Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])=O.[NH4+:4].[OH:5][C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][C:8]([C:16](=O)[C:17]([OH:19])=[O:18])([CH2:9]3)[CH2:7]1)[CH2:13]2.[OH-].[NH4+]>C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3O)C=2N=1.SC[C@H]([C@@H](CS)O)O>[NH2:4][C@@H:16]([C:8]12[CH2:14][CH:12]3[CH2:11][CH:10]([CH2:15][C:6]([OH:5])([CH2:13]3)[CH2:7]1)[CH2:9]2)[C:17]([OH:19])=[O:18]
Reactant: O=C(O)C(=O)C12CC3CC(CC(O)(C3)C1)C2
Reactant: [NH4+]
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Agent: O=C[O-]
Agent: O[C@H](CS)[C@H](O)CS
Product: N[C@H](C(=O)O)C12CC3CC(CC(O)(C3)C1)C2
Yield: 105.5 %

Procedure:
A 266 ml solution was prepared containing ammonium formate (16.74 g, 0.2654 moles) and (3-hydroxy-adamantan-1-yl)-oxo-acetic acid (29.76 g, 0.1327 moles) and brought to pH 8.0 with 12.7 ml concentrated ammonium hydroxide. NAD (372 mg, 0.561 mmoles) and dithiothreitol (81.8 mg, 0.530 mmoles) were added, then the solution was added to the bottle containing the Escherichia coli extract. The bottle was maintained at 40° on a shaker at 40 rpm. Concentrated ammonium hydroxide was added periodically to maintain pH 8.0 After 38 hours, the solution contained 31.5 grams (0.140 moles, 100% yield) (S)-amino-(3-hydroxy -adamantan-1-yl)-acetic acid as measured by HPLC analysis and no R-enantiomer of the amino acid.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C@H:10]2[C@@H:16]([OH:17])[C:15](=[O:18])[N:14]([CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])[C:13]3[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:12]=3[S:11]2)=[CH:6][CH:5]=1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>>[ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([C@H:10]2[C@@H:16]([O:17][C:29](=[O:31])[CH3:30])[C:15](=[O:18])[N:14]([CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])[C:13]3[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:12]=3[S:11]2)=[CH:8][CH:9]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc([C@@H]2Sc3cc(F)ccc3N(CCN(C)C)C(=O)[C@@H]2O)cc1
Agent: Cl
Product: COc1ccc([C@@H]2Sc3cc(F)ccc3N(CCN(C)C)C(=O)[C@@H]2OC(C)=O)cc1
Temperature: 100 °C

Procedure:
A mixture of 0.7 g of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-8-fluoro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride and 8 ml of acetic anhydride is heated at 100° C. for 4 hours. After the reaction is completed, the mixture is evaporated under reduced pressure to remove acetic anhydride and acetic acid. Toluene is added to the residue, and the mixture is evaporated under reduced pressure to remove solvent. The residue is recrystallized from a mixture of ethanol and ether. 0.68 g of (±)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(dimethylamino)ethyl]-8-fluoro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride 1/3H2O is obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.[NH2-].[Li+].C[N:13](CCN(C)C)C>COCCOC.[Cl-].[Zn+2].[Cl-]>[CH3:9][O:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[NH2:13]
Reactant: CN(C)CCN(C)C
Reactant: COc1cccc(Br)c1
Agent: [Cl-]
Agent: [Li+]
Agent: [NH2-]
Solvent: COCCOC
Product: COc1cccc(N)c1

Procedure:
The advantageous effect of adding zinc chloride to an amination reaction was demonstrated in the amination reaction of 3-bromoanisole, the results of which are summarized in Table 10. When 3-bromoanisole was reacted under the standard lithium amide amination conditions, using lithium amide (10 eq.) in the presence of (CyPF-t-Bu)PdCl2 (1 mol %) in DME gave a complicated mixture of products was obtained (Table 10, Entry 1). When conducted in the presence of zinc chloride and TMEDA, however, the reaction could successfully gave the desired monoarylation product, 3-methoxyaniline, although at high concentrations N,N-dimethyl-3-methoxyaniline was formed in a significant amount as a by-product (Table 10, Entries 3 and 4). Under optimized conditions (Table 10, Entries 8 and 9), 3-methoxyaniline was formed selectively in good yield.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][C:14](OC)=[O:15].[H-].[Al+3].[H-].[H-].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1.O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][OH:15]
Reactant: COC(=O)Cc1nc(-c2ccccc2)oc1C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Al+3]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1CCO
Yield: 118.4 %

