Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[C:8]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N+:32]([O-:34])=[O:33])=[CH:9][CH:10]=[C:11]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[N:17]=2)[CH:12]=1)=[O:6]>O.O1CCOCC1>[CH3:25][O:24][C:21]1[CH:20]=[CH:19][C:18]([C:16]2[N:17]=[C:13]([C:11]3[CH:12]=[C:7]([C:5]([OH:6])=[O:4])[C:8]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[N+:32]([O-:34])=[O:33])=[CH:9][CH:10]=3)[S:14][CH:15]=2)=[CH:23][CH:22]=1
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(OC)cc3)cs2)ccc1-c1ccccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(-c2csc(-c3ccc(-c4ccccc4[N+](=O)[O-])c(C(=O)O)c3)n2)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 55.2 %

Procedure:
Sodium hydroxide (200 mg, 5 mmol) was added to a suspension of 4-[4-(4-methoxy-phenyl)-thiazol-2-yl]-2′-nitro-biphenyl-2-carboxylic acid methyl ester (187 mg) in a mixture of water (8 mL) and dioxane (8 mL). The reaction mixture was stirred at 50° C. for 2 h. The reaction mixture was evaporated to dryness and water (15 mL) was added. The mixture was filtered and the filtrate was made acidic to pH 3-4 by the addition of concentrated HCl. The precipitate was collected by filtration and dried to give 4-[4-(4-methoxy-phenyl)-thiazol-2-yl]-2′-nitro-biphenyl-2-carboxylic acid (100 mg, 37% for two steps). 1H NMR (300 MHz, DMSO-d6) δ 13.17 (br s, 1H), 8.56 (d, J=1.8 Hz, 1H), 8.24 (dd, J=8.0, 1.9 Hz, 1H), 8.11-8.16 (m, 2H), 8.01 (d, J=8.8 Hz, 2H), 7.76-7.81 (m, 1H), 7.63-7.68 (m, 1H), 7.41-7.47 (m, 2H), 7.05 (d, J=8.8 Hz, 2H), 3.82 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:7])([CH3:4])[CH3:3].CC(C)([O-])C.[K+].I[CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([C:38](=[O:42])[CH2:39][CH2:40][CH3:41])=[CH:34][CH:33]=1.C(OCC)(=O)C>CN(C=O)C>[C:38]([C:35]1[CH:36]=[CH:37][C:32]([O:31][CH2:30][CH2:29][O:28][CH2:27][CH2:26][O:25][CH2:24][CH2:23][N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])=[CH:33][CH:34]=1)(=[O:42])[CH2:39][CH2:40][CH3:41]
Reactant: CCCC(=O)c1ccc(OCCOCCOCCI)cc1
Reactant: CC(C)(C)OC(=O)NC(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCC(=O)c1ccc(OCCOCCOCCN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1
Reaction time: 18 h
Yield: 48.8 %

