Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1([Si](OC)(OC)OC)C=CC=CC=1.C(O[Si](OCC)(OCC)OCC)C.C[Si](OCC)(OCC)OCC.[C:38]([O-:41])(=[O:40])[CH3:39].CO[Si](CC[N+:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)(OC)OC.Cl.C(OCC(O)C)C>O.CC(C)=O.CO.C(O)C>[C:38]([O-:41])(=[O:40])[CH3:39].[NH+:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1
Reactant: CO[Si](CC[n+]1ccccc1)(OC)OC
Agent: CC(=O)[O-]
Agent: CCOCC(C)O
Agent: CCO[Si](C)(OCC)OCC
Solvent: O
Solvent: CCO
Solvent: CC(C)=O
Product: c1cc[nH+]cc1
Temperature: 25 °C

Procedure:
4.93 g of phenyltrimethoxysilane, 72.52 g of tetraethoxysilane, 22.08 g of methyltriethoxysilane, 0.48 g of the 30% methanol solution of trimethoxysilylethylpyridinium acetate, and 150 g of acetone were charged into a 500 mL flask to be dissolved and the resultant mixed solution was warmed while stirring the mixed solution with a magnetic stirrer to reflux. Next, 33.15 g of 0.01 M hydrochloric acid was added to the mixed solution. The mixed solution was subjected to the reaction for 240 minutes and then the resultant reaction solution was cooled down to room temperature. Then, 200 g of propylene glycol monoethyl ether was added to the reaction solution, and ethanol and methanol as reaction by-products, acetone, water, and hydrochloric acid were distilled off under reduced pressure to obtain a hydrolysis-condensation product. The polymer thus obtained corresponded to Formula (VII-16):
Reaction SMILES: I[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.[CH2:11]([NH:13][C:14](=[O:31])[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17](B2OC(C)(C)C(C)(C)O2)[CH:16]=1)[CH3:12].C(=O)([O-])O.[Na+].O>C(O)(C)C.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>[CH2:11]([NH:13][C:14](=[O:31])[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([C:2]2[CH:10]=[C:9]3[C:5]([CH:6]=[N:7][NH:8]3)=[CH:4][CH:3]=2)[CH:16]=1)[CH3:12]
Reactant: CCNC(=O)c1ccc(C)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Ic1ccc2cn[nH]c2c1
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: CC(C)O
Solvent: O
Product: CCNC(=O)c1ccc(C)c(-c2ccc3cn[nH]c3c2)c1
Temperature: 150 °C
Yield: 48.5 %

Procedure:
A stirred mixture of 6-iodo-1H-indazole (0.45 g), N-ethyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (Intermediate 10, 0.54 g) tetrakis(triphenylphosphine)palladium(0) (0.05 g) and aqueous sodium hydrogen carbonate (1M, 1 ml) in isopropanol (10 ml) was heated at 150° C. for 30 min in a microwave oven. The reaction mixture was poured into water (50 ml) and extracted with ethyl acetate (3×25 ml). The extracts were washed with water (25 ml) dried (Na2SO4) and concentrated under vacuum. The residual oil was purified by column chromatography on silica (50 g) eluting with ether/ethyl acetate (7:3) to give the title compound as a pale yellow foam (0.25 g).
Reaction SMILES: [Cl:1][CH2:2]C1C(C)=CC2OCOC=2C=1.[CH3:13][O:14][C:15]1[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=1[CH3:23]>>[CH3:13][O:14][C:15]1[C:16]([CH3:23])=[C:17]([C:18]([CH3:22])=[CH:19][C:20]=1[CH3:21])[CH2:2][Cl:1]
Reactant: COc1c(C)cc(C)cc1C
Reactant: Cc1cc2c(cc1CCl)OCO2
Product: COc1c(C)cc(C)c(CCl)c1C

