Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC=CC=1.[Cl:8][C:9]1[CH:26]=[CH:25][C:12]([C:13]([N:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])[CH3:16])=[O:14])=[CH:11][C:10]=1B1OC(C)(C)C(C)(C)O1.Br[C:37]1[CH:38]=[CH:39][C:40]([Cl:43])=[N:41][CH:42]=1.C([O-])([O-])=O.[Na+].[Na+]>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>[Cl:8][C:9]1[CH:26]=[CH:25][C:12]([C:13]([N:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])[CH3:16])=[O:14])=[CH:11][C:10]=1[C:37]1[CH:42]=[N:41][C:40]([Cl:43])=[CH:39][CH:38]=1
Reactant: COc1ccccc1N(C)C(=O)c1ccc(Cl)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Clc1ccc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccccc1N(C)C(=O)c1ccc(Cl)c(-c2ccc(Cl)nc2)c1
Temperature: 100 °C
Yield: 38.9 %

Procedure:
A mixture of toluene (1.5 mL) and water (0.5 mL) containing 4-chloro-N-(2-methoxy-phenyl)-N-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (60 mg, 0.15 mmol), 5-bromo-2-chloro-pyridine (29 mg, 0.15 mmol), Pd(PPh3)4 (12 mg, 0.01 mmol), Na2CO3 (2N, 0.15 mL, 0.3 mmol), was bubbled with N2 for 5 min, then heated at 100° C. for 12 hrs. The mixture was filtered and purified by prep. LCMS to yield 4-chloro-3-(6-chloro-pyridin-3-yl)-N-(2-methoxy-phenyl)-N-methyl-benzamide 2-1 (22.6 mg). MS: 386.7 (M+H)+; tR=7.77 min (method 2).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH:5]([NH:11][CH:12]=[O:13])[CH:6](O)[CH:7]=[CH:8][CH3:9])[CH3:2].S(Br)(Br)=O.[P:19]([O:26]CC)([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22]>>[CH2:1]([O:3][C:4](=[O:14])[CH:5]([NH:11][CH:12]=[O:13])/[CH:6]=[CH:7]/[CH:8]([P:19]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])=[O:26])[CH3:9])[CH3:2]
Reactant: CCOP(OCC)OCC
Reactant: CC=CC(O)C(NC=O)C(=O)OCC
Agent: O=S(Br)Br
Product: CCOC(=O)C(/C=C/C(C)P(=O)(OCC)OCC)NC=O

Procedure:
The starting material is manufactured as follows: Reaction of crotonaldehyde with isocyanoacetic acid ethyl ester in a manner analogous to that described in Example 1 yields 5-(propen-1-yl)-2-oxazoline-4-carboxylic acid ethyl ester. By hydrolysis of the 5-(propen-1-yl)-2-oxazoline-4-carboxylic acid ethyl ester analogously to Example 1, 2-formylamino-3-hydroxy-4-hexenoic acid ethyl ester is obtained. Reaction of the 2-formylamino-3-hydroxy-4-hexenoic acid ethyl ester with thionyl bromide and subsequent treatment with triethyl phosphite in a manner analogous to that described in Example 1 (12 hours) yields E-2-formylamino-5-diethylphosphono-5-methyl-3-pentenoic acid ethyl ester.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([S:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14]/[C:13]/1=[CH:18]\[C:19]1[N:20]=[N:21][N:22]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH:23]=1)(=[O:10])[CH3:9].Br[CH:30]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[F:42])[C:31]([CH:33]1[CH2:35][CH2:34]1)=[O:32].[ClH:43]>C(N(CC)CC)C>[ClH:43].[C:8]([S:11][CH:12]1[CH2:17][CH2:16][N:15]([CH:30]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[F:42])[C:31]([CH:33]2[CH2:34][CH2:35]2)=[O:32])[CH2:14]/[C:13]/1=[CH:18]\[C:19]1[N:20]=[N:21][N:22]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH:23]=1)(=[O:10])[CH3:9]
Reactant: O=C(C1CC1)C(Br)c1ccccc1F
Reactant: COC(=O)Cn1cc(/C=C2\CNCCC2SC(C)=O)nn1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: COC(=O)Cn1cc(/C=C2\CN(C(C(=O)C3CC3)c3ccccc3F)CCC2SC(C)=O)nn1
Yield: 56 %