Procedure:
Di-tert-butyliminodicarboxylate (3.05 g, 14.07 mmol) and potassium tert-butoxide (1.58 g, 14.07 mmol) were stirred in DMF (50 mL) for 15 minutes followed by the addition of 1-(4-(2-(2-(2-iodoethoxy)ethoxy)ethoxy)phenyl)butan-1-one (43; 3.81 g, 9.38 mmol). The resulting mixture was stirred under nitrogen for 18 hours, and then poured into 200 mL of ethyl acetate. This solution was washed with water (2×) and sat. brine, dried over sodium sulfate, and concentrated to afford a liquid that was purified by flash silica gel column chromatography, eluting with 3:1 hexanes/ethyl acetate to afford 44 (2.27 g, 49%) as a clear oil: MS (ES+) m/z 496.2 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]([OH:6])=O)[CH2:3][CH2:2]1.[CH:7]1([NH2:10])[CH2:9][CH2:8]1.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:7]1([NH:10][C:4]([CH:1]2[CH2:3][CH2:2]2)=[O:6])[CH2:9][CH2:8]1
Reactant: NC1CC1
Reactant: O=C(O)C1CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(NC1CC1)C1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a magnetically stirred solution of cyclopropanecarboxylic acid (1.00 g, 11.6 mmol) and cyclopropylamine (0.995 g, 1.5 eq) in 8 mL of methylene chloride was added DMAP (4-dimethylaminopyridine, 2.13 g, 1.5 eq) followed by EDC (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 3.34 g, 1.5 eq). The reaction was stirred at room temperature for 2 h after which time it was diluted with 50 mL of methylene chloride and washed twice with 0.5 N aqueous HCl followed by water, saturated aqueous sodium bicarbonate, then brine. The solvent was removed under reduced pressure and the residue was purified by silica chromatography eluting with 1:1 hexane/ethyl acetate to afford N-cyclopropylcyclopropanecarboxamide (2-A).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][C:6]1[N:7]=[CH:8][S:9][CH:10]=1)[CH3:2].[OH2:12]>ClCCCl>[CH2:1]([O:3][C:4](=[O:11])[C:5]([C:6]1[N:7]=[CH:8][S:9][CH:10]=1)=[O:12])[CH3:2]
Reactant: O
Reactant: CCOC(=O)Cc1cscn1
Solvent: ClCCCl
Product: CCOC(=O)C(=O)c1cscn1

Procedure:
Alternatively, the 1,3-thiazol-4-yl-glyoxyl ester is obtained by heating 17.1 g of 1,3-thiazol-4-yl-acetic acid ethyl ester in 50 ml of 1,2-dichloroethane together with 10.5 g of SeO2 with reflux on a water separator. When the separation of water is complete, the mixture is filtered with suction, the residue is washed with 1,2-dichloroethane, the combined dichloroethane phases are concentrated and the residue is distilled.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8].[CH3:9][C:10]1[C:15](O)=CC=C[CH:11]=1>>[C:10]([C:4]1[CH:5]=[C:6]([OH:7])[CH:1]=[C:2]([CH3:8])[CH:3]=1)([CH3:15])([CH3:11])[CH3:9]
Reactant: Cc1ccccc1O
Reactant: Cc1cccc(O)c1
Product: Cc1cc(O)cc(C(C)(C)C)c1
Yield: 80 %

Procedure:
Run D of Example 1 is repeated except that 3-cresol is substituted for the cresylic acid mixture. The process results in a selectivity of better than 80 percent of 5-t-butyl-3-cresol.
Reaction SMILES: CN(C)C1C=CC=CC=1.[N+:10]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[N:21]=[CH:20][NH:19][C:18]2=O)([O-:12])=[O:11].O=P(Cl)(Cl)[Cl:26]>>[Cl:26][C:18]1[C:17]2[C:22](=[C:13]([N+:10]([O-:12])=[O:11])[CH:14]=[CH:15][CH:16]=2)[N:21]=[CH:20][N:19]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2c([N+](=O)[O-])cccc12
Solvent: CN(C)c1ccccc1
Product: O=[N+]([O-])c1cccc2c(Cl)ncnc12
Temperature: 65 °C
Yield: 59.6 %

