Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([N:17]2[CH:21]=[C:20]([CH:22]=[O:23])[C:19]([CH3:24])=[N:18]2)[CH:14]=[CH:15][CH:16]=1>O1CCCC1>[CH:1]1([CH:22]([C:20]2[C:19]([CH3:24])=[N:18][N:17]([C:13]3[CH:14]=[CH:15][CH:16]=[C:11]([O:10][CH3:9])[CH:12]=3)[CH:21]=2)[OH:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cccc(-n2cc(C=O)c(C)n2)c1
Reactant: Br[Mg]C1CCCCC1
Solvent: C1CCOC1
Product: COc1cccc(-n2cc(C(O)C3CCCCC3)c(C)n2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 70 %

Procedure:
To a solution (15 mL) of in 1-(3-methoxyphenyl)-3-methyl-1H-pyrazole-4-carbaldehyde (0.62 g) synthesized in the above-mentioned (2) in tetrahydrofuran under ice-cooling was added dropwise cyclohexylmagnesium bromide (4.3 mL, 1M tetrahydrofuran solution). After the completion of the dropwise addition, the ice bath was removed, and the mixture was stirred at room temperature for 15 min. To the reaction mixture was added aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2, volume ratio) to give the title object compound (0.60 g, 70%) as a pale-yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:20])[C:5]2[N:9]=[C:8]([C:10]3[C:11]([O:17]C)=[N:12][CH:13]=[CH:14][C:15]=3I)[NH:7][C:6]=2[CH:19]=1.[ClH:21]>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH3:20])[C:5]2[N:9]=[C:8]([C:10]3[C:11](=[O:17])[NH:12][CH:13]=[CH:14][C:15]=3[Cl:21])[NH:7][C:6]=2[CH:19]=1
Reactant: COc1nccc(I)c1-c1nc2c(C)cc(Br)cc2[nH]1
Reactant: Cl
Solvent: C1COCCO1
Product: Cc1cc(Br)cc2[nH]c(-c3c(Cl)cc[nH]c3=O)nc12
Temperature: 80 °C
Yield: 100 %

Procedure:
The suspension of 6-bromo-2-(4-iodo-2-methoxy-pyridin-3-yl)-4-methyl-1H-benzimidazole (4 g, 9.03 mmol) and 60 mL of 4 M HCl in dioxane was heated to 80° C. for 6 h and cooled to room temperature. The precipitate was filtered and dried to yield the title compound (3.0 g, 100%) as a brown powder. The crude product was used for the next step without purification. 1H NMR (300 MHz, CD3OD) δ 7.55 (1H, s), 7.42 (1H, d, J=6.0 Hz), 7.17 (1H, s), 6.91 (1H, d, J=6.0 Hz), 2.55 (3H, s). LCMS (M+H)+ m/z 338 (t=1.33 min.).
Reaction SMILES: COC([NH:5][C@:6]12[CH2:14][N:13](C(OC)=O)[CH2:12][C@H:11]1[CH:10]=[CH:9][CH:8]=[CH:7]2)=O.CO>O>[CH2:12]1[C@@H:11]2[C@@:6]([NH2:5])([CH:7]=[CH:8][CH:9]=[CH:10]2)[CH2:14][NH:13]1
Reactant: COC(=O)N[C@@]12C=CC=C[C@@H]1CN(C(=O)OC)C2
Solvent: O
Solvent: CO
Product: N[C@@]12C=CC=C[C@@H]1CNC2

Procedure:
Analogously to Step F, 11 g of crude methyl (1S,6R)-1-methoxycarbonylamino-8-azabicyclo[4.3.0]nona-2,4-diene-8-carboxylate are hydrolysed in 150 ml of water using 42 g of Ba(OH)2.8 H2O and worked up accordingly. Yield: 3 g (44.6% of theory based on Step G), boiling point: 70° C./0.1 mbar, [α]D =+235.9° (c=1,14, methanol).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1.[OH:12]O>C(O)=O.O>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)=[O:12]
Reactant: OO
Reactant: ClCCCSc1ccccn1
Solvent: O
Solvent: O=CO
Product: O=S(CCCCl)c1ccccn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.5 %