Procedure:
Following a procedure similar to that described in Example 150-(g), (E)-4-(acetylsulfanyl)-3-{[1-(methoxycarbonylmethyl)-1H-1,2,3-triazol-4-yl]methylidene}piperidine hydrogen trifluoroacetate (550 mg) was subjected to the reaction with 2-bromo-2-(2-fluorophenyl)-1-cyclopropylethanone and triethylamine, and the free base that was obtained by chromatographic purification on silica gel was treated with hydrogen chloride to yield the title compound (380 mg, yield: 56%) as a pale yellow amorphous solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([CH3:13])=[N:7][C:8]([Cl:12])=[CH:9][C:10]=1[CH3:11])=[O:4].[Br:14]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C.C(O)(=O)C>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:6]([CH2:13][Br:14])=[N:7][C:8]([Cl:12])=[CH:9][C:10]=1[CH3:11])=[O:4]
Reactant: COC(=O)c1c(C)cc(Cl)nc1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CC(=O)O
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1c(C)cc(Cl)nc1CBr

Procedure:
To a solution of 710 mg, (3.6 mmol) 6-chloro-2,4-dimethyl-pyridine-3-carboxylic acid methylester in CCl4 (16 ml) were added 688 mg (3.90 mmol) N-bromosuccinimide, 59 mg (0.36 mmol) AIBN and 210 μl (3.72 mmol) acetic acid. The reaction mixture was irradiated with a 200 W Wolfram lamp at 60° C. for 24 h. The mixture was then filtered through celite, washed with CCl4 and concentrated in vacuo. After CC (hexane/EtOAc 97:3) of the residue a mixture of 6-chloro-2,4-dimethyl-pyridine-3-carboxylic acid methylester, 4-(bromomethyl)-6-chloro-2-methyl-pyridine-3-carboxylic acid methylester and 2-(bromomethyl)-6-chloro-4-methyl-pyridine-3-carboxylic acid methylester was obtained. This mixture was dissolved in dioxane (10 ml) and added at 0° C. to a solution prepared by dissolving 594 mg (25.8 mmol) sodium in MeOH (11 ml) at 0° C. This reaction mixture was stirred at RT for 3 h. Then the reaction solution was poured into water and extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated in vacuo. After CC (hexane/EtOAc 97:3) of the residue again a mixture of 6-chloro-4-(methoxymethyl)-2-methyl-pyridine-3-carboxylic acid methylester and 6-chloro-2-(methoxymethyl)-4-methyl-pyridine-3-carboxylic acid methylester was obtained. This material was dissolved in NMP (7.8 ml) and 860 μl (9.85 mmol) morpholine and 1.36 g (9.85 mmol) K2CO3 were added followed by heating at 100° C. for 5 h. Then the mixture was poured into water and extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 9:1) provided 90 mg (0.32 mmol, 9%) 2-(methoxymethyl)-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid methylester.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH2:2]1.NC1C=CC=CC=1S.C=O.C(N(C(C)C)CC)(C)C.[CH2:29]([O:36][C:37]1[C:45]([C:46]([F:49])([F:48])[F:47])=[CH:44][C:40]([C:41](Cl)=[O:42])=[CH:39][C:38]=1[O:50][CH3:51])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl>[CH2:29]([O:36][C:37]1[C:45]([C:46]([F:47])([F:48])[F:49])=[CH:44][C:40]([C:41]([N:3]2[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[S:1][CH2:2]2)=[O:42])=[CH:39][C:38]=1[O:50][CH3:51])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: c1ccc2c(c1)NCS2
Reactant: COc1cc(C(=O)Cl)cc(C(F)(F)F)c1OCc1ccccc1
Agent: C=O
Agent: Nc1ccccc1S
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C(=O)N2CSc3ccccc32)cc(C(F)(F)F)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,3-dihydro-1,3-benzothiazole synthesized from 2-aminobenzenethiol (346 mg) and 37% formalin (0.23 mL) in the same manner as in Example 1 was dissolved in dichloromethane (3 mL), and diisopropylethylamine (0.63 mL) and 4-benzyloxy-3-methoxy-5-trifluoromethylbenzoyl chloride (657 mg) were added to the solution, and then the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure and water was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=6:1) to obtain the title compound (578 mg) as a yellow oily substance.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.Br[CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][N:15]([CH2:22][CH2:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Reactant: BrCCCc1ccccc1
Product: Cc1noc(C)c1Cn1cc(N2C(=O)CN(CCCc3ccccc3)C2=O)cn1
Yield: 36 %