Procedure:
N, N-dimethylaniline (0.37 ml, 1.23 mmol) was added dropwise to a solution of 8-nitro-3H-quinazolin-4-one 476 (200 mg, 1.04 mmol) in POCl3 (1.25 ml, 10.5 mmol) at 0° C. The mixture was heated at 65° C. for 1.5 h. After cooling, the mixture was concentrated in vacuo. The residue was quenched with sat. NaHCO3 solution and the aqueous phase was extracted with EtOAc (25 ml, ×2). The combined organic phase was dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by column chromatography with n-hexane/DCM (80:20) to give the title compound (130 mg, 59.63%).
Reaction SMILES: [ClH:1].O1CCOCC1.OC(C(F)(F)F)=O.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]2[O:25][CH:26]=[C:27]([C:29]([N:31]3[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH:32]3[CH2:44][O:45][C:46]3[CH:47]=[N:48][CH:49]=[CH:50][CH:51]=3)=[O:30])[N:28]=2)=[CH:19][CH:18]=1>CO>[ClH:1].[ClH:1].[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([NH:23][C:24]2[O:25][CH:26]=[C:27]([C:29]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH:32]3[CH2:44][O:45][C:46]3[CH:47]=[N:48][CH:49]=[CH:50][CH:51]=3)=[O:30])[N:28]=2)=[CH:21][CH:22]=1
Reactant: COc1ccc(Nc2nc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3COc3cccnc3)co2)cc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Nc2nc(C(=O)N3CCNCC3COc3cccnc3)co2)cc1
Reaction time: 8 h
Yield: 73 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of tert-butyl 4-(2-(4-methoxyphenylamino)oxazole-4-carbonyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate TFA salt (35.5 mg, 0.057 mmol) in MeOH (1 mL). After stirring overnight, the reaction mixture was concentrated under reduced pressure and purified by HPLC (5 to 50% MeCN/0.1% TFA in H2O/0.1% TFA gradient). The fractions containing the desired product were concentrated under reduced pressure, dissolved in MeOH (1 mL), and treated with 4 M HCl in 1,4-dioxane (6 mL). The mixture was concentrated under reduced pressure to give 20 mg (73%) of the title compound as a white solid. LC-MS: RT=3.51 min, [M+H]+=410.0.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Al+3].[Cl-].[Cl-].[Cl:11][C:12]1[O:16][C:15]([CH:17](O)[C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1.N>O1CCCC1>[Cl:11][C:12]1[O:16][C:15]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([CH2:22][NH2:23])=[CH:24][CH:25]=2)=[CH:14][CH:13]=1
Reactant: N#Cc1ccc(C(O)c2ccc(Cl)o2)cc1
Agent: N
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Product: NCc1ccc(Cc2ccc(Cl)o2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.6 %

Procedure:
To a mixture of lithium aluminum hydride (3.3 g, 69 mmol) and tetrahydrofuran (100 mL) was added aluminum chloride (13 g, 96 mmol) at 0° C., which was stirred for 1 hour at room temperature. A mixture of 4-((5-chloro-furan-2-yl)-hydroxy-methyl)-benzonitrile (3.2 g) described in Manufacturing Example 62-1-1 and tetrahydrofuran was added dropwise into the reaction mixture, and stirred for 1 hour at room temperature. A 28% aqueous ammonia solution was added dropwise into the reaction mixture at 0° C. to quench the excess reagent. The reaction mixture was allowed to room temperature and filtered through a Celite pad. The solvent was evaporated from the filtrate under a reduced pressure, and the residue was filtered after addition of diethyl ether. The filtrate was concentrated under a reduced pressure to obtain the title compound (2.6 g) as a crude product.
Reaction SMILES: C(OC(=O)[NH:10][C@H:11]([C:15]([N:17]([CH3:19])[CH3:18])=[O:16])[CH:12]([CH3:14])[CH3:13])C1C=CC=CC=1>CCO.[C].[Pd]>[NH2:10][C@@H:11]([CH:12]([CH3:14])[CH3:13])[C:15]([N:17]([CH3:19])[CH3:18])=[O:16]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(C)[C@H](N)C(=O)N(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
A suspension of 2.04 g of the compound obtained in Step 82-1 and 0.3 g of 10% palladium-carbon in EtOH (20 ml) was stirred at room temperature for two hours under hydrogen atmosphere. The insoluble matter was separated by filtration and the filtrate was concentrated to obtain 1.05 g of the title compound (pale yellow oil).
Reaction SMILES: [C:1]1([CH3:24])[CH:6]=[CH:5][C:4]([C:7]2[CH:23]=[C:10]3[CH:11]=[C:12]([C:15]4[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=4)[CH:18]=[O:19])[CH:13]=[CH:14][N:9]3[N:8]=2)=[CH:3][CH:2]=1.[C:25]([Mg]Br)#[CH:26]>O1CCCC1>[C:1]1([CH3:24])[CH:2]=[CH:3][C:4]([C:7]2[CH:23]=[C:10]3[CH:11]=[C:12]([C:15]4[CH:16]=[C:17]([CH:18]([OH:19])[C:25]#[CH:26])[CH:20]=[CH:21][CH:22]=4)[CH:13]=[CH:14][N:9]3[N:8]=2)=[CH:5][CH:6]=1
Reactant: Cc1ccc(-c2cc3cc(-c4cccc(C=O)c4)ccn3n2)cc1
Reactant: C#C[Mg]Br
Solvent: C1CCOC1
Product: C#CC(O)c1cccc(-c2ccn3nc(-c4ccc(C)cc4)cc3c2)c1
Yield: 53.9 %