Procedure:
3-Methoxy-2,4,6-trimethylbenzyl chloride was synthesized in the same fashion as for 5-chloromethyl-6-methylbenzo[d][1,3]dioxole (Example 7) except that 1-methoxy-2,4,6-trimethylbenzene was used instead of 5-methylbenzo[d][1,3]dioxole.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C@H:8]1[CH2:17][CH2:16][C:15]2[CH:14]=[C:13]([C:18]#[N:19])[CH:12]=[CH:11][C:10]=2[CH2:9]1.O=[C:21]1[CH2:30][CH2:29][C:28]2[CH:27]=[C:26]([C:31]#[N:32])[CH:25]=[CH:24][C:23]=2[CH2:22]1>>[O:1]=[C:2]1[CH2:7][N:6]([CH:21]2[CH2:30][CH2:29][C:28]3[CH:27]=[C:26]([C:31]#[N:32])[CH:25]=[CH:24][C:23]=3[CH2:22]2)[CH2:5][CH2:4][N:3]1[C@H:8]1[CH2:17][CH2:16][C:15]2[CH:14]=[C:13]([C:18]#[N:19])[CH:12]=[CH:11][C:10]=2[CH2:9]1
Reactant: N#Cc1ccc2c(c1)CCC(=O)C2
Reactant: N#Cc1ccc2c(c1)CC[C@H](N1CCNCC1=O)C2
Product: N#Cc1ccc2c(c1)CCC(N1CCN([C@H]3CCc4cc(C#N)ccc4C3)C(=O)C1)C2

Procedure:
The title compound was prepared from (6S)-6-(2-Oxopiperazin-1-yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile and 6-Oxo-5,6,7,8-tetrahydronaphthalene-2-carbonitrile following essentially the same procedure as Example 6. The product was purified by mass-directed reverse phase HPLC (AcCN-Water with 0.1% TFA). LC-MS (IE, m/z): 411 [M+1]+.
Reaction SMILES: [CH2:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[C:2]1=[O:13].[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20](Cl)=[O:21]>>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([C:9]1[CH:8]=[C:7]2[C:12]3=[C:11]([CH2:1][C:2](=[O:13])[N:3]3[CH2:4][CH2:5][CH2:6]2)[CH:10]=1)=[O:21]
Reactant: O=C1Cc2cccc3c2N1CCC3
Reactant: O=C(Cl)CCCCCBr
Product: O=C(CCCCCBr)c1cc2c3c(c1)CC(=O)N3CCC2

Procedure:
Using 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-one and 6-bromohexanoyl chloride according to the same method as that of Reference Example 1, the title compound (5.13 g) was obtained as colorless crystals having a melting point of 86 to 87° C.
Reaction SMILES: [Na].[C:2]([CH2:4][C:5]([NH2:7])=[O:6])#[N:3].[Cl:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([CH3:28])[C:18]=1[C:19](=[O:27])[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)[CH2:12][N:13]=[N+:14]=[N-:15].C(O)(=O)C>C(O)C>[NH2:3][C:2]1[N:13]([CH2:12][C:11]2[CH:16]=[C:17]([CH3:28])[C:18]([C:19](=[O:27])[C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)=[C:9]([Cl:8])[CH:10]=2)[N:14]=[N:15][C:4]=1[C:5]([NH2:7])=[O:6]
Reactant: N#CCC(N)=O
Reactant: Cc1cc(CN=[N+]=[N-])cc(Cl)c1C(=O)c1ccc(Cl)cc1
Agent: [Na]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1cc(Cn2nnc(C(N)=O)c2N)cc(Cl)c1C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 67.3 %

