Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[N:7]=[CH:6][CH:5]=1.[Cl:15][C:16]1[S:20][CH:19]=[N:18][N:17]=1.O.CN([CH:25]=[O:26])C>>[Cl:14][C:10]1[CH:9]=[C:8]2[C:13]([C:4]([NH:3][C:25]([C:19]3[S:20][C:16]([Cl:15])=[N:17][N:18]=3)=[O:26])=[CH:5][CH:6]=[N:7]2)=[CH:12][CH:11]=1
Reactant: CN(C)C=O
Reactant: Nc1ccnc2cc(Cl)ccc12
Reactant: Clc1nncs1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: O=C(Nc1ccnc2cc(Cl)ccc12)c1nnc(Cl)s1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 60 %

Procedure:
NaH (0.023 g, 0.58 mmol) was added in portions to a solution of 4-amino-7-chloro-quinoline (0.1 g, 0.56 mmol) in DMF (6 ml) at room temperature and the mixture was stirred for 20 min. 5-Chloro-[1,3,4]thiadiazole derivative (0.108 g, 0.56 mmol) was then added in one portion and the mixture heated at 80° C. (oil bath temperature) for 18 h. The reaction mixture was allowed to cool to room temperature and water (15 ml) was added. The precipitate was separated by filtration, washed with Et2O and dried to afford the product (0.08 g, 60% yield).
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[C:13]([Si:17]([CH3:29])([CH3:28])[O:18][CH:19]1[CH2:24][CH2:23][CH:22]([C:25]([OH:27])=[O:26])[CH2:21][CH2:20]1)([CH3:16])([CH3:15])[CH3:14].CI>O1CCCC1>[C:13]([Si:17]([CH3:29])([CH3:28])[O:18][CH:19]1[CH2:24][CH2:23][C:22]([CH3:1])([C:25]([OH:27])=[O:26])[CH2:21][CH2:20]1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(C(=O)O)CC1
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: CC1(C(=O)O)CCC(O[Si](C)(C)C(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 70.7 %

Procedure:
To a cold (−78° C.) of diisopropylamine (3.44 mL, 24.5 mmol) in tetrahydrofuran (49 mL) was added n-butyl lithium (2.5 M in hexanes, 9.81 mL, 24.5 mmol) dropwise over 10 minutes. The ice bath was removed, and the reaction mixture was allowed to warm to 0° C. and then cooled back to −78° C. A solution of Example 45B (3.3 g, 12.3 mmol) in tetrahydrofuran (10 mL) was then added. The ice bath was removed and the reaction mixture was heated at 50° C. for 2 hours. The reaction mixture was then cooled back to −78° C. and methyl iodide (0.84 mL, 13.5 mmol) was added followed by stirring for 2 hours. The cooling bath was removed, and the reaction mixture was stirred at room temperature for 1 hour. The reaction solution was then poured into diethyl ether (200 mL) and 1M HCl (200 mL). The layers were separated and the aqueous layer was further extracted with diethyl ether (2×200 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to a crude yellow oil. The crude oil was purified by flash chromatography with 15% ethyl acetate/84% hexane/1% methanol to afford the titled compound (2.37 g) as a light yellow oil. MS (CI) m/z 273 (M+1)+.
Reaction SMILES: [CH2:1]([OH:16])[C@H:2]1[O:7][C@H:6]([O:8][P:9]([OH:12])([OH:11])=[O:10])[C@H:5]([OH:13])[C@@H:4]([OH:14])[C@@H:3]1[OH:15].C(O)[C@H]1OC(OP(O)(O)=O)[C@H](O)[C@@H](O)[C@@H]1O.[CH:33]1[C:39](=[O:40])[NH:38][C:36](=[O:37])[N:35]([C@@H:41]2[O:45][C@H:44]([CH2:46][O:47][P:48]([O:51][P:52]([O:55]P(O)(O)=O)([OH:54])=[O:53])([OH:50])=[O:49])[C@@H:43]([OH:60])[C@H:42]2[OH:61])[CH:34]=1>>[CH:33]1[C:39](=[O:40])[NH:38][C:36](=[O:37])[N:35]([C@@H:41]2[O:45][C@H:44]([CH2:46][O:47][P:48]([O:10][P:9]([O:8][C@H:6]3[O:7][C@H:2]([CH2:1][OH:16])[C@@H:3]([OH:15])[C@H:4]([OH:14])[C@H:5]3[OH:13])([OH:12])=[O:11])([OH:50])=[O:49])[C@@H:43]([OH:60])[C@H:42]2[OH:61])[CH:34]=1.[O-:49][P:48]([O:51][P:52]([O-:55])([O-:54])=[O:53])(=[O:47])[O-:50]
Reactant: O=P(O)(O)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reactant: O=c1ccn([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: O=P(O)(O)OC1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Product: O=P([O-])([O-])OP(=O)([O-])[O-]
Product: O=c1ccn([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)O[C@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)[C@@H](O)[C@H]2O)c(=O)[nH]1