Procedure:
The procedure described in stage 2.5 is followed, starting with 0.105 g (0.34 mmol) of 3-(2-{p-tolyl}pyrazolo[1,5-a]pyridin-5-yl)benzaldehyde obtained in stage 8.4, in solution in 15 ml of tetrahydrofuran, followed by addition of 3.20 ml (1.60 mmol) of an ethynylmagnesium bromide solution (0.5M in tetrahydrofuran) and after chromatography on silica gel, elution being carried out with a mixture of cyclohexane and ethyl acetate (8/2), 0.062 g (54%) of the expected product is obtained in the form of a yellow powder.
Reaction SMILES: C[O:2][C:3]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:4]=1[CH:5]=[O:6].[Cl-].[Li+].O.Cl>CN(C)C=O>[OH:2][C:3]1[CH:10]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:8]=[CH:7][C:4]=1[CH:5]=[O:6]
Reactant: COc1cc(C(F)(F)F)ccc1C=O
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(C(F)(F)F)cc1O
Yield: 97.1 %

Procedure:
A mixture of 2-methoxy-4-trifluoromethyl benzaldehyde (Description 96; 18 g, 88 mmol) and lithium chloride (11.19 g; 264 mmol) in anhydrous N,N-dimethylformamide (100 ml) was heated at reflux for 3 hours. The mixture was cooled and poured into water (200 ml), then acidified by the addition of 1N HCl. The mixture was extracted with ether (3×200 ml) then the combined ether layers washed with water (2×500 ml), sat NaCl (100 ml), dried over Na2SO4, filtered and evaporated to give the title compound (16.25 g, 97%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:10]=[C:11]([NH2:14])[S:12][CH:13]=1.[CH3:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:10]=[C:11]([NH:14][C:20](=[O:21])[C:19]2[CH:23]=[CH:24][C:16]([CH3:15])=[CH:17][CH:18]=2)[S:12][CH:13]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: COc1ccccc1-c1csc(N)n1
Solvent: c1ccncc1
Product: COc1ccccc1-c1csc(NC(=O)c2ccc(C)cc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(2-Methoxy-phenyl)-thiazol-2-ylamine (41.3 mg, 0.200 mmol) and 4-methyl-benzoyl chloride (30.9 mg, 0.200 mmol) were dissolved in 1 mL of pyridine. The reaction mixture was stirred at room temperature overnight and then purified by reverse-phase preparative liquid chromatography (7.32 mg, 0.0226 mmol, 11.3%). ESI-MS m/z calc. 324.1. found 325.2 (M+1)+ Retention time 3.75 minutes.
Reaction SMILES: [CH:1]1([O:6][N:7]=[C:8]([C:31]2[N:36]=[C:35]([NH:37]C=O)[CH:34]=[CH:33][N:32]=2)[C:9]([NH:11][CH:12]2[C:29](=[O:30])[N:14]3[C:15]([C:26]([O-:28])=[O:27])=[C:16]([CH2:19][N+:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:17][S:18][C@H:13]23)=[O:10])[CH2:5][CH2:4][CH:3]=[CH:2]1>C(=O)(O)[O-].[Na+]>[CH:1]1([O:6][N:7]=[C:8]([C:31]2[N:36]=[C:35]([NH2:37])[CH:34]=[CH:33][N:32]=2)[C:9]([NH:11][CH:12]2[C:29](=[O:30])[N:14]3[C:15]([C:26]([O-:28])=[O:27])=[C:16]([CH2:19][N+:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:17][S:18][C@H:13]23)=[O:10])[CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: O=CNc1ccnc(C(=NOC2C=CCC2)C(=O)NC2C(=O)N3C(C(=O)[O-])=C(C[n+]4ccccc4)CS[C@H]23)n1
Agent: O=C([O-])O
Agent: [Na+]