Procedure:
A stirred, 60° C. solution of sodium (88.7 mg, 3.84 mmol) in absolute ethanol (9.6 ml) was treated with 2-cyanoacetamide (323 mg, 3.84 mmol), kept 5 min., and treated with 3-chloro-4-(4-chlorobenzoyl)-5-methylbenzyl azide (1.03 g, 3.20 mmol). The mixture was refluxed 1 hour, cooled to ambient temperature, acidified with glacial acetic acid (487 μl, 511 mg, 7.68 mmol), and evaporated to dryness at 30° C. under vacuum. The residue was chromatographed on a column of silica gel (150 g) eluted in 17 ml fractions with 19:1 (v/v) dichloromethane-methanol. Fractions 22-38 were combined and evaporated to dryness. The residual glass was kept 18 hours at ambient temperature with diethyl ether (25 ml), filtered, washed with diethyl ether, and dried to provide 870 mg (67%) crystalline 5-amino-1-(3-chloro-4-[4-chlorobenzoyl]-5-methylbenzyl)-1,2,3-triazole-4 -carboxamide, m.p. 205°-206° C.
Reaction SMILES: [H-].[Na+].[C:3]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:15])[CH2:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].Cl[C:25]1[C:30]([N+:31]([O-:33])=[O:32])=[CH:29][C:28]([C:34]([F:37])([F:36])[F:35])=[CH:27][N:26]=1.Cl>COCCOC.C1(C)C=CC=CC=1>[CH2:8]([O:7][C:5]([CH:4]([C:3]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15])[C:25]1[C:30]([N+:31]([O-:33])=[O:32])=[CH:29][C:28]([C:34]([F:35])([F:36])[F:37])=[CH:27][N:26]=1)=[O:6])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cnc1Cl
Reactant: O=C(CC(=O)OCc1ccccc1)OCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: Cc1ccccc1
Product: O=C(OCc1ccccc1)C(C(=O)OCc1ccccc1)c1ncc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 8 h

Procedure:
In a dry flask was placed sodium hydride as a 60% suspension in oil (800 mg, 2.0 mmol). Most of the oil was removed by washing twice with hexanes. The remaining solid sodium hydride was then suspended in dry 1,2-dimethoxyethane (DME) (20 mL). A solution of dibenzyl malonate (5.0 mL, 2.0 mmol) in DME (15 mL) was then added dropwise with stirring. The mixture was stirred at room temperature for 0.5 hr after which a solution of 2-chloro-3-nitro-5-trifluoromethyl pyridine (2.3 g, 10.2 mmol) in DME (15 mL) was added. Stirring at room temperature was continued overnight and the reaction mixture was poured into ice/water. Following acidification to pH 3 with 1N HCl solution, the mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and concentrated in vacuo to leave an oil. This was subjected to flash chromatography on silica gel using toluene as eluant. All fractions containing the desired product were combined and concentrated to leave a tan solid; 3.8 g (79%): mp 82°-84° C.
Reaction SMILES: C1([Mg]Cl)C=CC=CC=1.[N+:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1I)([O-:11])=[O:10].[C:19]1(=[O:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.[Cl-].[NH4+]>C1COCC1.CCCCCC.CCOC(C)=O>[N+:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:19]1([OH:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)([O-:11])=[O:10]
Reactant: O=C1CCCCC1
Reactant: O=[N+]([O-])c1ccccc1I
Agent: Cl[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccccc1C1(O)CCCCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
40.16 mL (80.32 mmol) of phenylmagnesium chloride (2 M in THF) is added dropwise at −50° C. to a solution of 20.0 g (80.32 mmol) of 2-nitroiodobenzene in absolute THF (150 mL) under a nitrogen atmosphere. After stirring for 15 minutes, 9.98 mL (96.30 mmol) of cyclohexanone is added quickly. The mixture is heated to RT and stirred for a further 2 hours. Saturated aqueous ammonium chloride solution is added and the aqueous phase is exhaustively extracted with EtOAc. The combined organic extracts are washed with saturated aqueous NaCl solution, dried with sodium sulfate, and evaporated down in vacuo. After column chromatography (silica gel, hexane/EtOAc 20:1), the product is obtained as a brownish oil. Yield: 5.20 g (29%); Rf=0.26 (silica gel, hexane/EtOAc 10:1); ESI-MS: [M+H−H2O]+=204.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][C:37]=1[F:38])[CH2:5][N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([NH:14][CH2:15][C:16]2[CH:17]=[C:18]([C:22]3[C:30]4[C:25](=[N:26][CH:27]=[C:28]([C:31]([NH2:33])=[O:32])[CH:29]=4)[NH:24][CH:23]=3)[CH:19]=[CH:20][CH:21]=2)=[O:13])[C:7]1=[O:34].F[C:40]1C=C(C=C[C:75]=1F)CN1C=CC=C(C(NCC2C=C(C3C4C(=NC=C(C(O)=O)C=4)NC=3)C=CC=2)=O)C1=O.Cl.C(N)C>>[CH2:40]([NH:33][C:31]([C:28]1[CH:29]=[C:30]2[C:22]([C:18]3[CH:19]=[CH:20][CH:21]=[C:16]([CH2:15][NH:14][C:12]([C:8]4[C:7](=[O:34])[N:6]([CH2:5][C:4]5[CH:35]=[CH:36][C:37]([F:38])=[C:2]([F:1])[CH:3]=5)[CH:11]=[CH:10][CH:9]=4)=[O:13])[CH:17]=3)=[CH:23][NH:24][C:25]2=[N:26][CH:27]=1)=[O:32])[CH3:75]
Reactant: NC(=O)c1cnc2[nH]cc(-c3cccc(CNC(=O)c4cccn(Cc5ccc(F)c(F)c5)c4=O)c3)c2c1
Reactant: O=C(O)c1cnc2[nH]cc(-c3cccc(CNC(=O)c4cccn(Cc5ccc(F)c(F)c5)c4=O)c3)c2c1
Agent: CCN
Agent: Cl
Product: CCNC(=O)c1cnc2[nH]cc(-c3cccc(CNC(=O)c4cccn(Cc5ccc(F)c(F)c5)c4=O)c3)c2c1