Procedure:
2-(3-Chloropropyl)thiopyridine (4.4 g) prepared in Reference Example 3 is dissolved in formic acid (40 ml). 30% Aqueous hydrogen peroxide (2.7 g) is added to the solution and the mixture is stirred at room temperature for 3 hours. The mixture is allowed to stand at room temperature for overnight, diluted with water and extracted with chloroform. The chloroform solution is washed with water, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride and dried over magnesium sulfate. Chloroform is distilled off and the residue is purified by column chromatography (Kieselgel 60). The column is eluted with chloroform-methanol (50:1) to obtain 2-pyridyl 3-chloropropyl sulfoxide (2.7 g) as colorless liquid.
Reaction SMILES: [C:1]1(=O)[C:13]2[C:5]([C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:4][CH:3]=[CH:2]1.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:12]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[NH2:15])[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2
Reactant: Nc1ccccc1
Reactant: O=C1C=CC=C2C1=Cc1ccccc12
Product: Nc1ccccc1C1(c2ccccc2N)c2ccccc2-c2ccccc21

Procedure:
More specifically, a symmetrical compound can be synthesized by the following method: A mixture containing a fluorenone and an aniline is refluxed in the presence of an acid catalyst to produce an intermediate 9,9-bis(aminophenyl)fluorene. The intermediate is subsequently reacted with aryl halides (Ar—X and Ar′—X, stepwise) in the presence of a catalyst such as palladium to obtain the desired symmetrical product. An asymmetrical compound, on the other hand, can be synthesized as follows: A reaction mixture containing a fluorenone and two different anilines (e.g., an aniline and a 2-fluoroaniline as shown in the above scheme) is refluxed in the presence an acid catalyst to produce a mixture including an asymmetric fluorene intermediate. The asymmetric fluorene intermediate is then reacted with aryl halides (Ar—X and Ar′—X, stepwise) in the presence of a catalyst such as palladium to produce the desired asymmetrical product.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:13])[C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:14][NH2:15]>C(O)C>[CH3:14][NH:15][CH:3]([C:11]1[C:10](=[O:12])[C:9]2[C:4]([C:3](=[O:13])[C:2]=1[OH:1])=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:2][CH2:11][CH3:10]
Reactant: CN
Reactant: O=C1C=C(O)C(=O)c2ccccc21
Solvent: CCO
Product: CCCC(NC)C1=C(O)C(=O)c2ccccc2C1=O

Procedure:
3.50 g (20.1 mmol) of 2-hydroxy-1,4-naphthoquinone (lawson) was added to 50 ml of ethanol, and 1.60 g (20.6 mmol) of an aqueous monomethylamine solution (40% by weight) was further added thereto to obtain uniform solution of the amine salt. Then, 1.90 g (26.4 mmol) of butylaldehyde was added thereto, and the mixture was reacted at 25° C. for 1.5 hours. In about 20 minutes, crystals started to precipitate. After completion of the reaction, precipitated crystals were collected by filtration and washed with methanol to obtain 4.43 g (17.1 mmol) of crude crystals of the desired product. The yield was 85.1 mol %.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:17]=[CH:18][CH:19]=[C:20]3[C:24]=2[NH:23][CH:22]=[C:21]3[S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[O:27])=[O:26])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:34]I.O>CN(C=O)C>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:17]=[CH:18][CH:19]=[C:20]3[C:24]=2[N:23]([CH3:34])[CH:22]=[C:21]3[S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[O:26])=[O:27])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3c(S(=O)(=O)c4ccccc4)c[nH]c23)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(S(=O)(=O)c2ccccc2)c2cccc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.9 %

Procedure:
Sodium hydride (0.12 g of 60% dispersion in mineral oil, 3 mmol) was added to a solution of 4-(3-benzenesulfonyl-1H-indol-7-yl)-piperazine-1-carboxylic acid tert-butyl ester (1 g, 2.3 mmol) in 20 mL of DMF with ice cooling. After stirring 15 min at room temperature the mixture was treated with methyl iodide (0.17 mL, 3 mmol). Water was added and the mixture was extracted with ethyl acetate. The extract was washed with water and brine, dried (sodium sulfate) and evaporated. Silica gel chromatography (20% ethyl acetate-hexane) afforded 0.9 g of 4-(3-benzenesulfonyl-1-methyl-1H-indol-7-yl)-piperazine-1-carboxylic acid tert-butyl ester as a foam, mass spec. M+ 455.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[O:10][C:11]([C:14]2[N:19]=[C:18]([S:20][CH3:21])[C:17]([Cl:22])=[CH:16][N:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:31])C=1>C(Cl)Cl>[C:1]([NH:5][S:6]([C:9]1[O:10][C:11]([C:14]2[N:19]=[C:18]([S:20]([CH3:21])=[O:31])[C:17]([Cl:22])=[CH:16][N:15]=2)=[CH:12][CH:13]=1)(=[O:7])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1nc(-c2ccc(S(=O)(=O)NC(C)(C)C)o2)ncc1Cl
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1nc(-c2ccc(S(=O)(=O)NC(C)(C)C)o2)ncc1Cl
Reaction time: 0.5 h