Product: Nc1ccnc(C(=NOC2C=CCC2)C(=O)NC2C(=O)N3C(C(=O)[O-])=C(C[n+]4ccccc4)CS[C@H]23)n1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
This solution was added to the activated acid solution prepared above, and the mixture was stirred at -19° to -10° C. for half an hour and at ambient temperature for additional half an hour. The reaction mixture was poured into an aqueous solution (100 ml) of sodium bicarbonate (8.47 g). The aqueous layer containing 7-[2-(2-cyclopenten-1-yloxyimino)-2-(4-formamidopyrimidin-2-yl)acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer) was separated out, adjusted to pH 1 with 6 N hydrochloric acid and washed with ethyl acetate, followed by standing at 5° C. for 15 hours. This aqueous solution was subjected to column chromatography on a non-ionic adsorption resin "Diaion HP-20" (200 ml). After the column was washed with water, elution was carried out with 10% aqueous isopropyl alcohol. The eluates containing a desired compound were collected, evaporated to remove isopropyl alcohol under reduced pressure. The resultant solution was lyophilized to give yellowish white powder of 7-[2-(2-cyclopenten-1-yloxyimino)-2-(4-aminopyrimidin-2-yl)acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer) (1.97 g), mp 160°-175° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[NH:11][C:10]3=[CH:13][C:14]([C:16]([OH:18])=O)=[N:15][N:9]3[C:8](=[O:19])[C:7]=2[CH:6]=[C:5]([O:20][CH3:21])[CH:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.O.[NH2:35][C:36]1[NH:40][N:39]=[N:38][N:37]=1>CN(C=O)C>[CH3:1][O:2][C:3]1[C:12]2[NH:11][C:10]3=[CH:13][C:14]([C:16]([NH:35][C:36]4[NH:40][N:39]=[N:38][N:37]=4)=[O:18])=[N:15][N:9]3[C:8](=[O:19])[C:7]=2[CH:6]=[C:5]([O:20][CH3:21])[CH:4]=1
Reactant: COc1cc(OC)c2[nH]c3cc(C(=O)O)nn3c(=O)c2c1
Reactant: Nc1nnn[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OC)c2[nH]c3cc(C(=O)Nc4nnn[nH]4)nn3c(=O)c2c1
Yield: 43.8 %

Procedure:
From 4,9-dihydro-5,7-dimethoxy-9-oxo-pyrazolo-[5,1-b]quinazoline-2-carboxylic acid (1.54 g; 5 mmole), DMF (300 ml), 1,1'-carbonyldiimidazole (1.8 g; 11 mmole) and 5-amino-1H-tetrazole, monohydrate (0.52 g; 5 mmole), following the procedure of Example 3, there is obtained 4,9-dihydro-5,7-dimethoxy-9-oxo-N-1H-tetrazol-5-yl-pyrazolo-[5,1-b]quinazoline-2-carboxamide (0.78 g); mp 338°-342° (d).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[N:5][C:6]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)=[N:7][CH:8]=1.[O:21]1[CH2:26][CH2:25][CH:24]([C:27](O)=[O:28])[CH2:23][CH2:22]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(OCC)(=O)C.ClCCl>[Cl:16][C:12]1[CH:11]=[C:10]([NH:9][C:6]2[N:5]=[C:4]([C:17]([F:20])([F:19])[F:18])[C:3]([CH2:2][NH:1][C:27]([CH:24]3[CH2:25][CH2:26][O:21][CH2:22][CH2:23]3)=[O:28])=[CH:8][N:7]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: NCc1cnc(Nc2cccc(Cl)c2)nc1C(F)(F)F
Reactant: O=C(O)C1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(NCc1cnc(Nc2cccc(Cl)c2)nc1C(F)(F)F)C1CCOCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 29 %