Procedure:
Prepared as in example 10-52 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) and (3-bromopropyl)benzene. Yield: 36%. MS M+H calculated 394.2; found 394.2. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.26 μM.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][NH2:14])[CH2:10][C@H:9]1[C:15]([N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:22]1([C:28](Cl)=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][NH:14][C:28]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:29])[CH2:10][C@H:9]1[C:15]([N:17]1[CH2:18][CH2:19][CH2:20][CH2:21]1)=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)C1CCCCC1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CN)C[C@H]1C(=O)N1CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H](CNC(=O)C2CCCCC2)C[C@H]1C(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of (2S, 4R)-4-aminomethyl-2-(pyrrolidine-1-carbonyl)pyrrolidine-1-carboxylic acid tert-butyl ester (0.15 g, 0.51 mmol, Example 39C) in dichloromethane (2 mL) at room temperature was added cyclohexanecarbonyl chloride (0.092 g, 0.65 mmol) and triethylamine (0.10 mL, 0.75 mmol). The mixture was stirred at room temperature for 12 hours, concentrated under reduced pressure and the residue taken up in water and extracted with ethyl acetate (2×). The combined ethyl acetate layers were washed consecutively with saturated aqueous NaHCO3, 10% KHSO4 (aq), brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography with 30-40% ethyl acetate:hexane to provide the title compound. MS (CI) m/z 408 (M+1)+; 1H NMR (300 MHz, CDCl3) δ ppm 4.40-4.28 (m, 1H), 3.88-3.66 (m, 2H), 3.56-3.25 (m, 4H), 3.22-3.16 (m, 2H), 2.57 (m, 2H), 2.55 (m, 1H), 1.99-1.61, (m, 13H), 1.41 (m, 9H), 1.51 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:7]([Br:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[O:9]1[C:13]2([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[O:12][CH2:11][CH2:10]1>>[Br:8][C:7]1[C:2]([N:16]2[CH2:17][CH2:18][C:13]3([O:12][CH2:11][CH2:10][O:9]3)[CH2:14][CH2:15]2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: C1CC2(CCN1)OCCO2
Reactant: Clc1ncccc1Br
Product: Brc1cccnc1N1CCC2(CC1)OCCO2

Procedure:
The title compound was prepared from 2-chloro-3-bromopyridine and 1,4-dioxa-8-azaspiro[4,5]decane in a manner similar to that of Description 10.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[N:15]12[CH2:22][CH2:21][CH2:20][C:19]1([CH2:23][NH2:24])[CH2:18][CH2:17][CH2:16]2>>[N:15]12[CH2:22][CH2:21][CH2:20][C:19]1([CH2:23][NH:24][C:2]1[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])[CH2:18][CH2:17][CH2:16]2
Reactant: O=[N+]([O-])c1ccc2ccccc2c1Cl
Reactant: NCC12CCCN1CCC2
Product: O=[N+]([O-])c1ccc2ccccc2c1NCC12CCCN1CCC2
Yield: 84.1 %

