Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([F:18])=[C:4](F)[C:3]=1[F:20].[Cl:21][C:22]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:23]=1[NH2:24]>>[Cl:21][C:22]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:23]=1[NH:24][C:4]1[C:3]([F:20])=[C:2]([F:1])[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]=1[F:18].[Cl:21][C:22]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:23]=1[NH:24][C:4]1[C:3]([NH:24][C:23]2[C:22]([Cl:21])=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:29])=[C:2]([F:1])[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]=1[F:18]
Reactant: Nc1c(Cl)cccc1Cl
Reactant: O=C1c2ccccc2C(=O)c2c(F)c(F)c(F)c(F)c21
Product: O=C1c2ccccc2C(=O)c2c(F)c(Nc3c(Cl)cccc3Cl)c(F)c(F)c21
Product: O=C1c2ccccc2C(=O)c2c(F)c(Nc3c(Cl)cccc3Cl)c(Nc3c(Cl)cccc3Cl)c(F)c21

Procedure:
2 g of 1,2,3,4-Tetrafluoroanthraquinone and 20 g of 2,6-dichloroaniline were charged in a 50 cc, four necked flask and then the reaction was carried out at 230° Cl for about 8 hours. After completion of reaction, 2,6-dichloroaniline was distilled out from the reaction solution, and a column purification thereof using a column with a silica gel was effected to give rise to 1.39 g of 2-(2,6-dichloroanilino)-1,3,4-trifluoroanthraquinone (Dye 10') (yield 46.1 mol %) and 0.78 g of 2,3-bis(2,6-dichloroanilino)-1,4-difluoroanthraquinone (Dye 25') (yield 19.4 mol %). The physical properties of Dye 10' and analytical values defining the compound are tabulated in Table 22 and the physical properties of Dye 25' and analytical values defining the compound are tabulated in Table 23.
Reaction SMILES: [NH2:1][OH:2].C(=O)([O-])[OH:4].[Na+].OC1C=CC=C2C=1N=CC=C2.[F:19][C:20]1[C:27]([F:28])=[CH:26][CH:25]=[C:24]([C:29]([F:32])([F:31])[F:30])[C:21]=1[C:22]#[N:23]>CO.O>[F:19][C:20]1[C:27]([F:28])=[CH:26][CH:25]=[C:24]([C:29]([F:32])([F:30])[F:31])[C:21]=1[C:22](=[N:1][OH:2])[NH2:23].[F:19][C:20]1[C:27]([F:28])=[CH:26][CH:25]=[C:24]([C:29]([F:32])([F:30])[F:31])[C:21]=1[C:22]([NH2:23])=[O:4]
Reactant: NO
Reactant: O=C([O-])O
Reactant: N#Cc1c(C(F)(F)F)ccc(F)c1F
Agent: Oc1cccc2cccnc12
Agent: [Na+]
Solvent: CO
Solvent: O
Product: NC(=NO)c1c(C(F)(F)F)ccc(F)c1F
Product: NC(=O)c1c(C(F)(F)F)ccc(F)c1F
Temperature: 60 °C
Reaction time: 9 h

