCCC1.O>[CH:18]1([C:11]2[C:10]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([N:28]4[CH:32]=[CH:31][CH:30]=[N:29]4)=[CH:26][CH:27]=3)=[C:9]([CH3:33])[C:8]3[C:13](=[C:14]([F:17])[CH:15]=[CH:16][C:7]=3[O:6][C@@H:4]([CH3:5])[C:3]([OH:34])=[O:2])[N:12]=2)[CH2:20][CH2:19]1
Reactant: COC(=O)[C@H](C)Oc1ccc(F)c2nc(C3CC3)c(Cc3ccc(-n4cccn4)cc3)c(C)c12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(Cc2ccc(-n3cccn3)cc2)c(C2CC2)nc2c(F)ccc(O[C@@H](C)C(=O)O)c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.9 %

Procedure:
A solution of (S)-2-[2-cyclopropyl-8-fluoro-4-methyl-3-(4-pyrazol-1-ylbenzyl)quinolin-5-yloxy]propionic acid methyl ester (0.033 g) in tetrahydrofuran (0.18 mL) and water (0.18 mL) was treated with lithium hydroxide (0.018 g), and the resulting mixture was stirred at room temperature for 4 hours. The mixture was cooled to 0° C., diluted with water (10 mL) and acidified by the addition of 1.0M aqueous hydrochloric acid. The mixture was extracted with ethyl acetate and the combined extracts were dried over magnesium sulfate and concentrated under reduced pressure to afford title compound as a yellow solid (0.023 g).
Reaction SMILES: C(OC([N:8]1[CH2:16][CH:15]2[CH:10]([C:11](=[O:28])[N:12]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:13][CH2:14]2)[CH2:9]1)=O)(C)(C)C.[ClH:29]>C(OCC)(=O)C>[ClH:29].[F:27][C:24]([F:25])([F:26])[O:23][C:20]1[CH:21]=[CH:22][C:17]([N:12]2[CH2:13][CH2:14][CH:15]3[CH2:16][NH:8][CH2:9][CH:10]3[C:11]2=[O:28])=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CC2CCN(c3ccc(OC(F)(F)F)cc3)C(=O)C2C1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C1C2CNCC2CCN1c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-oxo-5-(4-trifluoromethoxy-phenyl)-octahydro-pyrrolo[3,4-c]pyridine-2-carboxylic acid tert-butyl ester (900 mg, 2.25 mmol) was added to a solution of saturated hydrochloride in ethyl acetate (4 mL). The reaction mixture was stirred at ambient temperature overnight. The solvent was removed under reduced pressure, then the crude product (800 mg) was obtained which was used without further purification. 1H NMR (300 MHz, d6-DMSO): δ 7.51-7.38 (m, 4H), 3.79-3.25 (m, 6H), 3.04-3.01 (m, 1H), 2.84-2.81 (m, 1H), 2.06-2.03 (m, 1H), 1.82-1.80 (m, 1H); LC-MS: [M+1]+ 302.7.
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[CH:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[N+:9]([O-])([O-:11])=[O:10].[K+]>OS(O)(=O)=O>[CH:1]([N:4]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])[O-]
Reactant: CC(C)n1cccn1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC(C)n1cc([N+](=O)[O-])cn1
Temperature: 50 °C
Yield: 45.3 %

Procedure:
To a solution of 1-isopropyl-1H-pyrazole (5 g, 45.5 mmol) in conc. H2SO4 (50 mL) was added KNO3 (5.0 go, 50 mmol) portionwise at 0° C. After the addition, the resulting mixture was heated to 50° C. for 8 h. The reaction mixture was cooled to RT, poured into ice water, and the mixture was extracted with EtOAc. The combined organics were washed with saturated Na2CO3 solution, brine, dried (Na2SO4), concentrated in vacuo and purified via column chromatography to provide 1-isopropyl-4-nitro-1H-pyrazole (3.2 g, 46% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.99 (s, 1 H), 8.32 (s, 1H), 4.65 (m, 1 H), 1.51 (d, J=6.8 Hz, 6 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[N:14][CH:13]=[CH:12][N:11]3[C:16]=2[C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[N:18]=2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41].C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[N:14][CH:13]=[CH:12][N:11]3[C:16]=2[C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH:24]3[CH2:29][CH2:28][N:27]([S:40]([CH3:39])(=[O:42])=[O:41])[CH2:26][CH2:25]3)[N:18]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Fc1ccc(-c2nc3cnccn3c2-c2ccnc(NC3CCNCC3)n2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)N1CCC(Nc2nccc(-c3c(-c4ccc(F)cc4)nc4cnccn34)n2)CC1
Reaction time: 144 h