Procedure:
Except where indicated, 3-[3-({[1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carbonyl]-amino}-methyl)-phenyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethylamide was synthesized as per Example 81, 3-[3-({[1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carbonyl]-amino}-methyl)-phenyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid amide using 3-[3-({[1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carbonyl]-amino}-methyl)-phenyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (53 mg, 0.00010 mol) as carboxylic acid and ethylamine hydrochloride (15 mg, 0.00018 mol; Aldrich) as amine, to yield the product. 1H NMR (400 MHz, CDCl3) d ppm 12.550 (s, 1H) 10.727 (s (br), 1H) 9.373 (s, 1H) 9.026 (s, 1H) 8.682-8.286 (m, 2H) 7.917 (s, 1H) 7.705 (s, 1H) 7.633-7.293 (m, 4H) 7.218-7.091 (m, 2H) 7.030 (m, 1H) 6.511 (m, 1H) 5.163 (s, 2H) 4.756 (m, 2H) 3.603 (m, 2H) 1.339 (t, J=7.5 Hz, 3H); MS m/z=542.38 M+H.
Reaction SMILES: [OH:1][C:2]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)C(=O)N[C:5](=[O:9])[NH:4][C:3]1=[O:10].[OH-].[Na+]>>[C:11]1([CH:2]2[O:1][C:5](=[O:9])[NH:4][C:3]2=[O:10])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C1NC(=O)C(O)(c2ccccc2)C(=O)N1
Agent: [Na+]
Agent: [OH-]
Product: O=C1NC(=O)C(c2ccccc2)O1

Procedure:
5-Hydroxy-5-phenyl-2,4,6(1H,3H,5H)-pyrimidinetrione (0.7 g.) is dissolved in 15 ml. of 1 N sodium hydroxide, stirred at room temperature for 15 minutes, extracted with ethyl acetate, made slightly acidic with about 1 ml. of glacial acetic acid, and extracted with 25 ml. of ethyl acetate. The latter ethyl acetate extract is back washed with about 6.5 ml. of water, filtered over a bed of anhydrous magnesium sulfate and evaporated to yield 5-phenyloxazolidine-2,4-dione.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.CC(O)=O.[Br:16]Br>C(Cl)(Cl)(Cl)Cl>[Br:16][C:11]1[CH:10]=[C:5]([CH:4]=[CH:3][C:2]=1[OH:1])[C:6]([O:8][CH3:9])=[O:7]
Reactant: BrBr
Reactant: COC(=O)c1ccc(O)cc1
Solvent: CC(=O)O
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(O)c(Br)c1
Reaction time: 8 h
Yield: 60.6 %