Procedure:
Into a 2 L four-neck flask were added 95.0 g (1.44 mol) of 50% hydroxylamine aqueous solution, 960 ml of pure water, 7.6 g (0.09 mol) of sodium hydrogencarbonate, 480 ml of methanol, 0.09 g of 8-hydroxyquinoline and 124.3 g (0.06 mol) of 2,3-difluoro-6- trifluoromethylbenzonitrile (I″) at room temperature. After gradually raising temperature, the resulting solution was heated with stirring at 60° C. for 9 hours. It was conformed with HPLC that (I″) (tR 16.0 min) disappeared, 2,3 difluoro-6-trifluoromethylbenzamidoxime (II′) was mainly produced (yield 80.3%, tR 3.6 min) and 2,3-difluoro-6-trifluoromethylbenzamide (III′) was produced as a byproduct (yield 4.5%, tR 4.8min). Then, at about 45° C., methanol-water (about 800 g) in the reaction solution was removed under reduced pressure. The residue was extracted with 1.2 L of methyl-t-butylether (MTBE). The organic layer was washed with 120 ml of water, and hydrochlorinated and extracted with 300 ml of 7% hydrochloric acid. Further the organic layer was twice hydrochlorinated and extracted with 150 ml of 7% hydrochloric acid. The aqueous layers from the extraction after hydrochlorination were combined, cooled down below 15° C., neutralized with 170 g of 28% sodium-hydroxide aqueous solution, and extracted again with 300 ml of MTBE. The aqueous layer was further extracted with 300 ml of MTBE. The organic layers were combined, washed with 120 ml of water, and concentrated under reduced pressure to give 114 g of target 2,3-difluoro-6-trifluoromethylbenzamidoxime (II′) (m.p. 114 to 115° C., yield 78% and purity 98.7%).
Reaction SMILES: [H-].[Na+].F[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[CH3:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][OH:22])[CH2:16][CH2:15]1>CN(C=O)C>[CH3:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][O:22][C:4]2[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=2)[CH2:16][CH2:15]1
Reactant: CC1CCN(CCO)CC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1CCN(CCOc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
200 mg (4.2 mmol) of sodium hydride (55%) is added at 0° C. to a solution of 0.54 g (3.83 mmol) of 1-fluoro-4-nitrobenzene and 0.6 g (4.2 mmol) of 2-(4-methylpiperidin-1-yl)ethanol in 10 mL of DMF under an argon atmosphere. The reaction mixture is stirred for 2 hours at 0° C. and then stirred for a further 1.5 hours at ambient temperature. The reaction mixture is evaporated down and the residue is extracted between water and ethyl acetate. The organic phase is dried, the desiccant is filtered off and the filtrate is evaporated down. The purification is carried out by column chromatography on silica gel (eluant: dichloromethane/methanol (9:1)). Yield: 700 mg (69% of theory); C14H20N2O3 (M=264.32); calc.: molecular ion peak (M+H)+: 265; found: molecular ion peak (M+H)+: 265; Rf value: 0.7 (silica gel, dichloromethane/methanol (9:1)).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[CH2:11]([O:13][C:14](=[O:23])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1)[CH3:12].C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[CH2:11]([O:13][C:14](=[O:23])[CH2:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][CH:1]=[O:3])=[CH:20][CH:21]=1)[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)Cc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=CO
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccc(NC=O)cc1
Temperature: 60 °C
Reaction time: 16 h
Yield: 93 %

Procedure:
A mixture of acetic anhydride (0.33 mL, 3.57 mmol) and formic acid (0.17 mL, 4.46 mmol) was heated at 60° C. for 2 hours. The reaction mixture was cooled to 0° C., a solution of (4-amino-phenyl)-acetic acid ethyl ester (Preparation 267, 500 mg, 2.79 mmol) in THF (10 mL) was added slowly to the reaction mixture and the reaction was allowed to stir at room temperature for 16 hours. The reaction mixture was neutralized with sat. aq. Na2CO3 solution and extracted with diethyl ether (2×25 mL). The combined organic layers were dried (Na2SO4) and evaporated in vacuo. The crude material was purified by column chromatography on silica gel (gradient of DCM:MeOH 100:0 to 98:2) to afford the title compound as an oil in 93% yield, 500 mg.
Reaction SMILES: [C:1]1([C:7]2([OH:15])[CH2:13][CH:12]3[NH:14][CH:9]([CH2:10][CH2:11]3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][O:17][C:18]1[C:23]2[O:24][C@H:25]([CH2:28]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:26][O:27][C:22]=2[CH:21]=[CH:20][CH:19]=1>>[CH3:16][O:17][C:18]1[C:23]2[O:24][C@@H:25]([CH2:28][N:14]3[CH:9]4[CH2:10][CH2:11][CH:12]3[CH2:13][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)([OH:15])[CH2:8]4)[CH2:26][O:27][C:22]=2[CH:21]=[CH:20][CH:19]=1
Reactant: COc1cccc2c1O[C@H](COS(=O)(=O)c1ccc(C)cc1)CO2
Reactant: OC1(c2ccccc2)CC2CCC(C1)N2
Product: COc1cccc2c1O[C@@H](CN1C3CCC1CC(O)(c1ccccc1)C3)CO2
Yield: 76 %