Procedure:
1-Chloro-2-nitronaphthalene and (1-azabicyclo[3.3.0]octan-5-yl)methylamine were reacted in the same manner as in Example 1 to obtain the titled compound in a yield of 84.1%.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:12][CH:13]([F:16])[CH2:14][OH:15]>>[Cl:1][C:2]1[C:3]([O:15][CH2:14][CH:13]([F:16])[F:12])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: OCC(F)F
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Product: O=C(O)c1cnc(OCC(F)F)c(Cl)c1
Yield: 83 %

Procedure:
The title compound is prepared in 83% yield (4.12 g, a white solid) from 5,6-dichloronicotinic acid (4.00 g, 20.8 mmol) and 2,2-difluoroethanol instead of 2,2,2-trifluoroethanol by the similar manner in Step-1 of Amine-1.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:11][CH2:10]2)=[C:5]([CH2:20][CH3:21])[CH:4]=1)#[CH:2].[CH2:22]([O:24][C:25](=[O:33])[C:26]1[CH:31]=[CH:30][C:29](I)=[CH:28][CH:27]=1)[CH3:23]>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:13]([O:12][C:9]1([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[C:2][C:29]3[CH:30]=[CH:31][C:26]([C:25]([O:24][CH2:22][CH3:23])=[O:33])=[CH:27][CH:28]=3)=[CH:4][C:5]=2[CH2:20][CH3:21])[CH2:11][CH2:10]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: C#Cc1ccc(C2(OCc3ccccc3)CC2)c(CC)c1
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc(C3(OCc4ccccc4)CC3)c(CC)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.4 %

Procedure:
Using General Procedure F; 1-ethynyl-4-(1-benzyloxycyclopropyl)-3-ethyl-benzene (Intermediate 90, 90.0 mg, 0.33 mmol) and ethyl-4-iodo benzoate (Reagent A, 100.0 mg, 0.36 mmol) in triethylamine (5 mL) was treated with copper(I)iodide (21.0 mg, 0.11 mmol) and sparged with argon for minutes. Dichlorobis(triphenylphosphine)palladium(II) (77 mg, 0.11 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (2-4% EtOAc-hexanes) afforded 100.0 mg (72%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[C@@H:17]1([NH2:27])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][CH2:18]1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][NH:27][C@@H:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20][CH2:19][CH2:18]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2ccc(C=O)cc2)cc1
Reactant: N[C@H]1CCCc2ccccc21
Product: COc1ccc(-c2ccc(CN[C@H]3CCCc4ccccc43)cc2)cc1

Procedure:
4′-Methoxy[1,1′-biphenyl]-4-carbaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: [C-:1]#[N:2].[Na+].[CH3:4][C:5]1[C:12]([F:13])=[C:11]([F:14])[C:8]([CH:9]=[O:10])=[C:7]([F:15])[C:6]=1[F:16].CO>O>[C:1]([CH:9]([OH:10])[C:8]1[C:7]([F:15])=[C:6]([F:16])[C:5]([CH3:4])=[C:12]([F:13])[C:11]=1[F:14])#[N:2]
Reactant: [C-]#N
Reactant: Cc1c(F)c(F)c(C=O)c(F)c1F
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1c(F)c(F)c(C(O)C#N)c(F)c1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
1.66 g of sodium cyanide were introduced into a mixture of 4 g of 4-methyl-2,3,5,6-tetrafluorobenzaldehyde, 4 g of 4-methyl-2,3,5,6-tetrafluorobenzaldehyde, 70 ml of methyl alcohol and 20 ml of water and the mixture was cooled to 0° C. The reaction mixture was stirred for 1 hour at 0° C. and was poured into water. Extraction was carried out with ether and the ethereal phases were dried and evaporated to dryness under reduced pressure to obtain 4.54 g of the product melting at 124° C.
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[S:12][C:11]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:27]([O:29][CH2:30][CH:31]([CH3:33])[CH3:32])=[O:28]>CC(C)=O>[C:27](=[O:28])([O:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[S:12][C:11]([S:13](=[O:15])(=[O:14])[NH2:16])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1)[O:29][CH2:30][CH:31]([CH3:33])[CH3:32]
Reactant: CC(C)COC(=O)Cl
Reactant: NS(=O)(=O)c1ccc(C(=O)c2ccc(O)cc2)s1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(C)COC(=O)Oc1ccc(C(=O)c2ccc(S(N)(=O)=O)s2)cc1