Procedure:
To a mixture of 4-[2-(4-fluorophenyl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-ylpiperidin-4-ylamine (Example # H.1; 0.200 g, 0.514 mmol) and DIEA (0.18 mL, 1.0 mmol) in DCM (3 mL) at ambient temperature was added methanesulfonyl chloride (0.062 g, 0.539 mmol). After about six days, the mixture was treated with saturated aqueous NaHCO3 and the layers were separated. The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The crude material was triturated with EtOAc and filtered to yield the title compound after drying (0.090 g, 37%): LC/MS (Table 1, Method b) Rt=1.7 min; MS m/z: 468.6 (M+H)+.
Reaction SMILES: [CH2:1]([C@H:3]1[C@@H:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][C@H:5]([OH:28])[CH2:4]1)[CH3:2].[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[CH3:29][S:30]([O:28][CH:5]1[CH2:6][CH:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:26])([CH3:25])[CH3:27])[C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH:3]([CH2:1][CH3:2])[CH2:4]1)(=[O:32])=[O:31]
Reactant: CC[C@@H]1C[C@@H](O)C[C@@H]1c1nnc2cnc3c(ccn3COCC[Si](C)(C)C)n12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CCC1CC(OS(C)(=O)=O)CC1c1nnc2cnc3c(ccn3COCC[Si](C)(C)C)n12
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
To a solution of the scalemic mixture enriched in (1R,3R,4S)-3-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanol (0.5 g, 1.245 mmol) and TEA (0.347 mL, 2.49 mmol) in DCM (13 mL) was added MsCl (0.107 mL, 1.37 mmol) dropwise, and the reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue purified by silica gel column chromatography using 10 to 70% EtOAc in DCM to yield 3-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl methanesulfonate (0.48 g, 80%) as a white amorphous solid. LC/MS (Table 1, Method a) Rt=2.54 min; MS m/z: 480 (M+H)+
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[CH3:6][C@H:7]1[C:15]2[C:14](O)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9][CH2:8]1.C([O-])(O)=O.[Na+]>ClCCCl>[Cl:3][C:14]1[C:15]2[C@H:7]([CH3:6])[CH2:8][CH2:9][C:10]=2[N:11]=[CH:12][N:13]=1
Reactant: C[C@@H]1CCc2ncnc(O)c21
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: C[C@@H]1CCc2ncnc(Cl)c21
Reaction time: 1.17 h
Yield: 61.1 %