Procedure:
Acceptor specificity of the β1-4GlcA transferase activity of PmHS2 was also explored in one-pot three-enzyme system, as shown in FIG. 19. The first enzyme was a glucose-1-phosphate uridylyltransferase (GalU) which catalyzes the reversible conversion of Glc-1-P in the presence of UTP to produce UDP-Glc and inorganic pyrophosphate. The second enzyme was a UDP-glucose dehydrogenase (Ugd) for oxidation of 6-OH in glucose residue of UDP-Glc to form the UDP-glucuronic acid (UDP-GlcA) in the presence of its coenzyme NAD+. The third enzyme is PmHS2 transferring GlcA from UDP-GlcA for the formation of β1-4 linkage. As shown in FIG. 20, trisaccharides GlcAβ1-4GlcNAcα1-4GlcAβ2AAMe F20-1, GlcAβ1-4GlcNAc6N3α1-4GlcAβ2AAMe F20-3, GlcAβ1-4GlcNAcN3α1-4GlcAβ2AAMe F20-5 were synthesis by small-scale reaction and analyzed by HPLC method in 100%, 100% and 95% yields, respectively. The relative low yield (72%) for the formation of GlcAβ1-4GlcNTFAα1-4GlcAβ2AAMe F20-2 was due to the formation of byproduct GlcAβ1-4GlcNH2α1-4GlcAβ2AAMe in which the TFA group was removed. Disaccharide F18-4 with N-glycolyl group in C2 position of glucosamine residue acts as a good acceptor for PmHS2, leading to the formation of GlcAβ1-4GlcNGcα1-4GlcAβ2AAMe F20-4 in 75% yield, but the disaccharide F18-6 with N-glycolyl group in C6 position of GlcNAc was converted to trisaccharide GlcAβ1-4GlcNAc6NGcα1-4GlcAβ2AAMe F20-6 only in 14% yield. Taken together, these results indicate that the donor and acceptor substrate activity of PmHS2 can tolerate a limited number of modifications on C-2 and C-6 position of glucosamine residue.
Reaction SMILES: [O:1]([CH:8]([CH3:12])[C:9]([OH:11])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:26](=[O:27])[CH2:25][C:24](=[O:28])[NH:23][C:22]3[C:29]4[C:34]([CH:35]=[CH:36][C:21]2=3)=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:16][CH:15]=1.O(C(C)C(Cl)=O)C1C=CC=CC=1>>[O:1]([CH:8]([CH3:12])[C:9]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:26](=[O:27])[CH2:25][C:24](=[O:28])[NH:23][C:22]3[C:29]4[C:34]([CH:35]=[CH:36][C:21]2=3)=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:16][CH:15]=1)=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(Oc1ccccc1)C(=O)O
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Agent: CC(Oc1ccccc1)C(=O)Cl
Product: CC(Oc1ccccc1)C(=O)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Yield: 88.2 %

Procedure:
2-Phenoxypropionic acid (32 mg, 0.193 mmol) was made into acid chloride in a conventional manner. By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (30 mg, 0.095 mmol) obtained in Example 1, (3), and 2-phenoxypropionic acid chloride mentioned above, the title compound (39 mg, yield 88%) was obtained in the same manner as that of Example 1.
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][C:10]2[NH:9][N:8]=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=3)[CH2:6][C:5]=2[C:4](=[O:22])[CH2:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>N1C=CC=CC=1>[CH3:1][CH:2]1[CH2:11][C:10]2[N:9]=[N:8][C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=3)=[CH:6][C:5]=2[C:4](=[O:22])[CH2:3]1
Reactant: CC1CC(=O)C2=C(C1)NN=C(c1cccc(C(F)(F)F)c1)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccncc1
Solvent: O
Product: CC1CC(=O)c2cc(-c3cccc(C(F)(F)F)c3)nnc2C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 66 %