Procedure:
To the solution of N-tert-butyl-5-(5-chloro-4-(methylthio)pyrimidin-2-yl)furan-2-sulfonamide (150 mg, 0.42 mmol, 1.0 equiv.) in CH2Cl2 (3 mL) was added m-CPBA (124 mg, 0.54 mmol, 1.3 eq., 75% content) at 0° C. The reaction mixture was stirred for 30 minutes and then concentrated to produce N-tert-butyl-5-(5-chloro-4-(methyl sulfinyl)pyrimidin-2-yl)furan-2-sulfonamide. The residue was directly used for the next step. LC-MS (m/z)=378.0 [M+H]+.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]\[C@@H:9]2[CH2:25][N:13]3[CH2:14][CH2:15][N:16]([C:18]4[N:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=4)[CH2:17][C@@H:12]3[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>[Pd].C(O)C>[C:1]1([CH2:7][CH2:8][C@H:9]2[CH2:25][N:13]3[CH2:14][CH2:15][N:16]([C:18]4[N:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=4)[CH2:17][C@@H:12]3[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Fc1cnc(N2CCN3C[C@@H](/C=C\c4ccccc4)CC[C@H]3C2)nc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Fc1cnc(N2CCN3C[C@H](CCc4ccccc4)CC[C@H]3C2)nc1
Yield: 82.8 %

Procedure:
A mixture of 0.15 g (0.44 mmol) of Z-(7R,9aS)-7-(2-phenyl)ethenyl-2-(5-fluoropyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine, 0.015 g of 10% palladium on carbon and 25 mL of ethanol was shaken under 40 psig of hydrogen gas in a Parr apparatus for 6 h. The mixture was filtered through Celite, and the filtrate concentrated to give 0.124 g (83%) of (7R,9aS)-7-(2-phenyl)ethyl-2-(5-fluoropyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine. mp (.HCl) 250–252° C. HRMS calcd for C20H26FN4O (MH+): 341.2142, found: 341.2126.
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]2[N:12]=[CH:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:4]2[N:3]=1.P(Cl)(Cl)([Cl:21])=O>CN(C)C1C=CN=CC=1>[Cl:21][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]2[N:12]=[CH:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:4]2[N:3]=1
Reactant: COC(=O)c1cnn2c(C(F)(F)F)cc(O)nc12
Reactant: O=P(Cl)(Cl)Cl
Agent: CN(C)c1ccncc1
Product: COC(=O)c1cnn2c(C(F)(F)F)cc(Cl)nc12

Procedure:
A mixture of 2.70 g of methyl 5-hydroxy-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate and 1.26 g of 4-dimethylaminopyridine was heated to 100° for 2.5 hours in 50 ml of phosphorus oxychloride. The resulting solution was concentrated in a vacuum and then partitioned between ethyl acetate and saturated sodium chloride solution. The organic phase was washed in succession with 1N hydrochloric acid and saturated sodium chloride solution, dried over sodium sulphate, freed from solvent in a vacuum and the residue was crystallized from ethyl acetate/petroleum ether. There was obtained methyl 5-chloro-7-(tri-fluoromethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate as white crystals of m.p. 126°-127°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[CH2:9][CH:8]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][OH:26])[CH2:19][CH2:18]3)[C:7]=2[CH:27]=1.[C:28](Cl)(=[O:40])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[CH2:9][CH:8]([N:17]3[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][CH2:25][O:26][C:28](=[O:40])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:21][CH2:22]3)[C:7]=2[CH:27]=1
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: COc1ccc2c(c1)C(N1CCN(CCCO)CC1)Cc1ccccc1S2
Solvent: c1ccccc1
Product: CCCCCCCCCCCC(=O)OCCCN1CCN(C2Cc3ccccc3Sc3ccc(OC)cc32)CC1

