Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[N:15]=[CH:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[N:12]=2)[CH:8]=[CH:9][CH:10]=1)=[C:2]=[O:3].[CH2:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[NH:35][C:36]([NH2:38])=[S:37])[CH3:28]>>[CH2:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[NH:35][C:36]([NH:38][C:2]([NH:1][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[N:15]=[CH:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:25])([F:24])[F:26])=[CH:18][CH:17]=3)[N:12]=2)[CH:6]=1)=[O:3])=[S:37])[CH3:28]
Reactant: O=C=NCc1cccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)c1
Reactant: CCc1ccccc1NC(N)=S
Product: CCc1ccccc1NC(=S)NC(=O)NCc1cccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)c1

Procedure:
The title compound was prepared as described in Example 75 using 3-(3-(isocyanatomethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (CB34) and 1-(2-ethylphenyl)thiourea and isolated as an off-white solid (0.152 g, 37%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[NH:9]1[CH2:14][CH2:13][CH:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:11][CH2:10]1>CN1C(=O)CCC1.CCOC(C)=O>[Cl:8][C:4]1[N:3]=[C:2]([N:9]2[CH2:10][CH2:11][CH:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21])[CH2:13][CH2:14]2)[CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: Clc1cccc(Cl)n1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)NC1CCN(c2cccc(Cl)n2)CC1

Procedure:
TEA (0.13 ml, 0.99 mmol) and 2,6-dichloropyridine (0.14 g, 0.99 mmol) were added to a solution of tert-butyl piperidin-4-ylcarbamate (0.20 g, 0.99 mmol) in NMP (2 ml) at room temperature. Using a Smith Microwave Synthesizer, the mixture was subjected to single-mode microwave at 150° C. for 30 minutes. The mixture was diluted with EtOAc and washed with water three times. The organic phase was dried over magnesium sulfate and concentrated to give the title compound. (300 mg).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([C:10]([NH:12][C:13]([NH:15][C:16]2[CH:26]=[CH:25][C:19]3[O:20][C:21]([F:24])([F:23])[O:22][C:18]=3[CH:17]=2)=[S:14])=[O:11])[CH:7]=[C:6]([CH3:27])[N:5]=1.[CH3:28]I.O>C1COCC1>[Cl:3][C:4]1[CH:9]=[C:8]([CH:7]=[C:6]([CH3:27])[N:5]=1)[C:10]([NH:12][CH:13]([NH:15][C:16]1[CH:26]=[CH:25][C:19]2[O:20][C:21]([F:24])([F:23])[O:22][C:18]=2[CH:17]=1)[S:14][CH3:28])=[O:11]
Reactant: CI
Reactant: Cc1cc(C(=O)NC(=S)Nc2ccc3c(c2)OC(F)(F)O3)cc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CSC(NC(=O)c1cc(C)nc(Cl)c1)Nc1ccc2c(c1)OC(F)(F)O2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
NaH, 60% (2.2 g; 0.0550 mol) was stirred in THF (170 ml) on an ice bath under N2. Intermediate D1 (19.3 g; 0.500 mol) was then added and stirred for 1 hour at 0° C. CH3I (7.8 g; 0.0550 mol) was then added and the reaction mixture was allowed to warm to room temperature overnight. Water was added and the THF was evaporated in vacuo. The precipitate was filtered off, washed with water and dried. Yield: 22.86 g of intermediate D2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12]([OH:14])[CH3:13])[CH2:11][O:10]1.[CH:15]([C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH:28]=[CH:27][NH:26][C:25]2=O)=[CH:20][CH:19]=1)([CH3:17])[CH3:16].FC1C=C(F)C=CC=1[C@]1(OC1)[C@H](N1C=CN(C2C=CC(C(C)C)=CC=2)C1=O)C>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@H:12]([O:14][C:25]2[N:24]([C:21]3[CH:22]=[CH:23][C:18]([CH:15]([CH3:17])[CH3:16])=[CH:19][CH:20]=3)[CH:28]=[CH:27][N:26]=2)[CH3:13])[CH2:11][O:10]1
Reactant: CC(C)c1ccc(-n2cc[nH]c2=O)cc1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Agent: CC(C)c1ccc(-n2ccn([C@H](C)[C@@]3(c4ccc(F)cc4F)CO3)c2=O)cc1
Product: CC(C)c1ccc(-n2ccnc2O[C@H](C)[C@@]2(c3ccc(F)cc3F)CO2)cc1
Yield: 13.9 %