Procedure:
Neat POCl3 (463.9 mL, 5067 mmol) was added slowly by addition funnel to a 0° C. solution of (R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol (152.2 g, 1013 mmol) in DCE (1.2 L). After the addition was complete, the reaction mixture was warmed to about room temperature, then heated to reflux and stirred for about 70 minutes. The reaction was complete as determined by HPLC. The reaction mixture was cooled to about room temperature, and the excess POCl3 was quenched in 4 portions as follows: Reaction mixture transferred to separatory funnel and dripped into a beaker containing ice and saturated NaHCO3 solution cooled in an ice bath. Once the addition of each portion of the reaction mixture was completed, the quenched mixture was stirred about 30 minutes to ensure complete destruction of POCl3 prior to transfer to separatory funnel. The mixture was transferred to the separatory funnel and extracted twice with DCM. The combined extracts were dried (Na2SO4), filtered, and concentrated. The crude was purified on silica gel as follows: silica gel (1 kg) was slurried in 9:1 hexane:ethyl acetate onto a 3 L fritted funnel, silica settled under vacuum, topped with sand. The crude was loaded with a DCM/hexane mixture, and the compound was eluted using 1 L sidearm flasks under vacuum. High Rf byproducts eluted first, then (R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (104.4 g, 61.09% yield) as an oil. NMR (CDCl3, 400 MHz) δ 8.81 (s, 1H), 3.47 (m, 1H), 3.20 (m, 1H), 3.05 (m, 1H), 2.41 (m, 1H), 1.86 (m, 3H), 1.47 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH3:28])[C:10]([C:12]1[S:24][C:23]2[C:22]3[CH:21]=[C:20]([C:25]([OH:27])=O)[CH:19]=[CH:18][C:17]=3[O:16][CH2:15][C:14]=2[CH:13]=1)=[O:11].[OH:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH3:28])[C:10]([C:12]1[S:24][C:23]2[C:22]3[CH:21]=[C:20]([C:25]([N:33]4[CH2:34][CH2:35][CH:30]([OH:29])[CH2:31][CH2:32]4)=[O:27])[CH:19]=[CH:18][C:17]=3[O:16][CH2:15][C:14]=2[CH:13]=1)=[O:11]
Reactant: CN(C(=O)c1cc2c(s1)-c1cc(C(=O)O)ccc1OC2)c1ccc(F)cc1F
Reactant: OC1CCNCC1
Product: CN(C(=O)c1cc2c(s1)-c1cc(C(=O)N3CCC(O)CC3)ccc1OC2)c1ccc(F)cc1F

Procedure:
Following the procedure of Example 15 and General Procedure C, 2-((2,4-difluorophenyl)(methyl)carbamoyl)-4H-thieno[3,2-c]chromene-8-carboxylic acid and 4-hydroxypiperidine were coupled to give 118bp. 1H NMR (400 MHz, DMSO-d6), δ: 7.68 (m, 1H), 7.46 (m, 1H), 7.21-7.25 (m, 3H), 6.93 (m, 1H), 6.69 (m, 1H), 5.16 (s, 2H), 3.65 (m, 3H), 3.29 (s, 3H), 3.17 (m, 2H), 1.73 (m, 2H), 1.36 (m, 2H). LCMS (ESI) m/z: 485.1
Reaction SMILES: [CH2:1]([O:8][N:9]1[CH:13]=[CH:12][CH:11]=[N:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[Sn:19](Cl)([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH2:22][CH3:23]>C1COCC1>[CH2:1]([O:8][N:9]1[C:13]([Sn:19]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:20][CH2:21][CH2:22][CH3:23])=[CH:12][CH:11]=[N:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COn2cccn2)cc1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ccnn1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 106 %

Procedure:
To a solution of 1-benzyloxy-1H-pyrazole (1.17 g, 6.72 mmol) in THF (15 mL) at −78° C. was added dropwise n-BuLi (4.6 mL, 1.6M, 7.4 mmol). The mixture was stirred at −78° C. for 2 h before addition of Bu3SnCl (1.99 mL, 7.38 mmol). The mixture was kept at this temperature for 1 h and was then allowed to warm up to r.t. and stirred for 1 h. The mixture was concentrated in vacuo and hexanes was added. The insoluble material was removed by filtration and the filtrate was concentrated in vacuo to afford 1-benzyloxy-5-tributylstannanyl-1H-pyrazole (3.3 g, 100%) as a yellow syrup.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:23]=[C:22]([C:24]([OH:26])=O)[CH:21]=[C:20]([S:27][CH2:28][CH3:29])[N:19]=2)[CH2:14][CH2:13]1)=[O:10].Cl.[O:31]([NH2:33])[CH3:32]>>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:23]=[C:22]([C:24]([NH:33][O:31][CH3:32])=[O:26])[CH:21]=[C:20]([S:27][CH2:28][CH3:29])[N:19]=2)[CH2:14][CH2:13]1)=[O:10]
Reactant: CON
Reactant: CCSc1cc(C(=O)O)nc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)n1
Agent: Cl
Product: CCSc1cc(C(=O)NOC)nc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)n1