Procedure:
A solution of 5-(4-hydroxybenzoyl)thiophene-2-sulfonamide (0.00783 mole) in acetone (50 ml) at 0° C. is treated with triethylamine (0.00861 mole) followed by isobutyl chloroformate (0.00861 mole) dropwise, during 30 minutes at 0°-2° C.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13](O)=[O:14])[C:10]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[N:27]=[C:28]([C:32]4[O:33][CH:34]=[CH:35][CH:36]=4)[O:29][C:30]=3[CH3:31])=[C:20]([O:37][CH3:38])[CH:19]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C([N:42]=C=NCCCN(C)C)C.CN(C)C=O>O>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([NH2:42])=[O:14])[C:10]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[N:27]=[C:28]([C:32]4[O:33][CH:34]=[CH:35][CH:36]=4)[O:29][C:30]=3[CH3:31])=[C:20]([O:37][CH3:38])[CH:19]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: COc1cc(COc2nn(Cc3ccccc3)cc2C(=O)O)ccc1OCc1nc(-c2ccco2)oc1C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(COc2nn(Cc3ccccc3)cc2C(N)=O)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 92.2 %

Procedure:
A mixture of 1-benzyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1H-pyrazole-4-carboxylic acid (0.25 g), 1-hydroxybenzotriazole ammonia complex (0.11 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.14 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 3 days. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 1-benzyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1H-pyrazole-4-carboxamide as colorless crystals (0.23 g, yield 92%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 160-161° C.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([S:12]([NH:14][CH:15]([C:17]1[N:21]2[CH2:22][C@H:23]([C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[C:36]=3[F:42])[CH2:24][CH2:25][C@@H:26]([NH:27]C(=O)OC(C)(C)C)[C:20]2=[N:19][CH:18]=1)[CH3:16])=[O:13])([CH3:11])([CH3:10])[CH3:9].C(=O)(O)[O-].[Na+]>ClCCl>[NH2:27][C@@H:26]1[CH2:25][CH2:24][C@@H:23]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[C:36]=2[F:42])[CH2:22][N:21]2[C:17]([CH:15]([NH:14][S:12]([C:8]([CH3:9])([CH3:11])[CH3:10])=[O:13])[CH3:16])=[CH:18][N:19]=[C:20]12
Reactant: CC(NS(=O)C(C)(C)C)c1cnc2n1C[C@H](c1cccc(F)c1F)CC[C@H]2NC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(NS(=O)C(C)(C)C)c1cnc2n1C[C@H](c1cccc(F)c1F)CC[C@H]2N
Reaction time: 1.5 h

Procedure:
Trifluoroacetic acid (1 mL, 13.5 mmol) was added to a solution of tert-butyl [(6S,9R)-3-{1-[(tert-butylsulfinyl)amino]ethyl}-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-yl]carbamate (144 mg, 0.28 mmol) in dichloromethane (5 mL). After 1.5 h, saturated aqueous sodium bicarbonate was added and the mixture was extracted with dichloromethane (3×). The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. MS 411.1 (M+1).
Reaction SMILES: [I-:1].[K+].[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12]O)=[CH:6][CH:5]=1.P(=O)(O)(O)O>>[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][I:1])=[CH:6][CH:5]=1
Reactant: [I-]
Reactant: Cc1ccc(CCCO)cc1
Agent: O=P(O)(O)O
Agent: [K+]
Product: Cc1ccc(CCCI)cc1
Temperature: 120 °C
Yield: 68.3 %