Procedure:
To a stirred solution of methyl 4-hydroxybenzoate (10.0 g, 84.935 mmol) in CCl4 (30 mL) was added AcOH (20 mL, 2 Vol). Br2 (1.80 mL, 71.428 mmol) was then added slowly at 0° C. After the addition was completed, the reaction mixture was brought to RT and stirred for 8 h. Reaction mixture was quenched with water (50 mL), neutralized with saturated NaHCO3 solution and extracted with EtOAc (2×150 mL). The combined organic layers were washed with water (2×50 mL) and brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to obtain crude product. The crude material was purified via silica gel column chromatography eluting with 5% EtOAc-95% hexanes to afford methyl 3-bromo-4-hydroxybenzoate (10.0 g, 66%) as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([N:12]2[C:17](=[O:18])[C:16]([F:19])=[C:15]([C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])[NH:14][C:13]2=[O:27])=[C:4]([F:28])[CH:3]=1.[C:29](=O)(O)[O-].[Na+].S(OC)(OC)(=O)=O>CC(C)=O>[Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([N:12]2[C:17](=[O:18])[C:16]([F:19])=[C:15]([C:20]([F:25])([F:26])[C:21]([F:24])([F:23])[F:22])[N:14]([CH3:29])[C:13]2=[O:27])=[C:4]([F:28])[CH:3]=1
Reactant: CC(C)Oc1cc(-n2c(=O)[nH]c(C(F)(F)C(F)(F)F)c(F)c2=O)c(F)cc1Cl
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: CC(C)Oc1cc(-n2c(=O)c(F)c(C(F)(F)C(F)(F)F)n(C)c2=O)c(F)cc1Cl

Procedure:
using 3-(4-chloro-2-fluoro-5-isopropoxyphenyl)-5-fluoro-6-pentafluoroethyl-2,4(1H,3H)-pyrimidinedione in acetone with sodium bicarbonate and dimethyl sulphate there is obtained 3-(4-chloro-2-fluoro-5-isopropoxyphenyl)-5-fluoro-1-methyl-6-pentafluoroethyl-2,4(1H,3H)-pyrimidinedione, m.p. 107°-109° C.;
Reaction SMILES: S(Cl)(Cl)=O.[NH:5]([C:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:11])[CH2:6][C:7]([OH:9])=O.[NH2:27][C@H:28]([C:35]([OH:37])=[O:36])[CH2:29][C:30]1[N:34]=[CH:33][NH:32][CH:31]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[NH:5]([C:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:11])[CH2:6][C:7]([NH:27][C@H:28]([C:35]([OH:37])=[O:36])[CH2:29][C:30]1[N:34]=[CH:33][NH:32][CH:31]=1)=[O:9]
Reactant: N[C@@H](Cc1c[nH]cn1)C(=O)O
Reactant: CCCCCCCCCCCCCCCC(=O)NCC(=O)O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: CCCCCCCCCCCCCCCC(=O)NCC(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O