Procedure:
In the same manner as in Reference Example 5, starting from 0.83 g of (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 0.83 g of 1-(4-isopropylphenyl)-2(1H,3H)-imidazolone, 1-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-3-(4-isopropylphenyl)-2(1H,3H)-imidazolone (0.25 g) and 0.22 g of (2R)-2-(2,4-difluorophenyl)-2-[(1R)-1-[1-(4-isopropylphenyl)-2-imidazolyloxy]ethyl]oxiran were obtained.
Reaction SMILES: [CH3:1][N:2]([C:4]([NH:6][CH3:7])=[S:5])[NH2:3].N1C=CC=CC=1.[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[C:24](Cl)=[O:25]>O>[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[C:24]([NH:3][N:2]([CH3:1])[C:4]([NH:6][CH3:7])=[S:5])=[O:25]
Reactant: CNC(=S)N(C)N
Reactant: O=C(Cl)c1ccc2ccccc2c1
Solvent: O
Solvent: c1ccncc1
Product: CNC(=S)N(C)NC(=O)c1ccc2ccccc2c1

Procedure:
To a stirred solution of 2,4-dimethylthiosemicarbazide (2.39 g, 2.00×10-2 mole) and pyridine (20 ml) was added dropwise 2-naphthoyl chloride. (3.89 g, 2.04×1031 2 mole) After stirring at room temperature for 48 hours the reaction was evaporated to dryness, affording a beige solid which was treated with H2O (100 ml). Filtration of the aqueous mixture gave the desired compound as a beige product, 5.47 g (100%). If pure 1-(2-naphthoyl)-2,4dimethylthiosemicarbazide is desired, the crude product is purified by crystallization.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([NH2:24])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>CN(C)C=O>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([NH:24][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc([N+](=O)[O-])cn2)CC1
Temperature: 90 °C
Reaction time: 14 h
Yield: 90.2 %

Procedure:
A mixture of 2-bromo-5-nitro-pyridine (5 g, 24.6 mmol), 4-amino-piperidine-1-carboxylic acid tert-butyl ester (5 g, 25 mmol), and triethylamine (5 mL) in N,N-dimethylformamide (30 mL) was stirred at 90° C. for 14 h. The reaction mixture was then partitioned between water and ethyl acetate, and the two layers were separated. The aqueous layer was extracted with ethyl acetate three times. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography to give 7.15 g (90%) 4-(5-nitro-pyridin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester as a yellow solid. LCMS calcd for C15H22N4O4 (m/e) 322, obsd 323 (M+H).
Reaction SMILES: Br[CH2:2][C@H:3]1[O:7][C:6](=[O:8])[C@@H:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:4]1.[N-:17]=[N+:18]=[N-:19].[Na+]>CN(C=O)C>[N:17]([CH2:2][C@H:3]1[O:7][C:6](=[O:8])[C@@H:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:4]1)=[N+:18]=[N-:19]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](CBr)OC1=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](CN=[N+]=[N-])OC1=O
Temperature: 60 °C
Yield: 98.2 %

Procedure:
To a stirred slurry of compound 1A, (8.47 g, 28.8 mmol) in 127 mL of DMF at room temperature was added sodium azide (2.25 g, 34.6 mmol). The reaction mixture was then heated to 60° C. under argon for 9 h. The reaction mixture was then cooled, quenched with 200 mL of ice-cold water and extracted four times with 200 mL portions of ether. The combined organic extracts were washed three times with water, once with saturated NaCl and dried over Na2SO4, then MgSO4, filtered and evaporated under reduced pressure. Purification by silica gel chromatography (3:17 EtOAc/CH2Cl2) provided the title compound (7.25 g, 98%) as a colorless oil. MS [M+Na]+: found 278.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[NH:11][NH:10][C:9]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:15]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1)([O-:17])=[O:16].N12CCCNC1=NCCC2>C(Cl)Cl>[CH2:1]([N:8]1[C:9](=[O:14])[N:10]([CH2:22][C:21]2[CH:24]=[CH:25][C:18]([N+:15]([O-:17])=[O:16])=[CH:19][CH:20]=2)[NH:11][C:12]1=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH][nH]c(=O)n1Cc1ccccc1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: C1CN=C2NCCCN2C1
Solvent: ClCCl
Product: O=c1[nH]n(Cc2ccc([N+](=O)[O-])cc2)c(=O)n1Cc1ccccc1
Yield: 58.6 %