Procedure:
To a pyridine solution (1 mL) of 7-methyl-3-(3-trifluoromethylphenyl)-4,6,7,8-tetrahydro-1H-cinnolin-5-one (136.2 mg, 0.44 mmol) obtained in Example 65 was added p-toluenesulfonic acid hydrate (84 mg, 0.44 mmol) and stirred at room temperature for 3 days. The reaction liquid was concentrated, followed by purification of residue obtained with silica gel column chromatography (methylene chloride/methanol=30/1) to obtain an objective compound (89.0 mg, 66.1%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O)#[N:2].[CH2:12]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23]C)[CH:18]=1)[CH2:13][CH2:14][CH3:15].Cl>S(Cl)(Cl)=O>[CH2:12]([O:16][C:17]1[CH:22]=[CH:21][C:20]([C:6]([C:5]2[CH:4]=[C:3]([CH:11]=[CH:10][CH:9]=2)[C:1]#[N:2])=[O:8])=[C:19]([OH:23])[CH:18]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCOc1cccc(OC)c1
Reactant: N#Cc1cccc(C(=O)O)c1
Agent: Cl
Solvent: O=S(Cl)Cl
Product: CCCCOc1ccc(C(=O)c2cccc(C#N)c2)c(O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 5.5 %

Procedure:
First, 3-cyanobenzoic acid (20 grams) is heated under reflux for 1.5 hours in thionyl chloride (100 ml). The excess thionyl chloride is removed by distillation. The crude acid chloride which remains is diluted with nitrobenzene (200 ml). Anhydrous aluminum chloride (21.75 g) is added and the mixture cooled in an ice bath. Then, 1-butoxy-3-methoxybenzene (20 g, 0.11 mole) is added in one portion. The reaction mixture is stirred at room temperature overnight and then heated to 105° C. for 2 hours. The resulting mixture is cooled and poured into a mixture of ice water (1000 ml) and concentrated hydrochloric acid (100 ml). The product is extracted with ether (3×300 mls). The extract was dried over MgSO4, filtered and evaporated to dryness. The residual dark oil is chromatographed on silica gel (hexane:ether at 80:20) to yield 3-(4-butoxy-2-hydroxybenzoyl)benzonitrile (1.8 g) followed by 3-(2-hydroxy-4-methoxybenzoyl)benzonitrile (2.75 g). The 3-(4-butoxy-2-hydroxybenzoyl)benzonitrile thereby obtained, is heated under reflux in a mixture of acetic acid (18 g) and concentrated hydrochloric acid (18 g) for a hours. The resulting mixture is diluted with water (100 ml) and extracted with methylene chloride (3×50 ml). The extract is dried over magnesium sulfate, filtered, and evaporated to dryness. The residue is recrystallized from heptane/ethanol to yield 3-(4-butoxy-2-hydroxybenzoyl)benzoic acid (1.13 g), m.p. 175° C.
Reaction SMILES: C(OC([NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH2:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]([NH:26]C(OC(C)(C)C)=O)[CH:21]=2)=[CH:11][CH:10]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH2:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]([NH2:26])[CH:21]=2)=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(Cc2ccc(NC(=O)OC(C)(C)C)c3ccccc23)ccn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1cc(Cc2ccc(N)c3ccccc23)ccn1
Temperature: 0 °C

Procedure:
To a solution of (4-(tert-butoxycarbonyl)aminonaphthalen-1-yl)(2-(tert-butoxycarbonyl)amino pyridin-4-yl)methane (270 mg, 0.60 mmol) in dry DCM (6.0 mL) under N2 at 0° C. was added TFA (2.0 mL, 25 mmol). The reaction was maintained at 0° C. for a further 20 min and was then warmed to RT for 4 hr. The mixture was evaporated in vacuo and the residue was subjected to SCX capture and release to afford the title compound, Intermediate H1, (150 mg, 100%); Rt 0.79 min (Method 2); m/z 250 (M+H)+ (ES+).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Br[CH2:8][CH2:9]Br.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[SH:18]>CC(C)=O>[S:18]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][CH2:9][CH2:8]1
Reactant: Nc1ccccc1S
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: c1ccc2c(c1)NCCS2
Reaction time: 8 h
Yield: 66.1 %