Procedure:
A 750-ml 4-necked flask equipped with a mechanical stirrer, a thermometer, a dropping funnel and an argon inlet, cooled with a CO2/acetone bath, was charged with a solution of 49.15 g of crude methyl 2-(5-methyl-2-phenyl-4-oxazolyl)acetate (ca. 0.16 mol) and 90 ml of toluene and stirred. 400 ml of dusobutyl aluminiumhydride 1.2 M in toluene were added under argon at ca. −20 to −25° C. during 60 min. After additional 15 mi a solution of 191 g of citric acid monohydrate in 400 ml of deionized water was added with cooling during 30 min, so that the temperature did not exceed 5-10° C. The aqueous phase of the clear biphasic mixture was extracted with 200 ml of toluene. The combined organic phases were washed twice with 40 ml, a total of 80 ml of deionized water, twice with 40 ml, a total of 80 ml of brine and dried (Na2SO4). Rotary evaporation (50° C., 8 mbar, 1 h) afforded 38.5 g of crude 2-(5-Methyl-2-phenyl-4-oxazolyl)ethanol (theor. amount 32.4 g) which was used in the next step without further purification.
Reaction SMILES: Cl.[CH3:2][C:3]([CH3:8])([CH3:7])[C:4](=[NH:6])[NH2:5].Br[C:10]1[C:11](=O)[CH2:12][CH2:13][C:14]=1[O:15]C.C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>CN(C)C=O>[CH3:2][C:3]([C:4]1[NH:5][C:11]2[CH2:12][CH2:13][C:14](=[O:15])[C:10]=2[N:6]=1)([CH3:8])[CH3:7]
Reactant: CC(C)(C)C(=N)N
Reactant: COC1=C(Br)C(=O)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)c1nc2c([nH]1)CCC2=O
Temperature: 80 °C
Yield: 73.4 %

Procedure:
A mixture of 2,2-dimethylpropanimidamide hydrochloride (0.858 g), 2-bromo-3-(methyloxy)-2-cyclopenten-1-one (1 g) and potassium carbonate (2.53 g) in N,N-dimethylformamide (15 mL) were heated at 80° C. for 20 h. The reaction mixture was cooled down to room temperature and DCM (20 mL) was added. The mixture was filtered and the filtrate concentrated under vacuum. The residue was purified by reverse phase chromatography using Acetonitrile Water with an ammonium carbonate modifier gradient (5-40%). The desired fractions were combined and concentrated under vacuum to yield 685 mg of the title compound. LC/MS MH+ 179, Rt 1.48 min (5 minute run).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:17]3[CH:22]=[C:21]([O:23][CH2:24][CH2:25][N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[CH:20]=[CH:19][C:18]=3[CH3:32])=[O:16])=[C:11]([N+:33]([O-])=O)[CH:10]=2)=[C:4]([CH3:36])[CH:3]=1>CO.[Pd]>[NH2:33][C:11]1[CH:10]=[C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=2[CH3:36])[CH:14]=[CH:13][C:12]=1[C:15]([C:17]1[CH:22]=[C:21]([O:23][CH2:24][CH2:25][N:26]2[CH2:27][CH2:28][O:29][CH2:30][CH2:31]2)[CH:20]=[CH:19][C:18]=1[CH3:32])=[O:16]
Reactant: Cc1cc(F)ccc1Nc1ccc(C(=O)c2cc(OCCN3CCOCC3)ccc2C)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: Cc1cc(F)ccc1Nc1ccc(C(=O)c2cc(OCCN3CCOCC3)ccc2C)c(N)c1
Reaction time: 1 h

Procedure:
Compound 304 (0.041 g, 0.083 mmol) was dissolved in MeOH (2 mL). A catalytic amount of palladium on charcoal was added and the mixture was stirred under a hydrogen atmosphere for 1 h. The suspension was filtered and the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography using EtOAc/petroleum ether (40-60) 3:1→6:1 as the eluent. This afforded the title compound. 1H NMR (CDCl3) δ 7.19 (dd, 1H), 7.1.1 (d, 1H), 7.03 (d, 1H), 7.00-6.80 (m, 3H), 6.76 (d, 1H), 6.46 (bs, 2H), 5.89 (dd, 1H), 5.75 (d, 1H), 5.60 (s, 1H), 4.07 (t, 2H), 3.71 (m, 4H), 2.77 (t, 2H), 2.55 (m, 4H), 2.23 (s, 3H), 2.18 (s, 3H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]([CH:10]2[CH2:12][CH2:11]2)[OH:9])[C:3]=1[CH3:13]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([CH:10]2[CH2:11][CH2:12]2)=[O:9])[C:3]=1[CH3:13]
Reactant: Cc1c(Cl)ccnc1C(O)C1CC1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cc1c(Cl)ccnc1C(=O)C1CC1
Temperature: 25 °C
Reaction time: 45 h
Yield: 103.2 %