Procedure:
A mixture of 4-benzylurazole (3.8 g, JCS Perkin II, 1975, 1325), p-nitrobenzyl bromide (4.3 g, Aldrich) and polymer-supported 1,5,7-triazabicyclo[4.4.0]dec-5-ene (P-TBD, 6.3 g, Fluka) in DCM (400 ml) was refluxed under N2 for 24 hours. The P-TBD was filtered off and the filtrate evaporated to leave a gum which was flash chromatographed through a silica column using chloroform/methanol (19:1 v/v) to give the desired product as a solid (3.8 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:23])[CH2:15][O:14][CH2:13][CH2:12][N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[H-].[Na+].[CH3:26]I>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([O:23][CH3:26])[CH2:15][O:14][CH2:13][CH2:12][N:11]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCOCC(O)(c2ccc(Cl)c(Cl)c2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1(c2ccc(Cl)c(Cl)c2)COCCN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl (6RS)-6-(3,4-dichlorophenyl)-6-hydroxy-1,4-oxazepane-4-carboxylate (130 mg) in DMF (3.0 mL) were added 60% sodium hydride (44 mg) and methyl iodide (0.068 ml) at room temperature, and the mixture was stirred for 30 min. To the reaction mixture was added ice water, and the mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (186 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([NH:20][O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)=[O:19])=[CH:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:28][N:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30]1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[CH3:28][N:29]1[CH:33]=[C:32]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([N:11]3[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([NH:20][O:21][CH:22]4[CH2:27][CH2:26][CH2:25][CH2:24][O:23]4)=[O:19])=[CH:12]3)(=[O:10])=[O:9])=[CH:4][CH:3]=2)[CH:31]=[N:30]1
Reactant: O=C(/C=C/c1ccn(S(=O)(=O)c2ccc(Br)cc2)c1)NOC1CCCCO1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cn1cc(-c2ccc(S(=O)(=O)n3ccc(/C=C/C(=O)NOC4CCCCO4)c3)cc2)cn1

Procedure:
(E)-3-[1-(4-Bromo-benzenesulfonyl)-1H-pyrrol-3-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (966 mg) and 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (662 mg) are dissolved in DME (35 mL) and (Ph3P)3PdCl2 (298 mg) and 2M Na2CO3-solution (3.2 mL) are added. The mixture is heated 16 h to reflux temperature. The mixture is filtered and evaporated and the crude product is purified by silica gel flash chromatography.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]#[C:9][CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[C:3]1=[O:16].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl>[CH3:24][S:25]([O:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]#[C:9][CH2:10][N:11]2[CH2:12][CH2:13][CH2:14][CH2:15]2)[C:3]1=[O:16])(=[O:27])=[O:26]
Reactant: O=C1[C@@H](O)CCN1CC#CCN1CCCC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)O[C@H]1CCN(CC#CCN2CCCC2)C1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 1.76 g of (S)-3-hydroxy-1-[4-(1-pyrrolidinyl)-2-butynyl]-2-pyrrolidinone and 2.4 ml of triethylamine in 50 ml of dichloromethane was cooled to 0° C. A 1.2 ml portion of methane sulfonyl chloride was added dropwise and the solution was stirred at 0° C. for 1 hour. The mixture was washed with aqueous sodium bicarbonate and brine, dried, concentrated and reconcentrated from toluene. The residue was purified by chromatography (silica gel) to give 1.5 g of (S)-3-[(methanesulfonyl)oxy]-1-[4-(1-pyrrolidinyl)-2-butynyl]-2-pyrrolidinone as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[CH:6][N:7]=1.O.[NH2:16][NH2:17]>N1C=CC=CC=1>[NH:16]([C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[CH:6][N:7]=1)[NH2:17]
Reactant: Fc1ccc(-c2cnc(Cl)nn2)cc1
Reactant: NN
Solvent: c1ccncc1
Solvent: O
Product: NNc1ncc(-c2ccc(F)cc2)nn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 9.8 g. of 3-chloro-6-(p-fluorophenyl)-1,2,4-triazine in 125 ml. of pyridine is cooled to 0° C. and 15 ml. of hydrazine hydrate is added. The mixture is stirred at room temperature for one hour and then poured into icewater. The solid is recovered by filtration and washed with ethanol, giving 3-hydrazino-6-(p-fluorophenyl)-1,2,4-triazine as an orange solid.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C:9]1[CH:13]=[CH:12][S:11][C:10]=1[C:14]([O:16][CH3:17])=[O:15]>C1(C)C=CC=CC=1>[C:1]([NH:8][C:9]1[CH:13]=[CH:12][S:11][C:10]=1[C:14]([O:16][CH3:17])=[O:15])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1sccc1N
Solvent: Cc1ccccc1
Product: COC(=O)c1sccc1NC(C)=O
Temperature: 0 °C