Procedure:
K2CO3 (4.4 g, 31.9 mmol) and 1,2-dibromoethane (0.69 mL, 8.0 mmol) were added to a solution of 2-aminothiophenol (1.0 g, 8.0 mmol) in 20 mL of acetone at room temperature. The reaction mixture was stirred overnight. The insoluble material was filtered off and the solvent was removed under reduced pressure. The residue was purified on silica gel column to provide 3,4-dihydro-2H-1,4-benzothiazine (0.8 g, 66%). MS (ES+): 152 (M+1)
Reaction SMILES: Cl[C:2](=[O:7])[C:3]([O:5][CH3:6])=[O:4].[CH3:8][NH:9][CH2:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1.N1C=CC=CC=1>ClCCl>[CH3:8][N:9]([CH2:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)[C:2](=[O:7])[C:3]([O:5][CH3:6])=[O:4]
Reactant: CNCc1ccncc1
Reactant: COC(=O)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)C(=O)N(C)Cc1ccncc1
Yield: 28.2 %

Procedure:
A solution of methyl chlorooxoacetate (2.01 g, 16.37 mmol), N-methyl-N-(4-pyridinylmethyl)amine (2.0 g, 16.37 mmol) and pyridine (1.6 mL, 19.64 mmol) in anhydrous dichloromethane (10 mL) was stirred at 50° C. for 2 h. The mixture was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel (40%-100% EtOAc in hexanes) to afford methyl 2-(methyl(pyridin-4-ylmethyl)amino)-2-oxoacetate (77) as a pale yellow oil (0.96 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([N:10]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)=[CH:6][CH:5]=1.O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH:47](=[O:51])[CH:48]([CH3:50])[CH3:49].O>O1CCCC1>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]2[C:7](=[CH:8][CH:9]=1)[NH:10][CH:11]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)[C:48]([CH3:50])([CH3:49])[CH:47]2[OH:51])=[O:20]
Reactant: COC(=O)c1ccc(N=Cc2cccc(OC)c2)cc1
Reactant: CC(C)C=O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1cccc(OC)c1)N2
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.6 %

Procedure:
To a stirred mixture solution of 4-[(3-methoxy-benzylidene)-amino]-benzoic acid methyl ester (2.7 g, 10.0 mmol) and ytterbium(III) triflate hydrate (620.3 mg, 1.0 mmol) in dry tetrahydrofuran (10 mL) at 25° C. was added isobutyraldehyde (0.93 mL, 10.2 mmol) and water (0.2 mL, 10.2 mmol) dropwise. The reaction mixture was stirred at 25° C. for 16 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 4-hydroxy-2-(3-methoxy-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester (3.4 g, quant.) as a light yellow oil which was used for next step without further purification: LC/MS m/e calcd for C20H23NO4 (M+H)+: 342.41, observed: 324.2 & 342.2.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[Cl:15][C:16]1[C:26]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21][C:20]=2[CH:19]=[CH:18][C:17]=1[Cl:27].[C:28]([OH:33])(=[O:32])[C:29]([OH:31])=[O:30].CO>C(OCC)(=O)C>[C:28]([OH:33])(=[O:32])[C:29]([OH:31])=[O:30].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:23]3[CH2:22][CH2:21][C:20]4[CH:19]=[CH:18][C:17]([Cl:27])=[C:16]([Cl:15])[C:26]=4[CH2:25][CH2:24]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: Clc1ccc2c(c1Cl)CCNCC2
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCc2ccc(Cl)c(Cl)c2CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 6,7-dichloro-2,3,4,5-tetrahydro-1H-3-benzazepine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 77% overall yield. FDMS m/e=405 (M+ of free base). α[D]589 =-6.87 (c=0.44, methanol).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]2[C:8](=[O:25])[N:9]([CH2:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:6]=2[N:5]([CH3:26])[C:4]=1[C:27]([NH:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)=[O:28].I[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1.C(=O)([O-])[O-].[K+].[K+].BrC1C=CC=CN=1.C(N(CC)CC)C>CN(C=O)C.O>[CH3:1][O:2][C:3]1[C:7]2[C:8](=[O:25])[N:9]([CH2:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:6]=2[N:5]([CH3:26])[C:4]=1[C:27]([NH:29][CH:30]1[CH2:31][CH2:32][N:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=2)[CH2:34][CH2:35]1)=[O:28]
Reactant: COc1c(C(=O)NC2CCNCC2)n(C)c2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Reactant: Ic1ccccn1
Agent: Brc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(C(=O)NC2CCN(c3ccccn3)CC2)n(C)c2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Reaction time: 1 h
Yield: 11.5 %