Procedure:
To a mixture of 5-(aminomethyl)-N-(3-chlorophenyl)-4-(trifluoromethyl)pyrimidin-2-amine (103 mg) and dichloromethane (2 mL) were added tetrahydro-2H-pyran-4-carboxylic acid (53 mg), 1-hydroxybenzotriazole (69 mg), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (98 mg) in this order at room temperature, and the mixture was stirred at room temperature for 3 days. To the reaction mixture was added ethyl acetate (50 mL), the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine in this order, and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: chloroform-methanol), and the obtained product was solidified from a mixed solvent of ethanol and ethyl acetate to obtain N-({2-[(3-chlorophenyl)amino]-4-(trifluoromethyl)pyrimidin-5-yl}methyl)tetrahydro-2H-pyran-4-carboxamide (41 mg) as a colorless powder.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([C@@H:11]([OH:20])[CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:32][CH:33]1[N:39]=[C:38]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:37]2[CH:46]=[CH:47][CH:48]=[CH:49][C:36]=2[N:35]([CH3:50])[C:34]1=[O:51].O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl.C(OCC)(=O)C>[CH:1]1([CH2:6][C@H:7]([C@@H:11]([OH:20])[CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]([NH:32][CH:33]2[N:39]=[C:38]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:37]3[CH:46]=[CH:47][CH:48]=[CH:49][C:36]=3[N:35]([CH3:50])[C:34]2=[O:51])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)[C@H](CC1CCCC1)[C@@H](O)CCc1ccccc1
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CN1C(=O)C(NC(=O)[C@H](CC2CCCC2)[C@@H](O)CCc2ccccc2)N=C(c2ccccc2)c2ccccc21
Temperature: 0 °C

Procedure:
A mixture of acid 4 (250 mg, 0.900 mmol) and 3-amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one p-toluenesulfonate salt (364 mg, 0.820 mmol) in 4 mL of methylene chloride was stirred at 0° C. 1-Hydroxy-benzotriazole hydrate (133 mg, 0.980 mmol), 1-[3-(dimethylamine)propyl]-3-ethylcarbodiimide hydrochloride (314 mg, 1.64 mmol) and triethylamine (0.51 mL, 3.7 mmol) were added sequentially. After the mixture was stirred for 16 h, 30 mL of ethyl acetate was added. The organic layer was washed with 1 M HCl (15 mL), 5% NaHCO3 (30 mL) and brine (30 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Purification by chromatotron (30% ethyl acetate-hexane) afforded two diastereomers A and B. A: 120 mg (25%); 1H NMR (300 MHz, CDCl3) δ 7.20-7.70 (15H, m), 5.54 (1H, d, J=8.0 Hz), 4.02 (1H, m), 3.48 (3H, s), 2.83-3.00 (1H, m), 2.62-2.74 (1H, m), 2.40-2.48 (1H, m), 1.00-2.00 (13H, m); MS (ESI): 524 (M+H), 546 (M+Na), 522 (M−H), 558 (M+Cl). B: 120 mg (25%); 1H NMR (300 MHz, CDCl3) δ 7.60 (1H, d, J=6.9 Hz), 7.20-7.45 (14H, m), 5.56 (1H, d, J=8.4 Hz), 3.84 (1H, m), 3.48 (3H, s), 2.83-3.00 (1H, m), 2.62-2.74 (1H, m), 2.50-2.60 (1H, m), 1.00-1.95 (13H, m); MS (ESI): 524 (M+H), 546 (M+Na), 522 (M−H).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=O.C([O-])(=O)C.[NH4+].[N+:18]([CH3:21])([O-:20])=[O:19]>C(O)(=O)C>[CH3:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1/[CH:4]=[CH:21]/[N+:18]([O-:20])=[O:19]
Reactant: C[N+](=O)[O-]
Reactant: Cc1ccc([N+](=O)[O-])cc1C=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: Cc1ccc([N+](=O)[O-])cc1/C=C/[N+](=O)[O-]