Procedure:
With simultaneous heating in an oil bath, 567 ml of acetic anhydride are added dropwise to a mixture of 942 g of methyl 3-aminothiophene-2-carboxylate and 1000 ml of toluene, and the mixture is then boiled under reflux conditions for 1½ hours and subsequently cooled in an ice bath to about 0° C. The crystals are filtered off and washed twice with a little isopropanol and twice with diisopropyl ether. Methyl 3-acetylaminothiophene-2-carboxylate can be obtained from the filtrate by further concentration and crystallization. M.p. 93-95° C.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:11](=[O:12])[C:10]2[CH:13]=[C:14]([CH2:16][CH3:17])[S:15][C:9]=2[N:8]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[NH:35][C:34](=[O:36])[O:33][N:32]=3)=[CH:21][CH:20]=2)[C:7]1=[O:37].FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[CH2:16]([C:14]1[S:15][C:9]2[N:8]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]4[NH:35][C:34](=[O:36])[O:33][N:32]=4)=[CH:21][CH:20]=3)[C:7](=[O:37])[NH:6][C:11](=[O:12])[C:10]=2[CH:13]=1)[CH3:17]
Reactant: CCc1cc2c(=O)n(Cc3ccc(OC)cc3OC)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Temperature: 50 °C
Reaction time: 2 h
Yield: 93.5 %

Procedure:
A mixture of 3-(2,4-dimethoxybenzyl)-6-ethyl-1-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.3 g) and trifluoroacetic acid (5 mL) was stirred at 50° C. for 2 hr. To the reaction mixture was added toluene (10 mL), and the mixture was concentrated under reduced pressure. The obtained residue was dissolved in 1N aqueous sodium hydroxide solution, washed with chloroform, and adjusted to pH 4 with 1N hydrochloric acid. The precipitated solid was collected by filtration to give the title compound as colorless crystals (0.21 g, 93%).
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([CH:10]=O)[CH:7]=[CH:6][N:5]=2)[CH2:3][CH2:2]1.Cl.NO.C([N:17](CC)CC)C.CCCP(=O)=O>CN(C)C=O.O>[CH:1]1([C:4]2[N:9]=[C:8]([C:10]#[N:17])[CH:7]=[CH:6][N:5]=2)[CH2:3][CH2:2]1
Reactant: O=Cc1ccnc(C2CC2)n1
Reactant: CCN(CC)CC
Agent: CCCP(=O)=O
Agent: Cl
Agent: NO
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccnc(C2CC2)n1
Temperature: 50 °C
Reaction time: 16 h
Yield: 62 %

Procedure:
To a solution of 2-cyclopropylpyrimidine-4-carbaldehyde (1.0 g, 6.68 mmol) in N,N-dimethylformamide (10 mL) were added hydroxylamine hydrochloride (500 mg, 7.02 mmol) and triethylamine (1.2 mL). The reaction mixture was heated to 50° C. and propylphosphonic anhydride (T3P) was added dropwise. After 16 h at 110° C., the mixture was cooled to room temperature, diluted with water and quenched with solid sodium bicarbonate. The mixture was extracted with ethyl acetate, then the organic layer was dried over sodium sulfate, filtered, concentrated under reduced pressure. The residue was purified via silica gel chromatography to afford 2-cyclopropylpyrimidine-4-carbonitrile (600 mg, 62%) as a pale yellow liquid. MS (ES+APCI) (M+H) 145.9; LMCS retention time 2.224 min (Method G).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][N:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1CCNCC1
Reactant: ClCCCCCOCc1ccccc1
Product: O=C1CCN(CCCCCOCc2ccccc2)CC1