Procedure:
A solution of the compound of Example 77 (284 mg, 0.60 mmol), 2-iodopyridine (0.13 mL, 1.2 mmol) and potassium carbonate (208 mg, 1.5 mmol) in DMF (3.0 mL) was stirred at 90° C. for 5.5 hr. 2-Bromopyridine (0.23 mL, 2.5 mmol) and triethylamine (0.49 mL, 3.5 mmol) were added to the reaction mixture, and the mixture was stirred under microwave irradiation at 165° for 1 hr. The reaction mixture was diluted with water, and extracted twice with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by aminosilica gel chromatography (eluate; ethyl acetate/hexane=30/70-100/0) and recrystallized from THF-diethyl ether to give the title compound (38 mg, 12%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([O:22][CH2:23][CH2:24][C:25]([O:27]CC)=O)[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1.[CH3:30][NH2:31]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([O:22][CH2:23][CH2:24][C:25]([NH:31][CH3:30])=[O:27])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN
Reactant: CCOC(=O)CCOC(c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Solvent: CO
Product: CNC(=O)CCO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
(3R)-tert-butyl 3-((3-chlorophenyl)(3-ethoxy-3-oxopropoxy)methyl)piperidine-1-carboxylate (2.0 g, 4.71 mmol) was dissolved in a solution CH3NH2 in CH3OH ((180 mL) and stirred overnight at rt. After the reaction was complete by HPLC analysis, the solvent was removed in vacuo. The residue was purified by preparative HPLC and afforded the desired isomerically pure product (R)-tert-butyl 3-((R)-(3-chlorophenyl)(3-(methylamino)-3-oxopropoxy)methyl)piperidine-1-carboxylate (0.80 g, 1.95 mmol, 41% yield). MS (E/Z): 411 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([N+:10]([O-])=O)[N:7]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[N:6]=1)=[O:4].O.O.Cl[Sn]Cl>O(CCOC)C>[CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[N:6]=1)=[O:4]
Reactant: COC(=O)c1cc([N+](=O)[O-])n(C(=O)OCc2ccccc2)n1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1cc(N)n(C(=O)OCc2ccccc2)n1
Yield: 95 %

Procedure:
A mixture of 5-nitropyrazole-1,3-dicarboxylic acid 1-benzyl ester 3-methyl ester (3.2 g, 10.48 mmol) and SnCl2.2H2O (7.2 g, 31.9 mmol) in 1,2-dimethoxylethane (60 mL) was heated to reflux for 2 hours. The solvent was removed in vacuo. The residue was neutralized with saturated aqueous sodium carbonate. The resulting solution was filtered and the filtrate was extracted with ethyl acetate. The organic layer was separated and dried over anhydrous Na2SO4 and concentrated to give 5-aminopyrazole-1,3-dicarboxylic acid 1-benzyl ester 3-methyl ester (2.74 g, 90%). 1H NMR (300 MHz, CDCl3) δ 7.30-7.18 (m, 5H), 6.17 (s, 1H), 3.82 (s, 3H), 3.63 (s, br., 2H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([N+:12]([O-])=O)=[C:4]([F:15])[CH:3]=1.[H][H]>C(O)C.[Pt](=O)=O>[Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([NH:12][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:4]([F:15])[CH:3]=1
Reactant: CC(C)Oc1cc([N+](=O)[O-])c(F)cc1Cl
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCO
Product: CC(C)Oc1cc(Nc2ccccc2)c(F)cc1Cl
Yield: 69.3 %

