Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]([CH2:18][C:19]#[CH:20])[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7].[N+:21](=[CH:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[N-:22].C(N(CC)C(C)C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC=CC=1.O1CCCC1>[N+:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[S:6]([N:5]1[CH2:4][CH2:3][CH2:2][N:22]2[N:21]=[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:20]=[C:19]2[CH2:18]1)(=[O:8])=[O:7])([O-:17])=[O:16]
Reactant: C#CCN(CCCCl)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: CCOC(=O)c1cc2n(n1)CCCN(S(=O)(=O)c1ccccc1[N+](=O)[O-])C2
Temperature: 140 °C
Yield: 50.1 %

Procedure:
To a solution of N-(3-chloropropyl)-2-nitro-N-(prop-2-yn-1-yl)benzenesulfonamide (0.5 g, 1.59 mmol) and ethyl diazoacetate (0.251 mL, 2.384 mmol) in benzene (1.5 mL) was added N,N-diisopropylethylamine (0.27 mL, 1.6 mmol). The resulting solution was heated in a microwave reactor at 140° C. for 1 hour. Upon cooling to room temperature, cesium carbonate (0.621 g, 1.91 mmol) and tetrahydrofuran (1 mL) was added and the reaction mixture again heated at 140° C. for 30 minutes. Upon cooling to room temperature, the solvents were evaporated and the residue obtained was partitioned between water (10 mL) and EtOAc (15 mL). The aqueous layer was washed with additional EtOAc (15 mL), the combined organic layers were dried over anhydrous MgSO4, concentrated and purified via silica chromatography (20-90% EtOAc/hexane) to afford Intermediate 19 as a yellow oil (0.314 g, 50%). LC-MS: (FA) ES+395; 1H NMR (400 MHz, CDCl3) δ 7.96 (dd, J=7.8, 1.5 Hz, 1H), 7.73-7.60 (m, 3H), 6.77 (s, 1H), 4.58 (s, 2H), 4.52-4.47 (m, 2H), 4.37 (q, J=7.1 Hz, 2H), 3.72-3.65 (m, 2H), 2.10-2.04 (m, 2H), 1.37 (t, J=7.1 Hz, 3H).
Reaction SMILES: [Li]C(C)(C)C.[C:6]1([NH:12][C:13]2[N:14]([C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:15]=[CH:16][N:17]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:37][O:38][C:39]1[CH:40]=[C:41]([CH:45]=[C:46]([O:50][CH3:51])[C:47]=1[O:48][CH3:49])[C:42](Cl)=[O:43]>C1COCC1>[C:6]1([NH:12][C:13]2[N:14]([C:18]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:15]=[C:16]([C:42]([C:41]3[CH:45]=[C:46]([O:50][CH3:51])[C:47]([O:48][CH3:49])=[C:39]([O:38][CH3:37])[CH:40]=3)=[O:43])[N:17]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: c1ccc(Nc2nccn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1cc(C(=O)c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c(Nc3ccccc3)n2)cc(OC)c1OC
Reaction time: 8 h
Yield: 43.6 %

Procedure:
At −78° C., t-BuLi in THF (1.7 M, 0.34 mL, 0.58 mmol) was added to a solution of trityl protected compound (d) (116 mg, 0.289 mmol) in THF. Then 3,4,5-trimethoxybenzoyl chloride (66.5 mg, 0.289 mmol) was added and stirred overnight. The reaction mixture was quenched with saturated NH4Cl, and dried with MgSO4. Filtration and evaporation of the solvent followed by chromatography afforded compound (e) (75 mg, 43.7%). 1H NMR (500 MHz, CDCl3) δ 7.55-7.41 (m, 5H), 7.32 (s, 1H), 7.28-7.18 (m, 15H), 6.94 (s, 2H), 3.78 (s, 6H), 3.70 (s, 3H). MS: 594.2 (M−H)−; 596.3 (M+H)+.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:10]1([OH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[O:16]([C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: N#Cc1ccccc1F
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccccc1Oc1ccccc1
Temperature: 130 °C
Reaction time: 10 h
Yield: 93 %