Procedure:
The title compound was synthesized by an analogous method to Example 8 starting from 2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-6-(ethylthio)pyrimidine-4-carboxylic acid (Example 202) and methoxylamine hydrochloride.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Cl:20])[CH:14]=3)=[CH:11][C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:26][N:27]1CCCC1=O>[C-]#N.[Zn+2].[C-]#N.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>[Cl:20][C:15]1[CH:14]=[C:13]([C:12]2[N:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([C:26]#[N:27])[CH:3]=3)[N:9]=[C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:11]=2)[CH:18]=[CH:17][C:16]=1[F:19]
Reactant: CCOC(=O)c1cc(-c2ccc(F)c(Cl)c2)n(-c2cccc(Br)c2)n1
Reactant: CN1CCCC1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CCOC(=O)c1cc(-c2ccc(F)c(Cl)c2)n(-c2cccc(C#N)c2)n1
Temperature: 200 °C

Procedure:
100 mg (0.236 mmol) of the compound of Example 51A are provided in 1 ml of 1-methyl-2-pyrrolidone, 55.4 mg (0.472 mmol) of zinc cyanide and 27.3 mg (0.024 mmol) of tetrakis(triphenylphosphine)palladium(0) are added, and the mixture is heated in a closed glass vessel at 200° C. under microwave irradiation for 30 min. The reaction mixture is subsequently filtered through kieselguhr and eluted with methanol, the filtrate is rendered weakly acidic with a 1N aqueous hydrogen chloride solution and concentrated, and the residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient). 33 mg (34% of theory) of the title compound are obtained.
Reaction SMILES: Cl.[C:2]([C:5]1[CH:6]=[CH:7][C:8]([Cl:13])=[C:9]([NH:11]N)[CH:10]=1)([OH:4])=O.[CH3:14][O:15][C:16]1[CH:29]=[CH:28][CH:27]=[CH:26][C:17]=1[C:18]([CH:20]([CH2:24][CH3:25])C(O)=O)=O>>[Cl:13][C:8]1[C:9]2[NH:11][C:18]([C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[O:15][CH3:14])=[C:20]3[CH2:24][CH2:25][C:2](=[O:4])[C:5]([C:10]=23)=[CH:6][CH:7]=1
Reactant: CCC(C(=O)O)C(=O)c1ccccc1OC
Reactant: NNc1cc(C(=O)O)ccc1Cl
Agent: Cl
Product: COc1ccccc1-c1[nH]c2c(Cl)ccc3c2c1CCC3=O
Yield: 10.9 %

Procedure:
The procedure of Example 60, steps 1 to 3 was repeated using (5-carboxy-2-chlorophenyl)hydrazine hydrochloride (24.1 g) and (2-methoxybenzoyl)butyric acid (16 g) to yield 2.45 g (12%) of the titled compound as a yellow powder.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7](=O)[CH2:8][C:9]([O:11]CC)=O)=[CH:3][CH:2]=1.[CH3:15][NH:16][C:17]([NH2:19])=[S:18].N12CCCN=C1CCCCC2.CS(O)(=O)=O>C(O)C.O>[SH:18][C:17]1[N:16]([CH3:15])[C:9](=[O:11])[CH:8]=[C:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[N:19]=1
Reactant: CCOC(=O)CC(=O)c1ccncc1
Reactant: CNC(N)=S
Agent: CS(=O)(=O)O
Solvent: CCO
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: Cn1c(S)nc(-c2ccncc2)cc1=O
Yield: 76.5 %

Procedure:
A mixture containing 70.0 g (0.36 mol) of ethyl 3-(4-pyridinyl)-3-oxopropionate, 98.1 g (1.09 mol) of N-methylthiourea, 55.0 g (0.36 mol) of 1,8-diazabicyclo[5.4.0]undec-7-ene in 551 ml of ethanol is heated under reflux during 2 h. The cooled mixture is treated with 34.9 ml (0.36 mol) of methanesulfonic acid in 143.6 ml of water and the precipitate recovered by filtration to afford 60.4 g of pure product as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][CH:2]=1.[OH:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1.Cl.N>C(OC(=O)C)(=O)C>[OH:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[CH:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[CH:11][CH:10]=1
Reactant: Cc1ccncc1
Reactant: O=Cc1ccc(O)cc1
Agent: Cl
Agent: N
Solvent: CC(=O)OC(C)=O
Product: Oc1ccc(C=Cc2ccncc2)cc1
Reaction time: 1 h
Yield: 82.7 %