Procedure:
The title compound was prepared by the same procedure described in Example 1, Step 4 using 3-phenyl-8-azabicyclo[3.2.1]octan-3-ol in place of 3-naphthalen-2-yl-8-aza-bicyclo[3.2.1]octan-3-ol, and (S)-toluene-4-sulfonic acid 8-methoxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl ester in place of (S)-toluene-4-sulfonic acid 8-ethoxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl ester. Yield: 76%, white solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[C:3]1=[O:24].[CH2:25]([O:27][C:28](=[O:51])[C@H:29](OS(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O)[CH2:30][CH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[CH3:26].CN1CCOCC1>C(OCC)(=O)C.CCCCCC>[CH2:25]([O:27][C:28]([C@@H:29]([NH:1][C@@H:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]([CH3:21])([CH3:23])[CH3:22])=[CH:18][CH:19]=2)[C:3]1=[O:24])[CH2:30][CH2:31][CH:32]1[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]1)=[O:51])[CH3:26]
Reactant: CC(C)(C)c1ccc(CN2C(=O)C(N)CCc3ccccc32)cc1
Reactant: CCOC(=O)[C@@H](CCC1CCCCC1)OS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)[C@H](CCC1CCCCC1)N[C@@H]1CCc2ccccc2N(Cc2ccc(C(C)(C)C)cc2)C1=O

Procedure:
The reaction of 3.55 g of 3-amino-1-(p-tert-butylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one with 2.5 g of (R)-alpha-[[(4-nitrophenyl)sulfonyl]oxy]-4-cyclohexylbutyric acid ethyl ester and 1.03 ml of N-methylmorpholine yields the two diastereoisomeric esters 3-(S)-[(1-(S)-ethoxycarbonyl-3-cyclohexyl-propyl)-amino]-1-(p-tert-butylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one and 3-(R)-[(1-(S)-ethoxycarbonyl-3-cyclohexyl-propyl)-amino]-1-(p-tert-butylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one, Rf values (eluant ethyl acetate/hexane 1:2) non-polar component 0.42, polar component 0.26.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[N:11][C:12]1[CH:17]=[C:16]([C:18]([CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:20])[CH3:19])[CH:15]=[CH:14][C:13]=1[OH:26])([O-])=O.C1(C)C=CC=CC=1.CNC.[H][H]>[C].[Pd].O.CC(O)C>[OH:26][C:13]1[CH:14]=[CH:15][C:16]([C:18]([CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:20])[CH3:19])=[CH:17][C:12]=1[N:11]1[N:10]=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]2=[N:1]1
Reactant: CC(C)(C)CC(C)(C)c1ccc(O)c(N=Nc2ccccc2[N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Agent: CNC
Solvent: CC(C)O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)CC(C)(C)c1ccc(O)c(-n2nc3ccccc3n2)c1
Yield: 82.9 %

Procedure:
35.5 g (0.1 mol) of 2-nitro-2'-hydroxy-5'-t-octylazobenzene, 0.125 g of 5% palladium carbon, 100 ml of toluene, 100 ml of IPA, 50 ml of water and 7 g of 50% dimethylamine were charged into a 500-ml stainless autoclave with an agitator. Reaction was effected in the same way as that employed in Example 1 and stopped when no more hydrogen was absorbed by the reaction solution. After the reaction had been completed, after treatment was performed in the same way as in Example 1 to obtain 26.8 g of 2-(2'-hydroxy-5'-t-octylphenyl)benzotriazole (yield, 82.9%; melting point, 103° to 105° C.).
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10](Cl)(=[O:13])[CH2:11][CH3:12].Cl.[NH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([N:26]2[CH2:35][C:34]3[CH:33]=[N:32][N:31]([CH3:36])[C:30]=3[NH:29][C:28]3[CH:37]=[C:38]([Cl:41])[CH:39]=[CH:40][C:27]2=3)=[O:25])=[CH:20][C:19]=1[F:42].C1C(N=NC2C(=O)N(C3C=CC(S([O-])(=O)=O)=CC=3)N=C2C([O-])=O)=CC=C(S([O-])(=O)=O)C=1.[Na+].[Na+].[Na+]>ClCCl>[Cl:41][C:38]1[CH:39]=[CH:40][C:27]2[N:26]([C:24]([C:21]3[CH:22]=[CH:23][C:18]([CH2:17][NH:16][C:10](=[O:13])[CH2:11][CH3:12])=[C:19]([F:42])[CH:20]=3)=[O:25])[CH2:35][C:34]3[CH:33]=[N:32][N:31]([CH3:36])[C:30]=3[NH:29][C:28]=2[CH:37]=1
Reactant: Cn1ncc2c1Nc1cc(Cl)ccc1N(C(=O)c1ccc(CN)c(F)c1)C2
Reactant: CCC(=O)Cl
Agent: Cl
Agent: O=C([O-])C1=NN(c2ccc(S(=O)(=O)[O-])cc2)C(=O)C1N=Nc1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(=O)NCc1ccc(C(=O)N2Cc3cnn(C)c3Nc3cc(Cl)ccc32)cc1F
Reaction time: 2 h
Yield: 56 %