Procedure:
To a suspension of 2-fluorobenzonitrile (10.0 g, 82.6 mmol) and phenol (7.7 g, 5.1 mmol) in DMF (80 mL) was added K2CO3 (22.8 g, 165 mmol) at rt. The reaction was stirred at 130° C. for 10 h. The reaction mixture was diluted with water, extracted with EtAOAc (100 mL×3), washed with brine (100 mL), dried (Na2SO4), and concentrated to give 15.0 g, (93%) of the title compound as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 6.85 (1H, d, J=8.4 Hz), 7.07-7.14 (3H, m), 7.22 (1H, t, J=7.2 Hz), 7.40 (2H, t, J=8.0 Hz), 7.47 (1H, td, J=2.0, 8.4 Hz), 7.65 (1H, dd, J=1.2, 8.0 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:11][C:12]1[S:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][N:16]=1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:11][C:12]1[S:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][N:16]=1)=[O:5]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: Nc1ncc([N+](=O)[O-])s1
Solvent: c1ccncc1
Product: O=C(Nc1ncc([N+](=O)[O-])s1)c1ccccc1Cl

Procedure:
By following the procedure of the first part of Example 1, but using 2-chlorobenzoyl chloride (26.3 g), 2-amino-5-nitrothiazole (21.8 g) and pyridine (ca 150 ml), there was obtained 2-chloro-N-(5-nitro-2-thiazolyl)benzamide, m.pt 221°-222°, after recrystallisation from acetic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8][C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Si:17]([O:24][C@H:25]1[CH2:34][C@H:33](O)[C@H:32]2[C:27]([CH:28]=[CH:29][C@H:30]([CH3:53])[C@@H:31]2[CH2:36][CH2:37][C@H:38]2[O:43][C:42](=[O:44])[CH2:41][C@H:40]([O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[CH2:39]2)=[CH:26]1)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>>[Si:17]([O:24][C@H:25]1[CH2:34][C@H:33]([O:11][C:10](=[O:12])[C:9]([O:8][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:16][CH:15]=2)([CH3:14])[CH3:13])[C@H:32]2[C:27]([CH:28]=[CH:29][C@H:30]([CH3:53])[C@@H:31]2[CH2:36][CH2:37][C@H:38]2[O:43][C:42](=[O:44])[CH2:41][C@H:40]([O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:47])[CH3:48])[CH2:39]2)=[CH:26]1)([C:20]([CH3:21])([CH3:22])[CH3:23])([CH3:19])[CH3:18]
Reactant: CC(C)(Oc1ccc([N+](=O)[O-])cc1)C(=O)O
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Product: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](OC(=O)C(C)(C)Oc3ccc([N+](=O)[O-])cc3)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1

Procedure:
A procedure similar to that described in Example 1, above, was followed, but using 597 mg of 2-(4-nitrophenoxy)-2-methylpropionic acid and 731 mg of (4R,6R)-6-{(1S,2S,6S,8S,8aR)-2-[1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above], to give880 mg of the title compound as a colorless foam.
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1[N:22]2[C:23](=[O:33])[C@@H:24]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@H:21]2[S:20][CH2:19][C:18]=1[CH:34]=[CH:35][S:36][C:37]1[S:38][C:39]2[CH:47]=[C:46]([CH2:48]O)[CH:45]=[CH:44][C:40]=2[C:41](=[O:43])[CH:42]=1)=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:52])=O>C1C=CC=CC=1>[CH:1]([O:14][C:15]([C:17]1[N:22]2[C:23](=[O:33])[C@@H:24]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@H:21]2[S:20][CH2:19][C:18]=1[CH:34]=[CH:35][S:36][C:37]1[S:38][C:39]2[CH:47]=[C:46]([CH2:48][Cl:52])[CH:45]=[CH:44][C:40]=2[C:41](=[O:43])[CH:42]=1)=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=CSc3cc(=O)c4ccc(CO)cc4s3)CS[C@H]12
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=CSc3cc(=O)c4ccc(CCl)cc4s3)CS[C@H]12
Temperature: 25 °C
Yield: 88.9 %