Procedure:
In 65.8 g of acetic anhydride, 20.0 g of γ-picolin and 26.2 g of p-hydroxybenzaldehyde were refluxed for 24 hours. The resultant reaction mixture and 100 ml of 6 N hydrochloric acid added thereto were further refluxed for 60 minutes and then cooled. The reaction product was neutralized by addition of aqueous ammonia and stirred for 1 hour. The yellow crystals which consequently deposited therein were separated by filtration. The crystals were recrystallized from a mixed solvent of ethanol and ether, to afford 35 g of 4-[2-(4-hydroxyphenyl)-ethenyl]-pyridine having a melting point of 272° to 275° C.
Reaction SMILES: CN(C)C(=N)N(C)C.[CH2:9]([O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl-].[CH2:26]([O:28][CH:29]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH3:27]>ClCCl>[CH2:33]([O:32][C:30](=[O:31])[C:29]([O:28][CH2:26][CH3:27])=[CH:20][C:19]1[CH:22]=[CH:23][CH:24]=[C:17]([O:16][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:18]=1)[CH3:34]
Reactant: CCOC(=O)C(OCC)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cccc(OCc2ccccc2)c1
Agent: CN(C)C(=N)N(C)C
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)C(=Cc1cccc(OCc2ccccc2)c1)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.7 %

Procedure:
Tetramethylguanidine (6.5 g; 56.6 mmole) was slowly added to a solution of 3-benzyloxybenzaldehyde (11.7 g; 55 mmole) and (1,2-diethoxy-2-oxoethyl)(triphenyl) phosphonium chloride (20.1 g; 46.8 mmole) in dichloromethane (200 ml) at 0° C. After stirring at room temperature overnight the solvent was evaporated in vacuo. Diethyl ether was added and insoluble material was filtered off. The filtrate was washed with sodium bicarbonate solution, dried (magnesium sulfate), filtered and the solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel using tetrahydrofuran (0.5%) in dichloromethane as eluant. The remaining aldehyde was removed by stirring with sodium bisulfite in water and diethyl ether for 2 days. The phases were separated and the organic phase was evaporated in vacuo to give 10.5 g (yield 69%) of 3-(3-benzyloxyphenyl)-2-ethoxyacrylic acid ethyl ester.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[O:6][CH:7]1[CH2:10][N:9]([C:11](Cl)=[O:12])[CH2:8]1.C(=O)([O-])[O-].[K+].[K+].[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2([OH:38])[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:28][CH:27]=1>O1CCCC1.O>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2([OH:38])[CH2:33][CH2:34][N:35]([C:11]([N:9]3[CH2:10][CH:7]([O:6][C:5]4[CH:14]=[CH:15][CH:16]=[C:3]([C:2]([F:18])([F:17])[F:1])[CH:4]=4)[CH2:8]3)=[O:12])[CH2:36][CH2:37]2)=[CH:28][CH:27]=1
Reactant: O=C(Cl)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(N1CCC(O)(c2ccc(Cl)cc2)CC1)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Reaction time: 0.5 h
Yield: 113.4 %