Procedure:
Using thionyl chloride, N-palmitoyl-Gly was converted to the acid chloride in toluene at room temperature, then reacted with L-histidine using triethylamine as the base. However, only a trace amount of N-palmitoyl-Gly-His formed.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[CH:14][C:3]=1[NH:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.CCOC(C)=O>[Pd].CO>[F:1][C:2]1[CH:17]=[C:16]([NH2:18])[CH:15]=[CH:14][C:3]=1[NH:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: O=[N+]([O-])c1ccc(NCCCN2CCOCC2)c(F)c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ccc(NCCCN2CCOCC2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-fluoro-N-(3-morpholinopropyl)-4-nitroaniline (1.78 g, 6.28 mmol) in mixed solvents of EtOAc (15 mL) and MeOH (15 mL) was added catalyst Pd/C (0.30 g). The reaction was stirred at rt under H2 for 2 h, then filtered. The filtrate was concentrated in vacuo to give the crude product for the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:16]C(=O)C)[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1.Cl>C(O)C>[CH3:1][C:2]1[N:3]=[C:4]([NH2:16])[S:5][C:6]=1[C:7]1[CH:8]=[CH:9][C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=1
Reactant: CC(=O)Nc1nc(C)c(-c2ccc([N+](=O)[O-])cc2)s1
Agent: Cl
Solvent: CCO
Product: Cc1nc(N)sc1-c1ccc([N+](=O)[O-])cc1
Reaction time: 4 h

Procedure:
A solution of N-[4-methyl-5-(4-nitro-phenyl)-thiazol-2-yl]-acetamide (prepared by the method described in J. Liebscher, E. Mitzner, Synthesis, 1985, (4), p 414) (10 g, 36 mmol) in ethanol (200 ml) and 7M hydrochloric acid (50 ml) is heated at reflux with stirring for 4 hours. After standing at room temperature for 4 days the hydrochloride salt of the title compound (8.15 g) precipitates as yellow crystals which are removed by filtration and dried. The title compound (free base) is obtained by partitioning the hydrochloride salt between aqueous sodium hydroxide and ethyl acetate. The organic extract is separated, dried (MgSO4) and the solvent is removed to give an orange solid (6.58 g). 1N nmr (CDCl3): 2.38 (4H, s, Me), 5.02 (2H, br s, NH2), 7.45 (2H, d), 8.20 (2H, d)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7](=[O:13])[C:8](=[O:12])[NH:9]2)=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>C(#N)C>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7](=[O:13])[C:8](=[O:12])[N:9]2[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COc1ccc2c(c1)NC(=O)C2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc2c(c1)N(CC(=O)OC(C)(C)C)C(=O)C2=O
Yield: 95.5 %

Procedure:
To a solution of 6-methoxyindoline-2,3-dione (350 mg, 1.976 mmol) in acetonitrile (10 ml), K2CO3 (328 mg, 2.371 mmol) and tert-butyl 2-bromoacetate (350 μl, 2.371 mmol) were added, and the mixture was reacted at room temperature overnight. The insoluble inorganic salts were filtered off and the solvent was evaporated obtaining the crude title compound (550 mg, 1.888 mmol, 96% yield). MS/ESI+ 292.1 [MH]+. The crude was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:26]1([CH2:32][C:33](O)=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CCN=C=NCCCN(C)C>>[C:26]1([CH2:32][C:33]([NH:1][C:2]2[CH:3]=[C:4]([C:8]3[C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=4)[NH:10][N:9]=3)[CH:5]=[CH:6][CH:7]=2)=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: NC(=O)c1ccc2c(c1)c(-c1cccc(N)c1)nn2C1CCCCO1
Agent: CCN=C=NCCCN(C)C
Product: NC(=O)c1ccc2[nH]nc(-c3cccc(NC(=O)Cc4ccccc4)c3)c2c1
Yield: 11.7 %