Procedure:
7β-Tert-butoxycarbonylamino-3-[2-(7-hydroxymethyl-4-oxo-4H-1-benzothiopyran-2-yl)thiovinyl]-3-cephem-4-carboxylic acid benzhydryl ester (330 mg, 0.46 mmol) was suspended in anhydrous benzene (10 ml), added dropwise with thionyl chloride (0.55 ml, 7.59 mmol) while stirred at room temperature. Then, the reaction mixture was stirred at 50 minutes, added with ice water and extracted with ethyl acetate (50 ml). Ethyl acetate layer was washed with saturated saline solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was crystallized from isopropyl ether to obtain 300 mg (yield: 89%) of 7β-tert-butoxycarbonylamino-3-[2(7-chloromethyl-4-oxo-4H-1-benzothiopyran-2-yl)thiovinyl]-3-cephem-4-carboxylic acid benzhydryl ester. Further, the process similar to that shown in (2) of the Example 1 was conducted to obtain 160 mg (yield: 62%) of the titled compound.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([C:14]3[O:15][CH:16]=[C:17]([CH2:19][CH2:20][C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH2:30][CH3:31])=O)[N:18]=3)[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1.O.NN.C(O)COCCO.[OH-].[K+]>O>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([C:14]3[O:15][CH:16]=[C:17]([CH2:19][CH2:20][CH2:21][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH2:30][CH3:31])[N:18]=3)[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:2][CH2:3]1
Reactant: CCOc1ccccc1C(=O)CCc1coc(-c2ccc(OC)c(OCC3CC3)c2)n1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: CCOc1ccccc1CCCc1coc(-c2ccc(OC)c(OCC3CC3)c2)n1
Temperature: 150 °C
Reaction time: 1 h

Procedure:
A 0.5 g quantity of 3-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)propan-1-one obtained in Example 102 and 0.18 ml of hydrazine monohydrate were added to diethylene glycol. A 0.14 g quantity of potassium hydroxide was added thereto, and the mixture was stirred at 150° C. for 1 hour. The reaction mixture was allowed to cool, water was then added thereto, and extraction was performed with ethyl acetate. Drying was performed with anhydrous magnesium sulfate, and the solvent was removed. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1) to give 0.1 g of colorless oily 2-(3-cyclopropylmethoxy-4-methoxyphenyl)-4-[3-(2-ethoxyphenyl)propyl]oxazole.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([CH:17]2[CH2:26][CH2:25][C:24]3[CH:23]=[C:22](OS(C(F)(F)F)(=O)=O)[CH:21]=[CH:20][C:19]=3[CH2:18]2)[CH2:14][O:13][C:12]([CH3:16])([CH3:15])[O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:35]([O:42][C:43]1[CH:44]=[C:45]([SH:49])[CH:46]=[CH:47][CH:48]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.O1CCOCC1.C(N(CC)C(C)C)(C)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCOC(C)=O.CCCCCC>[CH2:35]([O:42][C:43]1[CH:44]=[C:45]([S:49][C:22]2[CH:23]=[C:24]3[C:19](=[CH:20][CH:21]=2)[CH2:18][CH:17]([C:9]2([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:14][O:13][C:12]([CH3:16])([CH3:15])[O:11][CH2:10]2)[CH2:26][CH2:25]3)[CH:46]=[CH:47][CH:48]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: Sc1cccc(OCc2ccccc2)c1
Reactant: CC(C)(C)OC(=O)NC1(C2CCc3cc(OS(=O)(=O)C(F)(F)F)ccc3C2)COC(C)(C)OC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCCCCC
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1(C2CCc3cc(Sc4cccc(OCc5ccccc5)c4)ccc3C2)COC(C)(C)OC1
Temperature: 25 °C
Yield: 69.4 %