Procedure:
DIEA (0.27 ml, 1.56 mmol) and propionyl chloride (0.048 ml, 0.55 mmol) were added to a solution of (4-aminomethyl-3-fluoro-phenyl)-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone hydrochloride from Example E102.2 (220 mg, 0.52 mmol) in dichloromethane (6 ml) at room temperature. The mixture was stirred for 2 h, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloromethane) to give a white powder identified as the title compound (129 mg, 56%).
Reaction SMILES: [CH3:1][C@@:2]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH2:4][NH:3]1.[C:10](Cl)(=[O:12])[CH3:11].C(N(CC)C(C)C)(C)C>CN(C)C(=O)C>[C:10]([N:3]1[CH2:4][CH2:5][CH2:6][C@@:2]1([CH3:1])[C:7]([OH:9])=[O:8])(=[O:12])[CH3:11]
Reactant: CC(=O)Cl
Reactant: C[C@@]1(C(=O)O)CCCN1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCC[C@@]1(C)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.3 %

Procedure:
To a solution of (S)-2-methyl-pyrrolidine-2-carboxylic acid (50.0 mg, 0.387 mmol) dissolved in N,N-dimethylacetamide (1.5 mL, 16 mmol) was added a solution of acetyl chloride (31.9 mg, 0.406 mmol) dissolved in N,N-dimethylacetamide (0.5 mL), and then N,N-diisopropylethylamine (1 mL, 6 mmol) was added and the reaction mixture stirred at room temperature for 30 minutes. The reaction mixture was concentrated to produce the title compound as a light brown oil (30 mg, 40% yield). (m/z): [M+H]+ calcd for C8H13NO3 172.10 found 172.2.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:7][CH:8]=1)=[O:2].[CH2:21](O)[CH2:22][OH:23]>C1(C)C=CC=CC=1>[O:2]1[CH2:21][CH2:22][O:23][CH:1]1[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:6]=[CH:7][CH:8]=1
Reactant: OCCO
Reactant: CCOC(=O)C(=Cc1cccc(C=O)c1)C(=O)OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=Cc1cccc(C2OCCO2)c1)C(=O)OCC
Temperature: 25 °C

Procedure:
The solution of product 32 in toluene, from the previous reaction, is filtered, transferred to a round bottom flask, and ethylene glycol (2.4 eq) is added, followed by p-toulenesulfonic acid (0.5 eq). The reaction mixture is refluxed overnight with a Dean-Stark trap, then cooled down to room temperature, washed with sat. aq NaHCO3, brine, and dried (Na2SO4). Product 33 is not purified further but used as is in the following step.
Reaction SMILES: [CH2:1]([C:3]([CH3:10])([CH2:8][CH3:9])[C:4]([O:6]C)=O)[CH3:2].[C:11](#[N:13])[CH3:12].[H-].[Na+]>O1CCCC1>[C:11]([CH2:12][C:4]([C:3]([CH2:1][CH3:2])([CH3:10])[CH2:8][CH3:9])=[O:6])#[N:13]
Reactant: CCC(C)(CC)C(=O)OC
Reactant: CC#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(C)(CC)C(=O)CC#N

Procedure:
A 16.5 Kg portion of methyl 2-ethylbutyrate was reacted with 60 Kg of n-butyl lithium, diisopropylamine, and 19.1 Kg of methyl iodide to provide 17.4 Kg of methyl 2-ethyl-2-methylbutyrate. A 7.5 Kg portion of the ester thus formed was reacted with 3.25 Kg of acetonitrile and 5.03 g of sodium hydride in 33 liters of tetrahydrofuran to provide 1-ethyl-1-methylpropyl cyanomethyl ketone. The ketone thus formed was reacted with 4.35 Kg of hydroxylamine hydrochloride and 2.54 Kg of sodium hydroxide in 44 liters of water to provide 5.65 Kg of 5-amino-3-(1-ethyl-1-methylpropyl)isoxazole.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:3])[CH3:2].[Cl:22][C:23]1[CH:27]=[CH:26][S:25][C:24]=1[C:28]1[O:33]C(C)(C)[O:31][C:30](=O)[CH:29]=1>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:10][C:9]=1[NH:20][C:30](=[O:31])[CH2:29][C:28]([C:24]1[S:25][CH:26]=[CH:27][C:23]=1[Cl:22])=[O:33])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)cc1N
Reactant: CC1(C)OC(=O)C=C(c2sccc2Cl)O1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)cc1NC(=O)CC(=O)c1sccc1Cl
Yield: 77 %