Procedure:
Manganese dioxide (1126 mg, 12.95 mmol) was added to a solution of (4-chloro-3-methylpyridin-2-yl)-cyclopropyl-methanol (250 mg, 1.214 mmol) in DCM (10 mL). The reaction mixture was stirred at room temperature for 45 h. The mixture was filtered over a porosity 4 filter. The filtrate was concentrated to dryness to yield white crystals (245 mg, 98%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](B2OC(C)(C)C(C)(C)O2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:25])[CH:11]=2)[CH:6]=1.Br[C:28]1[CH:33]=[CH:32][C:31]([S:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[Cl:41])=[CH:30][CH:29]=1.C(=O)(O)[O-].[Na+].O>C(COC)OC.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>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:28]2[CH:33]=[CH:32][C:31]([S:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[Cl:41])=[CH:30][CH:29]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:25])[CH:11]=2)[CH:6]=1
Reactant: Clc1ccccc1Sc1ccc(Br)cc1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(B2OC(C)(C)C(C)(C)O2)c1C
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: COCCOC
Solvent: O
Product: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(Sc3ccccc3Cl)cc2)c1C
Yield: 20.6 %

Procedure:
A stirred solution of [6-chloro-3-methyl-4-(4,4,5,5-tetra methyl-[1,3,2]-dioxaborolan-2-yl)-naphthalen-2-yl]-acetic acid methyl ester (0.2 g, 0.53 mmol) in dimethoxyethane (5 mL) was purged with argon for 5 minutes at room temperature. Tetrakis(triphenylphosphine)palladium(0) (0.031 g, 0.027 mmol), crude 1-bromo-4-(2-chlorophenylsulfanyl)-benzene (0.165 g) and 1.0 M aqueous sodium bicarbonate (5 mL, 5 mmol) were added simultaneously to the reaction mixture under argon. The reaction mixture was refluxed for 2 hours and then brought to room temperature. Water was added and the resulting mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was finally purified using flash chromatography (0-3% ethyl acetate in hexanes) to give {6-chloro-4-[4-(2-chloro-phenylsulfanyl)-phenyl]-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.051 g, 20%) as a solid. MS calcd. for C26H21Cl2O2S [(M+H)+] 467, obsd. 467.3.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:23]=[C:22]2[C:14]([N:15]3[C:20](=[CH:21]2)[C:19](=[O:24])[NH:18][CH2:17][CH2:16]3)=[N:13][CH:12]=1.C[C@@H]1CCCN1>>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:23]=[C:22]2[C:14]([N:15]3[C:20](=[CH:21]2)[C:19](=[O:24])[NH:18][CH2:17][CH2:16]3)=[N:13][CH:12]=1
Reactant: C[C@H]1CCCN1CCCOc1cnc2c(c1)cc1n2CCNC1=O
Agent: C[C@@H]1CCCN1
Product: C[C@@H]1CCCN1CCCOc1cnc2c(c1)cc1n2CCNC1=O
Yield: 32 %

Procedure:
The title compound was synthesized in analogy to example 2, from 7-(3-chloro-propoxy)-3,4-dihydro-2H-2,4a,5-triaza-fluoren-1-one (example 85, intermediate) and (R)-2-methylpyrrolidine (commercially available), to give the desired product as a colorless solid (32%).
Reaction SMILES: [C:1]1(=[O:7])[NH:5][C:4](=[O:6])[CH2:3][CH2:2]1.[H-].[B].[Na].Cl.[OH-].[K+].[CH:14](O)([CH3:16])[CH3:15]>>[CH:14]([O:6][CH:4]1[NH:5][C:1](=[O:7])[CH2:2][CH2:3]1)([CH3:16])[CH3:15]
Reactant: O=C1CCC(=O)N1
Reactant: CC(C)O
Agent: Cl
Agent: [B]
Agent: [H-]
Product: CC(C)OC1CCC(=O)N1
Temperature: -10 °C
Reaction time: 4 h