Procedure:
Trifluoromethanesulfonic acid 6-(5-tert-butoxycarbonylamino-2,2-dimethyl-1,3-dioxinan-5-yl)-5,6,7,8-tetrahydro-naphthalen-2-yl ester (0.310 g, 0.000608 mol), 3-benzyloxy-benzenethiol (0.145 g, 0.000669 mol), tris(dibenzylideneacetone)-dipalladium(0) (0.0167 g, 0.0000182 mol) and xantphos (0.0211 g, 0.0000365 mol) were dissolved in 1,4-dioxane (10 mL, 0.1 mol). The solution was degassed by applying low vacuum and backfilling with N2 for 5 times. The pre-degassed N,N-diisopropylethylamine (0.350 mL, 0.00201 mol) in the same way was added. The mixture was heated to reflux under an atmosphere of nitrogen for 14 hours then cooled to r.t. tris(dibenzylideneacetone)dipalladium(0) (0.0501 g, 0.0000548 mol) and xantphos (0.0634 g, 0.000110 mol) was added. The mixture was degassed three times, heated to reflux for 6 more hours, cooled to r.t. The mixture was filtered, and concentrated to give a crude residue. Chromatography with EtOAc-hexane (0:100 to 20:80) two times gave a solid product (243 mg, 43%). 1H NMR (CHLOROFORM-d) δ: 7.31-7.44 (m, 5H), 7.18-7.23 (m, 1H), 7.17 (d, J=2.0 Hz, 2H), 7.04-7.09 (m, 1H), 6.97-7.04 (m, 1H), 6.84-6.92 (m, 1H), 6.79-6.84 (m, 1H), 5.02 (s, 2H), 4.86 (s, br, 1H), 3.95-4.05 (m, 4H), 2.77-2.97 (m, 4H), 2.64-2.76 (m, 1H), 2.47-2.60 (m, 1H), 2.00-2.14 (m, 1H), 1.51-1.60 (m, 6H), 1.41-1.51 (m, 9H). MS (M+Na+): 598.0.
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]([CH2:8][C:9]2[S:13][C:12]([NH2:14])=[N:11][C:10]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[C:28](Cl)=[O:29]>>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[C:28]([NH:14][C:12]1[S:13][C:9]([CH2:8][C:7]2[CH:21]=[CH:22][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:11]=1)=[O:29]
Reactant: Nc1nc(-c2ccccc2)c(Cc2ccc([N+](=O)[O-])cc2)s1
Reactant: COc1ccc(C(=O)Cl)cc1OC
Product: COc1ccc(C(=O)Nc2nc(-c3ccccc3)c(Cc3ccc([N+](=O)[O-])cc3)s2)cc1OC
Yield: 64.7 %