Procedure:
1-(5-Benzyloxypentyl)-4-piperidone is prepared from 4-piperidone and 1-chloro-5-benzyloxypentane essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: Cl.[O:2]1[C:7]2=[CH:8][CH2:9][CH2:10][CH:6]2[NH:5][CH2:4][CH2:3]1.[F:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1[CH2:14][CH2:15][N:16]2[C:21](=[O:31])[CH2:22][C:23]1[NH:28][C:27](=[O:29])[CH:26]=[C:25](Cl)[N:24]=1.O>C(N(C(C)C)CC)(C)C>[F:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1[CH2:14][CH2:15][N:16]2[C:21](=[O:31])[CH2:22][C:23]1[NH:28][C:27](=[O:29])[CH:26]=[C:25]([N:5]2[CH:6]3[CH2:10][CH2:9][CH2:8][CH:7]3[O:2][CH2:3][CH2:4]2)[N:24]=1
Reactant: C1=C2OCCNC2CC1
Reactant: O=C(Cc1nc(Cl)cc(=O)[nH]1)N1CCc2c(F)cccc21
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(Cc1nc(N2CCOC3CCCC32)cc(=O)[nH]1)N1CCc2c(F)cccc21
Temperature: 100 °C
Yield: 23.2 %

Procedure:
532 mg of hexahydrocyclopenta[1,4]oxazine hydrochloride are added to a solution of 100 mg of 2-[2-(4-fluoro-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-chloro-3H-pyrimidin-4-one in 5 ml of diisopropylethylamine. The reaction medium is heated at 100° C. for 2 hours. The reaction medium is taken up with 10 ml of water. The solid formed is filtered off and washed with water and then dried so as to give 30 mg of 2-[2-(4-fluoro-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-(hexahydrocyclopenta[1,4]oxazin-4-yl)-3H-pyrimidin-4-one in the form of a beige solid, the characteristics of which are the following:
Reaction SMILES: [C:1]1([CH3:20])[CH:6]=[CH:5][C:4]([C:7]2[O:11][C:10]3[C:12]4[C:17]([CH:18]=[CH:19][C:9]=3[CH:8]=2)=[CH:16][CH:15]=[CH:14][CH:13]=4)=[CH:3][CH:2]=1.N([CH:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:30](=[O:31])[O:29]1)C1C=CC=CC=1>>[C:30]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:37]=1[CH:28]=[CH:20][C:1]1[CH:2]=[CH:3][C:4]([C:7]2[O:11][C:10]3[C:12]4[C:17]([CH:18]=[CH:19][C:9]=3[CH:8]=2)=[CH:16][CH:15]=[CH:14][CH:13]=4)=[CH:5][CH:6]=1)([OH:31])=[O:29]
Reactant: Cc1ccc(-c2cc3ccc4ccccc4c3o2)cc1
Reactant: O=C1OC(Nc2ccccc2)c2ccccc21
Product: O=C(O)c1ccccc1C=Cc1ccc(-c2cc3ccc4ccccc4c3o2)cc1

Procedure:
Following the procedure as in Example 8, 2-(p-tolyl)naphtho[1,2-b]furan was interacted with an equimolar quantity of 3-anilinophthalide to produce 2-[4-(2-carboxystyryl)phenyl]naphtho[1,2-b]furan which, when crystallized from chlorobenzene, melted at 210°-211°C. The measured wavelength of maximum excitation was 374 nm and wavelength of maximum emission was 438 nm.
Reaction SMILES: [OH-].[Na+].C(O)C.[CH2:6]([C:20]1[CH:21]=[C:22]([C:25]([O:27]C)=[O:26])[NH:23][CH:24]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>O>[CH2:6]([C:20]1[CH:21]=[C:22]([C:25]([OH:27])=[O:26])[NH:23][CH:24]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCCCCCCc1c[nH]c(C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCCCc1c[nH]c(C(=O)O)c1
Yield: 89.6 %