Procedure:
A suspension of 4-chloro-2-fluoro-5-isopropoxynitrobenzene (13.5 g) and platinum dioxide (0.4 g) in ethanol (300 ml) was subjected to catalytic reduction with hydrogen at room temperature (ca. 20° C.) under atmospheric pressure, whereby a designated amount of hydrogen was absorbed. The resultant mixture was filtered to remove insoluble materials, and the filtrate was concentrated. The residue was subjected to purification by silica gel chromatography to give 5.6 g of 4-chloro-2-fluoro-5-isopropoxyphenylaniline. nD24.5 1.5360.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8](=[O:20])[N:9]2[C:13](=[C:14]([C:16](=[O:19])CC)[CH:15]=1)[CH2:12][CH2:11][CH2:10]2)(=O)=O.C[Sn](C)(C)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1.[Li+].[Cl-].C1C[O:38]CC1>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:20]=[C:8]1[C:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)=[CH:15][C:14]([C:16]([OH:19])=[O:38])=[C:13]2[N:9]1[CH2:10][CH2:11][CH2:12]2
Reactant: C[Sn](C)(C)c1ccccn1
Reactant: C1CCOC1
Reactant: CCC(=O)c1cc(OS(=O)(=O)C(F)(F)F)c(=O)n2c1CCC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Product: O=C(O)c1cc(-c2ccccn2)c(=O)n2c1CCC2
Temperature: 160 °C

Procedure:
A mixture of 5-oxo-8-propionyl-1,2,3,5-tetrahydroindolizin-6-yl trifluoromethanesulfonate (0.50 g, 1.46 mmol), 2-trimethylstannyl pyridine (0.46 g, 1.90 mmol), LiCl (0.17 g, 4.38 mmol), and (Ph3P)4Pd (0.12 g, 0.11 mmol) in THF (10 mL) was heated by Microwave Synthesizer at 160° C. for 20 min. The reaction was cooled, diluted with H2O and extracted into EtOAc (3×). The organic layers were combined, dried over MgSO4 and concentrated. The concentrate was triturated in ether to give the salt of the title compound as a light green solid. The solid was dissolved in MeOH (5 mL), to which was added 2 eq. of 1N NaOH and the mixture was stirred for 2 h. The mixture was concentrated, taken up in H2O, neutralized by 10% HCl, extracted with CH2Cl2 (3×), dried over MgSO4, concentrated to give the title compound as a light yellow oil (0.32 g, 85%). MS (m/z, M+1): 257.1.
Reaction SMILES: [NH2:1]OS(O)(=O)=O.[CH:7]([CH:10]1[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]1)([CH3:9])[CH3:8].[OH-].[Na+]>C(O)=O>[CH:7]([CH:10]1[CH2:15][CH2:14][NH:1][C:13](=[O:16])[CH2:12][CH2:11]1)([CH3:9])[CH3:8]
Reactant: CC(C)C1CCC(=O)CC1
Reactant: NOS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Product: CC(C)C1CCNC(=O)CC1
Temperature: 25 °C

Procedure:
To a solution of hydroxylamine-O-sulfonic acid (60.5 g, 535 mmol) in formic acid (320 ml) was added dropwise a solution of 4-isopropyl cyclohexanone (50.0 g, 357 mmol) in formic acid (110 ml) at r.t. under an argon atmosphere. The reaction mixture was refluxed for 3 h, cooled to r.t. and slowly treated with ice-water (550 ml). 10 N NaOH (1.1 liter) was added to adjust the pH to 8 and the resultant mixture was extracted with CHCl3 (4×). The combined organic extracts were washed with water, brine, dried (MgSO4), filtered and concentrated under reduced pressure. The light-brown solid was crystallized from n-heptane: 42.4 g (75%);
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CN(C)C=O.F[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=1[N+:23]([O-:25])=[O:24]>O>[N+:23]([C:14]1[CH:15]=[C:16]([C:19]([F:20])([F:21])[F:22])[CH:17]=[CH:18][C:13]=1[N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)([O-:25])=[O:24]
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1N1CCOCC1
Reaction time: 3 h
Yield: 97.7 %

Procedure:
Morpholine (190 μl, 2.17 mmol, commercially available product) was added at room temperature to an N,N-dimethylformamide (DMF; 0.5 ml) solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (209 mg, 1.00 mmol, commercially available product). The resulting mixture was stirred for three hours. Water was added to the mixture, and the resulting mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20 g, hexane/ethyl acetate=3/1). Thus, 4-[2-nitro-4-(trifluoromethyl)phenyl]morpholine (270 mg, 97.7%) was yielded as an orange-colored oily material.