Procedure:
A procedure similar to that in Example 4 was used. 5-(4-nitro-benzyl)-4-phenyl-thiazol-2-ylamine prepared in Example 26 and 3,4-dimethoxy-benzoyl chloride prepared in the step 1 of Example 12 were used as starting materials, allowed to react at room temperature overnight, followed by post-treatment to obtain a crude product, which was purified by a silica gel column chromatography eluted with a gradient of dichloromethane and ethyl acetate (100:0-10:1) to obtain a product as a white solid in a yield of 64.7%, mp: 105-106 └. 1H-NMR (CDCl3, 400 MHz) δ: 3.90 (3H, s, OCH3), 3.96 (3H, s, OCH3), 4.35 (2H, s, CH2), 6.85 (1H, t, J=8.68 Hz, ArH), 7.30˜7.48 (9H, m, ArH), 8.18 (2H, t, J=8.68 Hz, ArH), 10.21 (1H, br, CONH); EI-MS m/e (%): 475.0 (M+, 20), 165.0 (100); HREI-MS Calcd. for C25H21N3O5S: 475.1202. found: 475.1210.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]1=O>CC(O)=O>[OH:8][C:6]1[CH:5]=[CH:4][C:3]2[N:9]3[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]3=[N:1][C:2]=2[CH:7]=1
Reactant: CCOC(=O)CC1CCN(c2ccc(O)cc2N)C1=O
Solvent: CC(=O)O
Product: CCOC(=O)CC1CCn2c1nc1cc(O)ccc12
Temperature: 75 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
Ethyl 2-(1-(2-amino-4-hydroxyphenyl)-2-oxopyrrolidin-3-yl)acetate (0.740 g, 2.66 mmol) was dissolved in AcOH (50 mL) and was warmed to 75° C. and stirred for 8 h. The reaction mixture was concentrated under reduced pressure and the residue was taken up in toluene and concentrated again. The black concentrate was filtered through a plug of silica eluting with 10% MeOH in DCM. The filtrate was concentrated to provide the title compound (666 mg). LCMS m/z=261.2 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.19 (t, J=7.1 Hz, 3H), 2.25-2.36 (m, 1H), 2.63 (dd, J=16.4, 8.8 Hz, 1H), 2.79-2.89 (m, 2H), 3.48-3.56 (m, 1H), 3.90-3.98 (m, 1H), 4.02-4.14 (m, 2H), 6.61 (dd, J=8.6, 2.3 Hz, 1H), 6.73 (d, J=2.0 Hz, 1H), 7.30 (d, J=8.6 Hz, 1H), 9.11 (bs, 1H).
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:26])[NH:6][C:7]2[C:12]([C:13]=1C)=[C:11]([C:15]([F:18])([F:17])[F:16])[C:10](OS(O)(=O)=O)=[CH:9][C:8]=2[O:24][CH3:25])(=[O:3])[CH3:2].[CH2:27]([NH2:31])[CH:28]([CH3:30])[CH3:29]>>[C:1]([C:4]1[C:5](=[O:26])[NH:6][C:7]2[C:12]([C:13]=1[NH:31][CH2:27][CH:28]([CH3:30])[CH3:29])=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=[CH:9][C:8]=2[O:24][CH3:25])(=[O:3])[CH3:2]
Reactant: COc1cc(OS(=O)(=O)O)c(C(F)(F)F)c2c(C)c(C(C)=O)c(=O)[nH]c12
Reactant: CC(C)CN
Product: COc1ccc(C(F)(F)F)c2c(NCC(C)C)c(C(C)=O)c(=O)[nH]c12
Yield: 69 %