Procedure:
A stirred mixture of 2.8 g (0.01 mole) of 3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarbonyl chloride and 1.4 g (0.01 mole) of potassium carbonate in 25 ml of tetrahydrofuran was treated with 2 g (0.01 mole) of 4-(4-chlorophenyl)-4-hydroxypiperidine added in small portions. After stirring for 30 min, a few pieces of ice were added and stirring continued for 16 hr. The reaction mixture was diluted with 200 ml of water and the oil which separated was extracted into methylene chloride (2×50 ml). The combined extracts were dried over magnesium sulfate and concentrated in vacuo to give a water-like oil (5.16 g). A crystalline solid was obtained by cooling to -78° C. and recrystallization was accomplished by dissolving the residue in 5 ml of acetone and 75 ml of isopropyl ether and reducing the volume under nitrogen to 40 ml. Upon cooling, filtration yielded 3.6 g (79.1%) of fine white crystals, m.p. 127°-128.5° C.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH3:25][C:26]([C:29]1[S:33][C:32]([NH2:34])=[N:31][N:30]=1)([CH3:28])[CH3:27]>CN(C=O)C.C(OCC)(=O)C.C(Cl)Cl>[CH3:25][C:26]([C:29]1[S:33][C:32]([NH:34][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[I:1])=[N:31][N:30]=1)([CH3:28])[CH3:27]
Reactant: CC(C)(C)c1nnc(N)s1
Reactant: O=C(O)c1ccccc1I
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)c1nnc(NC(=O)c2ccccc2I)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
2-Iodobenzoic acid (2 mmol), EDC (2 mmol), and HOBt (4 mmol) were added to 6 ml DCM and stirred at rt for 1 hour. 5-(1,1-dimethylethyl)-1,3,4-thiadiazol-2-amine (2 mmol) was added as a solution in 4 ml DMF. The reaction was stirred at rt for 1 hour and then diluted with ethyl acetate. The solution was washed with 1N HCl, sat. sodium bicarbonate, and brine. The organic layer was dried over sodium sulfate and then evaporated to give N-[5-(1,1-dimethylethyl)-1,3,4-thiadiazol-2-yl]-2-iodobenzamide (750 mg) pure by LCMS.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15](I)[CH:14]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[Br:12][C:13]1[CH:14]=[C:15]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][OH:1])[CH:4]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: Brc1cccc(I)c1
Reactant: OCc1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: OCc1cccc(-c2cccc(Br)c2)c1
Temperature: 80 °C
Reaction time: 6 h
Yield: 80 %

Procedure:
To a 0.2 M solution of [3-(hydroxymethyl)phenyl]boronic acid in DME were sequentially added 1-bromo-3-iodobenzene (0.83 eq.) and a 2M solution of Na2CO3 (3.0 eq.). The reaction mixture was degassed, trans-bis(triphenylphosphine)palladium(II) chloride (0.01 eq.) was added and it was stirred at 80° C. for 6 h. After cooling down to RT the reaction mixture was diluted with EtOAc and washed with saturated aq. NaHCO3, 1N HCl and brine. The residue was dried (Na2SO4) and evaporated under reduced pressure to afford an oil which was purified by flash chromatography (SiO2, PE:EtOAc=8:2) to afford the title compound 94 as an oil (80%). 1H NMR (400 MHz, DMSO-d6, 300 K) δ 7.87 (s, 1H), 7.71 (d, J 7.7, 1H), 7.66 (bs, 1H), 7.59 (t, J 6.8, 2H), 7.47 (t, J 7.7, 2H), 7.39 (d, J 7.7, 1H), 4.61 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([OH:18])[CH2:10][CH2:11][CH:12]2[NH:16][C:15](=[O:17])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>>[C:22]([Si:19]([CH3:21])([CH3:20])[O:18][CH:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH2:10][CH2:11][CH:12]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13]1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1CCC(CCC(O)Cc2ccc(F)cc2)N1
Product: CC(C)(C)[Si](C)(C)OC(CCC1CCC(=O)N1)Cc1ccc(F)cc1

Procedure:
Analogous to the procedure described for Example 1A, Step C, 5-[4-(4-fluoro-phenyl)-3-hydroxy-butyl]-pyrrolidin-2-one (1.95 g, 7.79 mmol) was reacted with tert-butyldimethylsilyl chloride (1.47 g, 9.76 mmol). Purification by medium pressure chromatography (1% MeOH in CH2Cl2) provided 5-[3-(tert-butyl-dimethyl-silanyloxy)-4-(4-fluoro-phenyl)-butyl]-pyrrolidin-2-one. 1H NMR (CDCl3) δ7.12 (m, 2H), 6.97 (m, 2H), 5.75 (m, 1H), 3.83 (m, 1H), 3.60 (m, 1H), 2.71 (m, 2H), 2.36-2.24 (m, 3H), 1.70-1.38 (m, 5H), 0.84 (s, 9H), −0.05 (d, 3H), −0.2 (d, 3H).