Procedure:
28.4 g of succinimide in 1200 cm3 of isopropanol is cooled to -10° C., 32.8 g of hydride of boron and sodium is added, and after agitating for 4 hours at 0°/-10° C., there is added a 2N solution of hydrochloric acid in isopropanol, adjusting the pH to 2-3. This is maintained for 2 hours at 0° C., then neutralised with a solution of potassium hydroxide in isopropanol. The solvent is evaporated under reduced pressure, the residue is taken up with chloroform, concentrated to dryness under reduced pressure, and 20.5 g of the expected product is obtained. m.p. 68°-71° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]1[CH2:13][N:12]([CH2:14][CH3:15])[CH2:11][C@H:10]1[C:16]([O:18]C)=[O:17].[ClH:20]>>[ClH:20].[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]1[CH2:13][N:12]([CH2:14][CH3:15])[CH2:11][C@H:10]1[C:16]([OH:18])=[O:17]
Reactant: CCN1C[C@@H](C(=O)OC)[C@H](c2ccc(F)cc2F)C1
Agent: Cl
Product: CCN1C[C@@H](C(=O)O)[C@H](c2ccc(F)cc2F)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Concentrated aqueous hydrochloric acid (10 ml) was added to methyl (3S,4R)-4-(2,4-difluorophenyl)-1-ethylpyrrolidine-3-carboxylate from Preparation 76 (500 mg, 1.85 mmol) and the resulting solution was stirred at room temperature for 16 hours. The reaction mixture was then evaporated to dryness in vacuo and the resultant residue was azeotroped with toluene (2×50 ml). This gave the title compound as an off-white foam, 500 mg.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:24]1C=CC=CC=1.C[Si](C=[N+]=[N-])(C)C>CO>[CH3:24][O:15][C:14]([C:11]1([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][CH2:12]1)=[O:16]
Reactant: c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)(c2ccc(Cl)cc2)CC1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)C1(c2ccc(Cl)cc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88 %