Procedure:
3-Acetyl-5- trifluoromehyl-8-methoxy-4-methylsulfoxy-2-quinolinone (3.4 7g, 0.01 mol) and isobutylamine (0.73g, 0.01 mol) were used, but the reaction was carried out as the above process of example 37 to obtain the desired product (2.46g, yield: 69%).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH3:9])=[O:7])[N:3]=[CH:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]([C:40]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:41])[CH2:32][C:31]1([CH3:49])[CH3:48].CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:9][O:8][C:6]([C:4]1[N:3]([CH:30]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[N:33]([C:40](=[O:41])[C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:32][C:31]2([CH3:49])[CH3:48])[CH:2]=[N:1][CH:5]=1)=[O:7]
Reactant: CC1(C)CN(C(=O)c2ccccc2)c2ccccc2C1O
Reactant: COC(=O)c1c[nH]cn1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cncn1C1c2ccccc2N(C(=O)c2ccccc2)CC1(C)C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
methyl 4-imidazolecarboxylate (55 mg, 0.44 mmol), PS-triphenylphosphine (2.15 mmol/g, 0.20 g, 0.43 mmol) are added to a solution of (4-hydroxy-3,3-dimethyl-3,4-dihydro-2H-quinolin-1-yl)-phenyl-methanone (80 mg, 0.28 mmol) in THF (10 mL) at room temperature. The mixture is stirred at room temperature for 5 minutes and then Cooled to 0° C. DIAD (0.083 mL, 0.43 mmol) is added, and then the mixture is stirred at room temperature. After 3 h, the reaction mixture is filtered to remove resin and washed with ethyl acetate. The ethyl acetate solution is washed with brine, and dried over anhydrous sodium sulfate. After concentration, the residue is purified by reverse phase HPLC (CH3CN:H2O=20 to 90% over 20 mins) and yields the title compound: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.74 (s, 3 H), 1.15 (s, 3 H), 3.52 (d, J=13.4 Hz, 1 H), 3.87 (d, J=13.1 Hz, 1 H), 3.92 (s, 3 H), 5.30 (s, 1 H), 6.40 (s, 1 H), 6.95-6.99 (m, 1 H), 7.01-7.06 (m, 1 H), 7.11-7.16 (m, 1 H), 7.28-7.33 (m, 2 H), 7.38-7.44 (m, 2 H), 7.45-7.50 (m, 1 H), 7.52-7.56 (m, 2 H). HRMS: calculated for C23H24N3O3: 390.1818. Found: 390.1800
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[H-].[Na+].[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@@H:26]1[CH2:30]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:24])([CH3:21])([CH3:20])[CH3:19]>CN(C=O)C>[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@@H:26]1[CH2:30][O:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][C:5]2[CH:14]=[CH:15][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:8][CH:9]=1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCCN2C(=O)OC(C)(C)C)cc1
Reactant: Oc1ccc(Oc2ccc(F)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Oc2ccc(F)cc2)cc1
Temperature: 2.5 °C
Reaction time: 0.25 h
Yield: 73.8 %

Procedure:
To a solution of 4-(4-Fluoro-phenoxy)-phenol (200 mg, 0.979 mmol) in DMF (3 mL) at 0-5° C. was added 60% NaH (70 mg, 1.76 mmol) at 0-5° C. The reaction mixture was stirred at rt for 15 min at 0-5° C. A solution of (R)-2-(Toluene-4-sulfonyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (348 mg, 0.979 mmol) in DMF (2 mL) was added to the above mixture at 0-5° C. The reaction mixture was warmed to rt and then heated at 90° C. for 15 h. The mixture was concentrated, diluted with saturated aq NaHCO3 and extracted with ethyl acetate. The aqueous layer was re-extracted with ethylacetate. The combined organic layers were dried over anhy. MgSO4 and the solvent was removed in vacuo to obtain the crude mixture, which was purified by silica gel flash chromatography to obtain title the product (280 mg, 74%).
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:9]=[C:10]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:11]3[N:16]=[C:15]([CH:17]=O)[S:14][C:12]=3[N:13]=2)[C:6]2[CH:25]=[CH:26][CH:27]=[CH:28][C:5]=2[N:4]=1)[CH3:2].[CH3:29][C:30]1([CH3:40])[NH:35][CH2:34][CH2:33][N:32]([CH:36]2[CH2:39][O:38][CH2:37]2)[CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:29][C:30]1([CH3:40])[CH2:31][N:32]([CH:36]2[CH2:37][O:38][CH2:39]2)[CH2:33][CH2:34][N:35]1[CH2:17][C:15]1[S:14][C:12]2[N:13]=[C:8]([N:7]3[C:6]4[CH:25]=[CH:26][CH:27]=[CH:28][C:5]=4[N:4]=[C:3]3[CH2:1][CH3:2])[N:9]=[C:10]([N:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)[C:11]=2[N:16]=1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)sc2n1
Reactant: CC1(C)CN(C2COC2)CCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(C4COC4)CC3(C)C)sc2n1
Reaction time: 5 h
Yield: 39.7 %