Procedure:
In accordance with the procedure described in the foregoing Examples, 12.96 grams of 8-methoxy-10-[4-(3-hydroxypropyl)piperazino]-10,11-dihydrodibenzo[b,f]thiepin was reacted with 13.1 grams of lauroyl chloride (dodecanoyl chloride) in 50 milliliters of benzene and the resulting crude 8-methoxy-10-[4-(3-dodecanoyloxypropyl)piperazino]-10,11-dihydrodibenzo[b,f]thiepin was purified by recrystallization of the maleate from acetone and recovered in the form of its di(hydrogen maleate). The salt was recovered in a yield of 14.9 grams and had a melting point of 126-129°C. The pure ester was recovered in the form of a viscous oil by adding the salt to a dilute aqueous ammonium hydroxide solution and extracting the resulting solution with benzene. EXAMPLE 4
Reaction SMILES: [CH3:1][N:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C:3]1=[CH:4][CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[C:22]([OH:24])=O.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([NH2:36])([CH3:35])[CH3:34])=[CH:29][CH:28]=1>>[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([NH:36][C:22]([CH:10]2[CH2:9][CH2:8][C@H:7]3[C@H:6]4[C@H:15]([CH2:14][CH2:13][C@:11]23[CH3:12])[C@:16]2([CH3:21])[C:3]([N:2]([CH3:1])[C:19](=[O:20])[CH2:18][CH2:17]2)=[CH:4][CH2:5]4)=[O:24])([CH3:34])[CH3:35])=[CH:29][CH:28]=1
Reactant: CN1C(=O)CC[C@@]2(C)C1=CC[C@H]1[C@@H]3CC[C@H](C(=O)O)[C@@]3(C)CC[C@@H]12
Reactant: COc1ccc(C(C)(C)N)cc1
Product: COc1ccc(C(C)(C)NC(=O)C2CC[C@H]3[C@@H]4CC=C5N(C)C(=O)CC[C@]5(C)[C@H]4CC[C@]23C)cc1
Yield: 72 %

Procedure:
The title compound was prepared in a yield of 72% in a similar manner to that described in Example 37 by reacting 4-methyl-3-oxo-4-azaandrost-5-ene-17β-carboxylic acid (prepared as described in Preparation 5) and 1-(4-methoxyphenyl)-1-methylethylamine.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[C:9]([CH2:11][O:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[N:10]=[C:6]2[N:5]([CH2:22][CH3:23])[C:4](=[O:24])[C:3]=1[N:25]=O.N.C(O)C.[O-]S(S([O-])=O)=O.[Na+].[Na+]>O>[NH2:25][C:3]1[C:4](=[O:24])[N:5]([CH2:22][CH3:23])[C:6]2[N:7]([N:8]=[C:9]([CH2:11][O:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[N:10]=2)[C:2]=1[NH2:1]
Reactant: CCn1c(=O)c(N=O)c(N)n2nc(COCc3ccc(OC)cc3)nc12
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCn1c(=O)c(N)c(N)n2nc(COCc3ccc(OC)cc3)nc12
Temperature: 25 °C
Yield: 83.2 %

Procedure:
At ambient temperature, 1.5 g of 7-amino-4-ethyl-2-[(4-methoxybenzyloxy)methyl]-6-nitroso-s-triazolo[1,5-a]pyrimidin-5-one are added to 64 ml of aqueous ammonia solution (25%) and 13 ml of ethanol and dissolved therein. At 30-35° C. a solution of 3.3 g of Na2S2O4 in 30 ml of water is added dropwise. The resulting mixture is stirred at ambient temperature until the reaction is complete (about 3-4 hours). After cooling in an ice bath, the crystals obtained are suction filtered and dried. 1.2 g of 6,7-diamino-4-ethyl-2-[(4-methoxybenzyloxy)methyl]-s-triazolo[1,5-a]pyrimidin-5-one are obtained, which is used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:12][OH:13]>>[CH3:12][O:13][C:4]([C:3]1[CH:7]=[CH:8][C:9]([F:11])=[CH:10][C:2]=1[F:1])=[O:5]
Reactant: CO
Reactant: O=C(Cl)c1ccc(F)cc1F
Product: COC(=O)c1ccc(F)cc1F
Reaction time: 2 h