Procedure:
A solution (1 ml) of 2N sodium hydroxide was added to an ethanol solution (5 ml) of 0.22 g (0.69 mmol) of methyl 4-tetradecylpyrrole-2-carboxylate prepared in Example 9 and heated under reflux for 13 hours. Water was added to the resulting mixture, and then washed with ether. After acidifying the aqueous layer with hydrochloric acid, the mixture was extracted with ether and dried over anhydrous magnesium sulfate. The removal of the solvent afforded 0.19 g (95% yield) of 4-tetradecylpyrrole-2-carboxylic acid, m.p. 148°-150° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[S:9][C:10]([CH:13]=O)=[CH:11][N:12]=1.[C:15]1([NH2:22])[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1.C([SiH](CC)CC)C>C(Cl)Cl.FC(C(O)=O)(F)F>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[S:9][C:10]([CH2:13][NH:21][C:18]2[CH:19]=[CH:20][C:15]([NH2:22])=[CH:16][CH:17]=2)=[CH:11][N:12]=1
Reactant: O=Cc1cnc(Nc2ccccn2)s1
Reactant: Nc1ccc(N)cc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(NCc2cnc(Nc3ccccn3)s2)cc1

Procedure:
A solution of 2-(pyridine-2-ylamino)-thiazole-5-carbaldehyde (0.10 g, 0.49 mmol, WO2004/001059), benzene-1,4-diamine (0.105 g, 0.97 mmol) and triethylsilane (0.19 mL, 1.2 mmol) in CH2Cl2-TFA (3:1, 4 mL) was stirred at ambient temperature for 4 h. The reaction mixture was concentrated in vacuo and the residue partitioned between CH2Cl2 and saturated aqueous NaHCO3 solution. The organic phase was washed with saturated aqueous NaHCO3 solution, brine, dried (MgSO4) and concentrated in vacuo. The crude product which contained the title compound along with the starting aldehyde and benzene-1,4-diamine was carried on directly into the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:19]=[CH:18][CH:17]=[CH:16][C:6]=1[C:7]([NH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:8].C(N(CC)CC)C.[C:32](Cl)(=[O:37])[CH2:33][CH:34]([CH3:36])[CH3:35]>C(Cl)Cl>[Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:19]=[CH:18][CH:17]=[CH:16][C:6]=1[C:7]([NH:9][CH:10]1[CH2:15][CH2:14][N:13]([C:32](=[O:37])[CH2:33][CH:34]([CH3:36])[CH3:35])[CH2:12][CH2:11]1)=[O:8]
Reactant: CC(C)CC(=O)Cl
Reactant: O=C(NC1CCNCC1)c1ccccc1Oc1ccc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CC(=O)N1CCC(NC(=O)c2ccccc2Oc2ccc(Cl)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78.8 %

Procedure:
To an ice cooled solution of 4-[2-(2,4-dichlorophenoxy)-N-piperidin-4-ylbenzamide (AMR01077, 100 mg, 0.274 mmol) in dry DCM (5 mL) were added triethylamine (0.2 mL, 1.37 mmol) and isovaleryl chloride (0.04 mL, 0.33 mmol). The reaction mixture was stirred at room temperature until completion by TLC (1.5 h), and quenched with saturated NaHCO3. The organic solution was evaporated to dryness and the oil obtained was purified by column chromatography using DCM/MeOH 95:5 as eluent. Further purification was carried out by treating a DCM solution of the obtained compound with trisamine scavenger (100 mg) for 2 h. The scavenger was filtered off, and the solvent evaporated to give 2-(2,4-dichlorophenoxy)-N-[1-(3-methylbutyryl)piperidin-4-yl]benzamide (97 mg, 79%) as a colorless oil. Rf: 0.15 (hexane/AcOEt 4:6) LC/MS (APCI) tr=4.44 min, m/z 451.43 (68), 449.42 (M++H, 100). HPLC tr=3.17 min (98.27%) 1H NMR (270 MHz, CDCl3) δ 0.95 (6H, d, J=6.7 Hz, 2CH3), 1.33 (3H, m, CH2+½CH2), 2.19 (2H, d, J=6.7 Hz, CH2CO), 2.83 (1H, m, ½CH2), 3.15 (1H, m, ½CH2), 3.76 (1H, m, ½CH2), 4.16 (1H, m, CH), 4.44 (1H, m, ½CH2), 6.79 (1H, dd, J=8.2, 1.0 Hz, ArH), 6.86 (1H, d, J=8.6 Hz, ArH), 7.20 (1H, dd, J=8.7, 2.5 Hz, ArH), 7.25 (1H, m, ArH), 7.29 (1H, br s, NH), 7.41 (1H, m, ArH), 7.49 (1H, d, J=2.5 Hz, ArH) and 8.16 (1H, dd, J=7.7, 1.7 Hz, ArH).