Procedure:
A mixture of 5-(2-ethylbenzoimidazol-1-yl)-7-morpholin-4-ylthiazolo[5,4-d]pyrimidine-2-carbaldehyde (200 mg, 0.51 mmol), 3,3-dimethyl-1-oxetan-3-ylpiperazine (100 mg, 0.65 mmol) and 4 Å powdered molecular sieves (200 mg) in DCE (10 mL) was allowed to stir at r.t. for 1 h before the addition of sodium triacetoxyborohydride (150 mg, 0.71 mmol). The resulting mixture was allowed to stir for 5 h then loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si-PCC, MeOH:EtOAc, 0-1%) followed by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 20 mM triethylamine in water on a gradient of acetonitrile 5-98%) affording 813 (111 mg, 40%). LCMS (method G): RT 6.17 min [M+H]+ 549.3. 1H NMR (CDCl3, 400 MHz): δ 8.01-8.00 (1 H, m), 7.75-7.74 (1 H, m), 7.32-7.22 (2 H, m), 4.67 (2 H, t, J=6.47 Hz), 4.59 (2 H, t, J=6.08 Hz), 4.40 (4 H, brd s), 3.87 (6 H, t, J=4.72 Hz), 3.47-3.46 (1 H, m), 3.34 (2 H, q, J=7.47 Hz), 2.75 (2 H, t, J=4.94 Hz), 2.37 (2 H, brd s), 2.15 (2 H, brd s), 1.43 (3 H, t, J=7.47 Hz), 1.20 (6 H, s)
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[CH3:19][CH:20]1[CH2:24][CH2:23][CH2:22][NH:21]1>CO>[Cl:1][C:2]1[N:3]=[C:4]([N:21]2[CH2:22][CH2:23][CH2:24][CH:20]2[CH3:19])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: CC1CCCN1
Reactant: Fc1ccc(C2CCc3c(Cl)nc(Cl)nc32)cc1
Solvent: CO
Product: CC1CCCN1c1nc(Cl)nc2c1CCC2c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 33.9 %

Procedure:
To a solution of 2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (Preparation H) (200 mg, 0.706 mmol) in MeOH (7064 mL) was added 2-Methylpyrrolidine (82 mL, 0.848 mmol). The resulting mixture was stirred at RT for 2 days. The reaction mixture was then concentrated in vacuo. The resulting oil was purified by flash chromatography (Silica, EtOAc/Hexanes) to give two racemic pairs of diasteriomers 2-chloro-7-(4-fluorophenyl)-4-(2-methylpyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine. (Hc1, Diastereomer 1, racemic, first to elute) (79.5 mg, 0.240 mmol, 33.9% yield). LC-MS (M+H)+=332.1; 1H NMR (500 MHz, MeOD) δ ppm 7.16 (2 H, d, J=5.49 Hz), 7.04 (2 H, s), 4.42-4.54 (1 H, m), 4.09-4.22 (1 H, m), 3.86-4.00 (1 H, m), 3.71-3.82 (1 H, m), 3.24-3.31 (1 H, m), 3.10-3.22 (1 H, m), 2.54-2.65 (1 H, m), 2.05-2.16 (2 H, m), 1.94-2.05 (2 H, m), 1.69-1.80 (1 H, m), 1.27 (3 H, d, J=6.10 Hz). (Hc2, Diastereomer 2, racemic, second to elute) (89.5 mg, 0.270 mmol, 38% yield). LC-MS (M+H)+=332.1; 1H NMR (500 MHz, MeOD) δ ppm 7.14 (2 H, d, J=5.49 Hz), 6.99-7.08 (2 H, m), 4.42-4.54 (1 H, m), 4.13-4.22 (1 H, m), 3.86-4.00 (1 H, m), 3.71-3.83 (1 H, m), 3.25-3.32 (1 H, m), 3.14-3.25 (1 H, m), 2.52-2.67 (1 H, m), 2.05-2.19 (2 H, m), 1.94-2.05 (2 H, m), 1.68-1.78 (1 H, m), 1.19-1.32 (3 H, m). The relative stereochemistry for Hc1 and Hc2 was not determined