Procedure:
Potassium iodide (0.90 g, 5.4 mmol) and 3-(p-methylphenyl)propan-1-ol (0.4 g, 2.7 mmol) was added to 85% phosphoric acid (5.4 mL) at rt. The solution was heated to 120° C. for 3 h, during which time an oil separated from the acid layer. The mixture was cooled to rt and poured into 150 mL of water and 150 mL of diethyl ether. The organic layer was separated, decolorized with saturated sodium bisulfite solution (100 mL), and washed with saturated sodium chloride solution (100 mL). The organic layer was then dried (MgSO4), filtered, and concentrated in vacuo to afford 3-(4-methylphenyl)-1-iodopropane (0.48 g, 68%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([CH:15]=O)[CH:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].Cl.[NH2:18][OH:19].N1C=CC=CC=1>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13](/[CH:15]=[N:18]/[OH:19])[CH:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6]
Reactant: NO
Reactant: CC(C)(C)OC(=O)c1cc(Br)cc(C=O)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)c1cc(Br)cc(/C=N/O)c1
Temperature: 68 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl 3-bromo-5-formylbenzoate (119 g, 417 mmol) in dioxane (2.4 L) were added hydroxylamine hydrochloride (44.0 g, 633 mmol) and pyridine (103 mL, 1.27 mol). The reaction mixture was heated to 68° C. After 16 h, the mixture was concentrated. Saturated aqueous amonium chloride was added the mixture was extracted with dichloromethane (3×). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated (125.0 g). MS 243 (M-tert-butyl).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[NH:11][C:10](=[O:15])[N:9]([CH3:16])[C:8]=2[N:7]=[CH:6]1)[C:2]#[C:3][CH3:4].[Cl:17]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[NH:11][C:10](=[O:15])[N:9]([CH3:16])[C:8]=2[N:7]=[C:6]1[Cl:17])[C:2]#[C:3][CH3:4]
Reactant: CC#CCn1cnc2c1c(=O)[nH]c(=O)n2C
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC#CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2C
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.1 %

Procedure:
3-Methylxanthine (1.1 g) was dissolved in N,N-dimethylformamide (15 ml), and potassium carbonate (1.0 g) and 1-bromo-2-butyne (0.64 ml) were added thereto. After stirring at room temperature overnight, the reaction mixture was diluted with ethyl acetate, and washed with water. Insoluble white solid was collected by filtration, and washed with ethyl acetate to give 1.3 g of 7-(2-butynyl)-3-methyl-3,7-dihydropurine-2,6-dione. Then, the resulting 7-(2-butynyl)-3-methyl-3,7-dihydropurine-2,6-dione (1.3 g) was dissolved in N,N-dimethylformamide (15 ml), and N-chlorosuccinimide (0.89 g) was added while cooling on ice. After stirring at room temperature for 3 hours, the reaction mixture was diluted with ethyl acetate, and washed with water. Insoluble white solid was collected by filtration, and washed with ethyl acetate to give 1.1 g of 7-(2-butynyl)-8-chloro-3-methyl-3,7-dihydropurine-2,6-dione. The resulting 7-(2-butynyl)-8-chloro-3-methyl-3,7-dihydropurine-2,6-dione (1.4 g) and 1-piperazine carboxylic acid tert-butyl ester (2.8 g) were stirred at 150° C. for 1 hour. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate, then the organic layer was washed with water and saturate brine, and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation at reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.1 g of the title compound from a fraction eluted with hexane-ethyl acetate (1:4).
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[O:9][CH2:8][C@@H:7]([S:10]C(=O)C)[CH2:6]1)=[N+:2]=[N-:3]>O1CCCC1.C[O-].[Na+].CO>[N:1]([CH2:4][C@H:5]1[O:9][CH2:8][C@@H:7]([SH:10])[CH2:6]1)=[N+:2]=[N-:3]
Reactant: CC(=O)S[C@@H]1CO[C@H](CN=[N+]=[N-])C1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: [N-]=[N+]=NC[C@@H]1C[C@H](S)CO1
Yield: 64.8 %

Procedure:
The title compound is prepared by the procedure of Example 16 using 0.310 g of product from Example 61 in 4.5 ml of tetrahydrofuran and 0.30 ml of 25% sodium methoxide/methyl alcohol to give 0.159 g of the desired product.