Procedure:
To 100 mL of MeOH, 2,4-difluorobenzoyl chloride (10 mL, 79.3 mmol) was added and the mixture stiffed at room temperature for 2 hours. The solvent was then evaporated affording the title compound as pale yellow oil (quantitative).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:18][CH2:19][CH3:20])[C:5]#[C:6][CH:7]([OH:17])[CH2:8][O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:2].N([O-])=O.[Na+]>O.[Pt]=O.C(O)C>[CH2:19]([O:18][CH:4]([O:3][CH2:1][CH3:2])[CH2:5][CH2:6][CH:7]([OH:17])[CH2:8][O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH3:20]
Reactant: CCOC(C#CC(O)COCc1ccccc1)OCC
Agent: O=[Pt]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(CCC(O)COCc1ccccc1)OCC
Yield: 204 %

Procedure:
A solution of 5-benzyloxy-4-hydroxy-2-pentynal diethyl acetal (43.2 g) in abs. ethanol (250 ml) is hydrogenated in the presence of 82.7% platinum oxide (1.4 g), sodium nitrite (14 mg) and 1 drop of water for 90 minutes in a Parr hydrogenation apparatus. The reaction is repeated exactly as above with another (43.2 g) portion of 5-benzyloxy-4-hydroxy-2-pentynal diethyl acetal; the two mixtures are combined and the catalyst is removed by filtration through a bed of celite and washed with ethanol. The combined filtrate is evaporated in vacuo to give a residue (89.4 g, 100%). A 200 mg portion of the residue is purified on Quantagram PQ1F plates (developed in 40% CHCl3 /hexane three successive times). The principal band is eluted with ethyl acetate and the solvent is evaporated in vacuo to give 5-benzyloxy-4-hydroxypentanal diethyl acetate (152 mg); ir (neat) 2.88 μ (OH); nmr (CDCl3,δ): 1.17 (t, 6 H, OCH2CH3), 1.62 (m, 4H, CHCH2CH2CH), 2.7 (b, 1H, >CH-OH), 3.53 (m, 7H, OCH2CH3 and OCH2CH and ##STR6## 4.47 (m, 1H, >CHOH), 4.5 (s, 2H φCH2O), 7.28 (s, 5H, φCH2O).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:12]([CH2:19][CH3:20])([CH2:17][CH3:18])[C:13](=[O:16])[NH:14][N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CC1C=CC(S(O[CH:32]2[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]2)(=O)=O)=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:12]([CH2:19][CH3:20])([CH2:17][CH3:18])[C:13](=[O:16])[N:14]([CH:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: CCC1(CC)C(=O)NN=C1c1ccc(OC)c(OC)c1
Product: CCC1(CC)C(=O)N(C2CCNCC2)N=C1c1ccc(OC)c(OC)c1

Procedure:
Prepared analogously as described for the example B1 (Alternative 1) using 5-(3,4-dimethoxyphenyl)-4,4-diethyl-2,4-dihydro-3H-pyrazol-3-one (compound C7) and tert-butyl 4-(Toluene-4-sulfonyloxy)piperidine-1-carboxylate (compound E1) as starting compounds resulting in the title compound. (compound B7)
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH3:10][C:11]1[C:15]([NH2:16])=[C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[NH:13][N:12]=1.O>N1C=CC=CC=1>[CH3:10][C:11]1[C:15]([NH:16][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)=[C:14]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:13][N:12]=1
Reactant: Cc1n[nH]c(-c2ccccc2)c1N
Reactant: O=C(Cl)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1n[nH]c(-c2ccccc2)c1NC(=O)c1ccncc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
205 mg of isonicotinoyl chloride*HCl were added to a solution of 200 mg of 3-methyl-5-phenyl-1H-pyrazol-4-ylamine in 2 ml of pyridine and the mixture was then stirred at RT for 12 h; water was then added and the whole was extracted with methylene chloride. The organic phase was dried over magnesium sulfate, concentrated under reduced pressure and purified by means of HPLC (Merk-Hibar-Lichrospher 100-RP-18, water (0.1% trifluoroacetic acid)/acetonitrile (0.1% trifluoroacetic acid)=80/20→10/90). The following was obtained: 27. C16H14N4O (278.32); MS (ESI) 279 (M+H)
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6](=[O:12])[NH:7][CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([NH2:33])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)=[CH:18][CH:17]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:7][CH2:8][C:9](=[O:11])[NH:33][CH:22]([C:19]2[CH:18]=[CH:17][C:16]([F:15])=[CH:21][CH:20]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[CH:24]=2)=[O:12])=[CH:13][CH:14]=1
Reactant: O=C(O)CNC(=O)c1ccc(F)cc1
Reactant: NC(c1ccc(F)cc1)c1cccc(C(F)(F)F)c1
Product: O=C(CNC(=O)c1ccc(F)cc1)NC(c1ccc(F)cc1)c1cccc(C(F)(F)F)c1