Procedure:
To a stirred 4-(4-chloro-phenyl)-piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (852 mg, 2.5 mmol) in methanol (5 ml)-benzene (17.5 ml) was added 15 ml (trimethylsilyl)diazomethane (2.0 M solution in hexanes) at room temperature. The mixture was stirred for 16 hours at room temperature and concentrated in vacuo. The residual yellow oil was purified by silica gel chromatography eluting with hexane-ethyl acetate (9:1) to give the corresponding ester (780 mg, 88%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[CH:11][C:10]([NH2:23])=[N:9]2)=[CH:4][CH:3]=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[CH:11][C:10]([NH:23][S:25]([CH3:24])(=[O:27])=[O:26])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: CS(=O)(=O)c1ccc(-c2cc(N)nn2-c2ccc(F)cc2)cc1
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cc(-c2ccc(S(C)(=O)=O)cc2)n(-c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 1-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]pyrazol-3-amine (0.8 g) and methanesulfonyl chloride (0.224 ml) in pyridine (8 ml) was stirred at ambient temperature for 2 hours. Pyridine was evaporated, and the residue was dissolved in ethyl acetate, washed with water and dilute hydrochloric acid, dried, and concentrated. The residual oil (1.1 g) was purified by column chromatography on silica gel (20 g) eluting with a mixture of toluene and ethyl acetate (2:1). The product (0.74 g) was recrystallized from ethanol to give pale brown crystals of N-{1-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3-pyrazolyl}methanesulfonamide (0.62 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](Cl)=[O:5].Cl.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][NH2:21]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([NH:21][NH:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[Cl:13])=[O:5]
Reactant: NNc1ccccc1Cl
Reactant: O=C(Cl)c1c(F)cccc1Cl
Agent: Cl
Solvent: c1ccncc1
Product: O=C(NNc1ccccc1Cl)c1c(F)cccc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
56.9 g (0.29 mol) of 2-chloro-6-fluorobenzoyl chloride are introduced dropwise into a solution, cooled to 0° C., of 52.8 g (0.29 mol) of 2-chlorophenylhydrazine hydrochloride in 290 ml of pyridine so that the temperature of the solution does not exceed 5° C. The solution is stirred at room temperature for 16 hours and the solvent is subsequently evaporated off azeotropically with toluene under reduced pressure. The resulting red-brown suspension is taken up in 350 ml of diethyl ether and the solution is washed in sequence twice with dilute hydrochloric acid and in each case once with 5% sodium bicarbonate solution and with saturated sodium chloride solution. The aqueous phases are back-extracted with 350 ml of diethyl ether and the combined organic phases are dried over anhydrous magnesium sulfate and then evaporated. After recrystallization of the residue from acetone/n-hexane there is obtained 2-chloro-6-fluoro-N'-(o-chlorophenyl)-benzhydrazide, m.p. 156°-158° C.; IR spectrum: 1692 cm-1.
Reaction SMILES: [Li]C.[CH2:3]([C:7]1[C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:9][CH:10]=[N:11][CH:12]=1)[CH2:4][CH2:5][CH3:6].[CH3:19]C(O)=O.[OH-].[Na+]>CCOCC.C1COCC1.O>[CH2:3]([C:7]1[C:12]([CH3:19])=[N:11][CH:10]=[N:9][C:8]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCc1cncnc1-c1ccccc1
Reactant: CC(=O)O
Agent: [Li]C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CCCCc1c(C)ncnc1-c1ccccc1
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
1.4 M MeLi in Et2O (1.54 ml, 2.16 mmol) is slowly added to a solution of 5-butyl-4-phenyl-pyrimidine (436 mg, 2.05 mmol) in Et2O (6 mL) at −30° C. under N2. The reaction mixture is stirred at −30° C. for 30 minutes and then at 0° C. for 45 minutes. Next, a solution of AcOH (0.12 mL) and H2O (0.02 mL) in THF (2 mL) is added, followed by a solution of 2,3-dichloro-5,6-dicyano-1,4-benzophenone (DDQ) (466 mg, 2.05 mmol) in THF (5 mL). The resulting mixture is stirred at room temperature for 5 minutes, recooled to 0° C., and then treated with 3.0 M aqueous NaOH. The mixture is stirred at 0° C. for 5 minutes, diluted with H2O, and extracted twice with Et2O. The combined extracts are dried over Na2SO4 and concentrated. The dark residue is purified by flash chromatography on silica gel. Elution with 2:1 Hex-EtOAc followed by 1:1 hexanes-EtOAc affords 5-butyl-4-methyl-6-phenyl-pyrimidine as a light yellow oil. 1H NMR (CDCl3, 300 MHz) δ 8.95 (s, 1H), 7.45 (m, 5H), 2.67-2.62 (m, 2H), 2.61 (s, 3H), 1.48-1.40 (m, 2H), 1.25 (sext, J=7.2 Hz), 0.82 (t, J=7.2 Hz, 3H) ppm. MS: m/z 227 [M+1].
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[C:3]1[CH:4]=[C:5]([CH:40]=[CH:41][CH:42]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:19]=[CH:18][C:17]=2[NH:28][C:29]([C:31]2[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=2)[C:34](O)=[O:35])=[O:30])[CH:11]=1)=[O:9].C[N:46]([CH2:90][CH2:91][N:92]1[CH2:97][CH2:96][O:95][CH2:94][CH2:93]1)[C:47](=O)[C:48]1[CH:88]=[CH:87][CH:86]=[C:50](C(NC2C=CC(N3CCCCC3)=CC=2C2C=C(C(=O)NCC3C=CC=C(C(F)(F)F)C=3)C=CN=2)=O)[CH:49]=1.C(NCCN1CCOCC1)C1C=CC=CC=1>>[CH2:47]([N:46]([CH2:90][CH2:91][N:92]1[CH2:93][CH2:94][O:95][CH2:96][CH2:97]1)[C:34](=[O:35])[C:33]1[CH:37]=[CH:38][CH:39]=[C:31]([C:29]([NH:28][C:17]2[CH:18]=[CH:19][C:20]([N:22]3[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]3)=[CH:21][C:16]=2[C:12]2[CH:11]=[C:10]([C:8](=[O:9])[NH:7][CH2:6][C:5]3[CH:40]=[CH:41][CH:42]=[C:3]([C:2]([F:43])([F:44])[F:1])[CH:4]=3)[CH:15]=[CH:14][N:13]=2)=[O:30])[CH:32]=1)[C:48]1[CH:88]=[CH:87][CH:86]=[CH:50][CH:49]=1
Reactant: O=C(O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reactant: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Agent: c1ccc(CNCCN2CCOCC2)cc1
Product: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(N3CCCCC3)ccc2NC(=O)c2cccc(C(=O)N(CCN3CCOCC3)Cc3ccccc3)c2)c1