Procedure:
Adapting literature known protocols (U.S. Pat. No. 8,344,028; and Kabalka and Varma, Org. Prep. Proced. Int., 1987, 19(4-5), 283-328), 1-methyl-4-nitro-2-[(E)-2-nitrovinyl]benzene (19a) is prepared by heating a solution of commercial 2-methyl-5-nitro-benzaldehyde (5j) (1.65 g, 10.0 mmol) (for a synthesis of (5j) see also Example 5, Method B), ammonium acetate (NH4OAc) (1.31 g, 17.0 mmol) in a mixture of nitromethane (MeNO2) (1.61 mL, 1.83 g, 30.0 mmol) and acetic acid (HOAc) (10.0 mL) to reflux for about 3 hours. Aqueous work-up and purification by silica gel column chromatography using ethyl acetate (EtOAc) and hexanes mixtures afford the title compound (19a).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].CN(C)C1C=CC=CC=1.[Br:19][CH2:20][C:21](Br)=[O:22]>CC(C)=O>[OH:9][C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[NH:1][C:21](=[O:22])[CH2:20][Br:19]
Reactant: Nc1cc(Cl)ccc1O
Reactant: O=C(Br)CBr
Solvent: CC(C)=O
Solvent: CN(C)c1ccccc1
Product: O=C(CBr)Nc1cc(Cl)ccc1O
Reaction time: 0.75 h
Yield: 52.6 %

Procedure:
To a mixture of 2-amino-4-chlorophenol (19.50 g.) and N,N-dimethylaniline (19.90 g.) in dry acetone (200 ml.) was added dropwise bromoacetyl bromide (33.2 g.) over a period of 15 minutes under ice-cooling at below 10° C. with stirring and stirring was continued for 45 minutes at the same temperature. The reaction mixture was evaporated and to the residue were added ethyl acetate and water. The ethyl acetate layer was washed with 5% hydrochloric acid (twice), water, 5% aqueous solution of sodium bicarbonate, water (twice) and a saturated aqueous solution of sodium chloride successively, dried over magnesium sulfate, treated with activated charcoal and then evaporated. The residue was recrystallized from a mixture of ethyl acetate and diisopropyl ether to give the title compound (18.91 g.).
Reaction SMILES: [S:1]1[C:9]2[CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5][C:4]=2[CH:3]=[C:2]1[C:17]([O:19][CH2:20][CH3:21])=[O:18].FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[S:1]1[C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[CH:3]=[C:2]1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)c1cc2c(s1)CCN(C(=O)OC(C)(C)C)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1cc2c(s1)CCNC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.7 %

Procedure:
Into a 100-mL round-bottom flask charged with 5-tert-butyl 2-ethyl 6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)-dicarboxylate (1 g, 3.21 mmol; prepared as described in J. Med. Chem. 2006, 49(15):4623-4637) and DCM (16 mL) was slowly added trifluoroacetic acid (1.48 mL, 19.3 mmol) at 0° C. The solution was then stirred at room temperature for 60 min. To the reaction mixture was then added saturated aqueous NaHCO3 solution (10 mL) and DCM (10 mL). Upon separation of the layers, the aqueous solution was further extracted with DCM (20 mL) twice. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated to give ethyl 4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate (0.547 g, 81%) as an oil. LCMS: (FA) ES+ 212.