Procedure:
Following Example 290, reaction of 3-(3-aminophenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxamide (250 mg, 0.74 mmol) with phenylacetic acid (0.15 g, 0.89 mmol) and EDCI (0.21 g, 1.11 mmol) furnished 32 mg (12% yield) of the title compound as a white solid. 1H NMR (DMSOd6) δ 13.2 (br s, 1H), 10.4 (s, 1H), 8.6 (s, 1H), 8.2 (bs, 1H), 8.1 (m, 1H), 7.9 (dd, 1H), 7.8–7.5 (m, 2H), 7.6 (dd, 1H), 7.5 (t, 1H), 7.4–7.3 (m, 3H), 7.3–7.2 (m, 1H), 3.7 (s, 2H); ES-MS (m/z) 371 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:47])([F:46])[C:3]1[CH:4]=[C:5]([N:13]([CH3:45])[C:14]([N:16]([CH3:44])[C@H:17]2[C@H:21]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH2:20][N:19]([C:29]([CH:31]3[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32]3)=[O:30])[CH2:18]2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[ClH:48].CC(O)C>>[ClH:48].[F:47][C:2]([F:1])([F:46])[C:3]1[CH:4]=[C:5]([N:13]([CH3:45])[C:14]([N:16]([C@H:17]2[C@H:21]([C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)[CH2:20][N:19]([C:29]([CH:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)=[O:30])[CH2:18]2)[CH3:44])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: CN(C(=O)N(C)[C@@H]1CN(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)C[C@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Solvent: CC(C)O
Product: CN(C(=O)N(C)[C@@H]1CN(C(=O)C2CCNCC2)C[C@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 45 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
A mixture of the compound (12 g) obtained in Example 303 and 2N hydrogen chloride/2-propanol (35 mL) was stirred at 45° C. for 3 hr, and concentrated under reduced pressure to give the title compound (11 g, 100%) as a white powder.
Reaction SMILES: C[O:2][C:3](=[O:28])[CH:4]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)[C:10]=1[N+:25]([O-:27])=[O:26])C(OC)=O>Cl>[N+:25]([C:10]1[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:4][C:3]([OH:28])=[O:2])([O-:27])=[O:26]
Reactant: COC(=O)C(C(=O)OC)c1cccc(Nc2cccc([N+](=O)[O-])c2)c1[N+](=O)[O-]
Agent: Cl
Product: O=C(O)Cc1cccc(Nc2cccc([N+](=O)[O-])c2)c1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
2-[2-Nitro-3-(3-nitro-phenylamino)-phenyl]-malonic acid dimethyl ester (1.26 g, 3.24 mmol) is heated in 6 N hydrochloric acid (100 ml) at 110° C. for 10 hours. It is then cooled to room temperature; the precipitate therefore formed is collected by vacuum filtration to give the desired compound: LC-MS: 318.0 (MH+).
Reaction SMILES: FC(F)(F)C([O-])=O.[CH2:8]([O:15][C:16]1[C:17]([C:34]([OH:36])=O)=[N:18][N:19]2[CH2:24][CH2:23][N:22]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[C:21](=[O:33])[C:20]=12)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH2:37][CH2:38][CH2:39][N:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>>[CH2:8]([O:15][C:16]1[C:17]([C:34]([NH:37][CH2:38][CH2:39][N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)=[O:36])=[N:18][N:19]2[CH2:24][CH2:23][N:22]([CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)[C:21](=[O:33])[C:20]=12)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NCCN1CCOCC1
Reactant: O=C(O)c1nn2c(c1OCc1ccccc1)C(=O)N(Cc1ccc(F)cc1)CC2
Agent: O=C([O-])C(F)(F)F
Product: O=C(NCCN1CCOCC1)c1nn2c(c1OCc1ccccc1)C(=O)N(Cc1ccc(F)cc1)CC2

Procedure:
The title compound was prepared as the trifluoroacetate salt from 3-benzyloxy-5-(4-fluorobenzyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylic acid using a procedure similar to that found in Example 15, Step 1, except that 4-(2-aminoethyl)morpholine was used in place of 1,2,3,4-tetrahydroisoquinoline. 1H NMR (400 MHz, CDCl3) δ 7.70-7.67 (t, 1H), 7.48-7.46 (m, 2H), 7.36-7.27 (m, 5H), 7.08-7.04 (m, 2H), 5.46 (s, 2H), 5.30 (s, 2H), 4.74 (s, 2H), 4.28-4.25 (t, 2H), 3.96 (br s, 4H), 3.78-3.68 (m, 4H), 3.61-3.58 (t, 2H), 3.30-3.26 (t, 2H); ES MS (M+1)=508.