Procedure:
Prepared from (3-amino-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G9) (100 mg, 0.35 mmol) and 6-(3-chloro-thiophen-2-yl)-2,2-dimethyl-[1,3]dioxin-4-one (Example J2) (95 mg, 0.39 mmol) according to the general procedure K. Obtained as a white solid (127 mg).
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C@H:9]1[C:14]([OH:16])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)Cl.O=S(Cl)Cl.[Cl-].[Al+3].[Cl-].[Cl-]>CN(C)C=O>[CH2:10]1[CH:9]2[N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=3[C:14]2=[O:16])[C:12](=[O:13])[CH2:11]1
Reactant: O=C(O)[C@@H]1CCC(=O)N1Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C1c2ccccc2CN2C(=O)CCC12
Reaction time: 8 h
Yield: 69.5 %

Procedure:
To a solution prepared from 11.68 g of (+)-N-benzylpyroglutamic acid (See E. Campaigne and D. P. Matthews, J. Het. Chem., 12, 391 (1975)), 100 ml of CH2Cl2 and a drop of dimethylformamide (DMF), 7.57 g of SOCl2 was added dropwise. The mixture was refluxed for five hours and allowed to stand overnight at ambient temperature. The reaction mixture was cooled in an ice-salt bath. Aluminum chloride (22.6 g) was added in portions with exclusion of moisture and vigorous stirring. The temperature did not exceed 10° C. during the addition. The mixture was stirred 1.5 hours and then ice was added gradually. The mixture was partitioned between water and CH2Cl2. The CH2Cl phase was washed with water, dried (Na2SO4), filtered and evaporated to give 10 g of a crude product. Recrystallization from toluene gave 7.45 g of crystals, m.p. 103°-105° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12](NC3C=CC=CC=3)=[N:11][C:10]=2[C:21]([OH:23])=O)=[CH:5][CH:4]=1.O.O[N:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2N=N1.Cl.C[N:37](C)CCCN=C=NCC.N.O1CCOCC1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:13][C:12]([NH:26][C:30]3[CH:29]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[N:11][C:10]=2[C:21]([NH2:37])=[O:23])=[CH:7][CH:8]=1
Reactant: On1nnc2ccccc21
Reactant: CCN=C=NCCCN(C)C
Reactant: COc1ccc(-c2oc(Nc3ccccc3)nc2C(=O)O)cc1
Agent: Cl
Agent: N
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(-c2oc(Nc3ccccc3)nc2C(N)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.5 %

Procedure:
To a stirred solution of 5-(4-methoxyphenyl)-2-(phenylamino)oxazole-4-carboxylic acid (0.012 g, 0.039 mmol), 1-hydroxybenzotriazole hydrate (0.009 g, 0.059 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.011 g, 0.057 mmol) in DMF (5 mL) was added a 0.5M ammonia in dioxane solution (0.116 mL, 0.058 mmol) and the resulting mixture stirred at room temperature overnight. The solvent was removed in vacuo and the residue purified by preparative HPLC to afford 5-(4-methoxyphenyl)-2-(phenylamino)oxazole-4-carboxamide (0.0045 g, 0.015 mmol, 38%). 1H NMR (DMSO) δ 3.82 (3H, s), 6.98 (1H, t), 7.04 (2H, d), 7.33 (2H, t), 7.51 (1H, br, s), 7.60 (1H, br, s), 7.73 (2H, d), 8.16 (2H, d), 10.40 (1H, s). LCMS (2) Rt: 2.67 min; m/z (ES+) 310.
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:7][S:8](Cl)(=[O:10])=[O:9].C(N(CC)CC)C>C(Cl)Cl>[CH:1]1([O:6][S:8]([CH3:7])(=[O:10])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)Cl
Reactant: OC1CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CCCC1
Reaction time: 1.5 h