Procedure:
This compound was prepared from 3-((2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)carbamoyl)benzoic acid 4.1e using the procedure described for the preparation of N1-methyl-N1-(2-morpholinoethyl)-N3-(4-(piperidin-1-yl)-2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)phenyl)isophthalamide 4.8. N-benzyl-2-morpholinoethanamine was used as the amine component in this coupling. MS (ES, m/z): 805 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=1.N1C=CC=CC=1.[C:17]1([P:23](Cl)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl>N1CCCC1=O.C(O)C.C(Cl)(Cl)Cl>[C:17]1([P:23]([NH:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:24])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: NC(=O)c1ccc(N)nc1
Reactant: O=P(Cl)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C1CCCN1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: CCO
Product: NC(=O)c1ccc(NP(=O)(c2ccccc2)c2ccccc2)nc1

Procedure:
6-Aminonicotinamide 1.37 g (0.01 mole) is dissolved in 10 ml of 2-pyrrolidinone and 3 ml of pyridine by gentle warming of the mixture. Diphenylphosphoryl chloride 6 ml (0.024 mole) is then slowly added to the mixture. After 1 hour of reaction at room temperature, the mixture is poured into 300 ml of 0.2 N HCl. A reddish syrup, 2.2 g which is formed in the bottom of the flask is isolated by decantation. The product may be purified as follows. The reddish syrup obtained above is dissolved in 3 ml of ethanol and the solution is admixed with 200 ml of 0.2 N HCl. Chloroform, 100 ml is added to the mixture to extract the product. After dried over anhydrous sodium sulfate the chloroform solution which contains the product is evaporated at 35° C. in vacuum to give a practically pure 6-diphenylphosphorylamino nicotinamide.
Reaction SMILES: C(OC(=O)COC1C=CC(Cl)=CC=1C#C[Si](C)(C)C)(C)(C)C.[C:23]([O:27][C:28](=[O:44])[CH2:29][O:30][C:31]1[C:32]([C:38]#[C:39][Si](C)(C)C)=[N:33][C:34]([CH3:37])=[CH:35][CH:36]=1)([CH3:26])([CH3:25])[CH3:24]>>[C:38]([C:32]1[C:31]([O:30][CH2:29][C:28]([O:27][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:44])=[CH:36][CH:35]=[C:34]([CH3:37])[N:33]=1)#[CH:39]
Reactant: Cc1ccc(OCC(=O)OC(C)(C)C)c(C#C[Si](C)(C)C)n1
Agent: CC(C)(C)OC(=O)COc1ccc(Cl)cc1C#C[Si](C)(C)C
Product: C#Cc1nc(C)ccc1OCC(=O)OC(C)(C)C
Yield: 91 %

Procedure:
Following the general method as outlined in Intermediate 2, starting from tert-butyl{[2-(trimethylsilyl-1-ethynyl)-6-methylpyridin-3-yl]oxy}acetate (Intermediate 85), the title compound was obtained in 91% yield as a brown oil after purification by flash column chromatography (silica), eluting with petroleum ether and ethyl acetate (98:2).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[NH:10][C:11](=[O:25])[C:12]3[CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][C:13]=3[N:14]=2)=[C:4]([F:26])[CH:3]=1.C(Cl)(Cl)Cl.CO.Cl>C(OCC)(=O)C>[ClH:1].[Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[NH:10][C:11](=[O:25])[C:12]3[CH2:17][NH:16][CH2:15][C:13]=3[N:14]=2)=[C:4]([F:26])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1Cc2nc(-c3cc(F)c(Cl)cc3F)[nH]c(=O)c2C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=c1[nH]c(-c2cc(F)c(Cl)cc2F)nc2c1CNC2

Procedure:
To a mixture of tert-butyl 2-(4-chloro-2,5-difluorophenyl)-4-oxo-3,5,6,7-tetrahydro-4H-pyrrolo[3,4-d]pyrimidine-6-carboxylate, chloroform, and MeOH, 4M hydrogen chloride (HCl) in ethyl acetate (EtOAc) solution was added, and the resultant mixture was stirred at ambient temperature for 5 hours to yield 2-(4-chloro-2,5-difluorophenyl)-3,5,6,7-tetrahydro-4H-pyrrolo[3,4-d]pyrimidin-4-one hydrochloride.