Procedure:
Prepared in analogy to example 1.1 from 4-fluoro-hippuric acid (CA [366-79-0]) and rac-C-(4-fluoro-phenyl)-C-(3-trifluoromethyl-phenyl)-methylamine (example 4.5).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:23])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([CH2:19]Cl)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:25][C:26]([C:29]([NH2:31])=[O:30])([CH3:28])[NH2:27]>>[Cl:1][C:2]1[C:3]([F:23])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([CH2:19][NH:27][C:26]([CH3:28])([C:29]([NH2:31])=[O:30])[CH3:25])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CCl
Reactant: CC(C)(N)C(N)=O
Agent: Cl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CNC(C)(C)C(N)=O
Yield: 49.1 %

Procedure:
N-(3-Chloro-2-fluorophenyl)-6-(chloromethyl)-7-methoxyquinazolin-4-amine (0.2 g, 0.568 mmol) was coupled with 2-methylalaninamide hydrochloride using an analogous method to that described for the equivalent step in Example 62 to give the title product (0.12 g, 49.1%); Mass Spectrum: (M+H)+ 418.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[N:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1.[CH2:20]([NH2:25])[CH2:21][CH:22]([CH3:24])[CH3:23].[BH4-].[Na+]>CO>[F:1][C:2]1[CH:17]=[C:16]([CH2:18][NH:25][CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[N:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1
Reactant: CC(C)CCN
Reactant: NC(=O)c1cnc(Oc2ccc(C=O)cc2F)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)CCNCc1ccc(Oc2cnc(C(N)=O)cn2)c(F)c1
Reaction time: 8 h
Yield: 44.2 %

Procedure:
Place 5-(2-fluoro-4-formylphenoxy)pyrazine-2-carboxamide (Example 737, Part E) (0.400 g, 1.53 mmol), isoamylamine (0.147 g, 1.68 mmol) and 3 {acute over (Å)} molecular sieves in a vial. Add methanol (7.7 mL), cap and stir overnight. Add NaBH4 (0.058 g, 1.53 mmol) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 40 g ISCO® column with 0% to 15% (2.0 M NH3 in methanol) in 80% (ethyl acetate in hexanes) to give the title compound (0.225 g, 50%): TOF MS ES+ 333.2 (M+H)+, HRMS calcd for C17H22N4O2F 333.1727 (M+H)+, found 333.1714, time 0.55 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18], tR=10.1 min, 100% purity.
Reaction SMILES: [CH3:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=O)[CH2:3]1.Cl.[NH2:13][OH:14].[OH-].[Na+]>CO.O>[CH3:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[N:13][OH:14])[CH2:3]1
Reactant: NO
Reactant: CC1CC(=O)c2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1CC(=NO)c2ccccc21
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 3-methylindan-1-one (221 mg, 1.51 mmol) and hydroxylamine hydrochloride (295 mg, 4.25 mmol) in MeOH (4.00 mL) was added a solution of NaOH (200 mg, 5.00 mmol) in H2O (2.00 mL) and the mixture was stirred at 80° C. for 2 h. The cooled reaction was concentrated in vacuo to remove most of the MeOH, and the residue was partitioned between DCM and H2O. The organic layer was concentrated in vacuo to afford the title compound as a waxy solid (232 mg, 95%). LC/MS: Rt=1.51 min, ES+ 162 (AA standard).