Procedure:
To a stirred solution of cyclopentanol (Aldrich, 2.58 g, 30 mmol) in methylene chloride (150 mL) at 0° C., Methane sulfonyl chloride (2.55 mL, 33 mmol) and triethyl amine (5.23 mL, 37.5 mmol) were added slowly and the mixture was stirred for 1.5 hrs. The reaction was quenched with water and the mixture was washed with 0.5 N HCl and brine solution. The organic layer was dried with sodium sulfate. Removal of solvent gave a colorless oil. 5.1 g.
Reaction SMILES: S(Cl)([Cl:3])=O.C(OC([NH:12][C@@H:13]([CH2:17][C:18]([F:21])([F:20])[CH3:19])[C:14]([OH:16])=[O:15])=O)(C)(C)C.[CH3:22]O>>[ClH:3].[NH2:12][C@@H:13]([CH2:17][C:18]([F:21])([F:20])[CH3:19])[C:14]([O:16][CH3:22])=[O:15]
Reactant: O=S(Cl)Cl
Reactant: CO
Reactant: CC(F)(F)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: COC(=O)[C@@H](N)CC(C)(F)F
Product: Cl
Temperature: 35 °C
Reaction time: 0.5 h

Procedure:
At approx. 5° C. (ice bath cooling), 8.2 ml of thionyl chloride (112.6 mmol; 1.5 eq.) were added dropwise to 100 ml of methanol (p.a.) under argon. The mixture was allowed to come to RT within 30 min and stirred for a further 30 min. 19.0 g of (S)-2-tert-butoxycarbonylamino-4,4-difluoropentanoic acid (75.0 mmol) were added in portions to this reaction mixture. The reaction mixture was stirred at RT for 2 h. Thereafter, the reaction mixture was warmed to 35° C. (internal temperature) and stirred at this temperature for another 3 h. Subsequently, the mixture was concentrated under reduced pressure, which afforded methyl (S)-2-amino-4,4-difluoropentanoate hydrochloride as a slightly brownish crystalline solid which was clean enough for further reactions. Yield: 13.5 g (89% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=O.Cl[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=1.ClC1C=C(Cl)C=CC=1C1[C:36]([C:37]2[NH:38][CH:39]=[CH:40][N:41]=2)=[CH:35][N:34]=[C:33]([NH:42][CH2:43][CH2:44][NH:45]C2C=CC([N+]([O-])=O)=CN=2)[N:32]=1>>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]1[C:36]([C:37]2[NH:38][CH:39]=[CH:40][N:41]=2)=[CH:35][N:34]=[C:33]([NH:42][CH2:43][CH2:44][NH:45][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=2)[N:32]=1
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Reactant: O=[N+]([O-])c1ccc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Product: Fc1ccc(-c2nc(NCCNc3ccc(C(F)(F)F)cn3)ncc2-c2ncc[nH]2)c(Cl)c1

Procedure:
[4-(2-chloro-4-fluorophenyl)-5-imidazol-2-ylpyrimidin-2-yl](2-{[5-(trifluoromethyl)(2-pyridyl)]amino}ethyl)amine was prepared from 2-chloro-4-fluorobenzoyl chloride and 2-chloro-5-(trifluoromethyl)pyridine using the general method for [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(5-nitro(2-pyridyl))amino]-ethyl}amine.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH:10]([CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].C(I)C.O.[O:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:13][CH:25]([CH2:24][CH3:23])[C:26](=[O:22])[C:10]([CH2:11][CH3:12])([CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: CC1CN(Cc2ccccc2)CCC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CCI
Solvent: O
Solvent: CCOC(C)=O
Product: CCC1CN(Cc2ccccc2)CC(C)(CC)C1=O
Reaction time: 1 h

Procedure:
1-Benzyl-3-methyl-piperidin-4-one (50 g, 246 mmole) was added to the stirred suspension of sodium hydride (12.0 g, 300.0 mmole) in tetrahydrofuran (500 ml) at ambient temperature and stirring was continued for 1 hr. Ethyl iodide (42.5 ml, 520.0 mmole) in dry tetrahydrofuran (100 ml) was added it at 0-5° C. The resulting mixture stirred at room temperature for 18 hr, water (100 ml) and ethyl acetate (800 ml) were added respectively. Organic layer was separated, dried (Na2SO4) and concentrated to give crude product, which was purified through column chromatography. Elute from 5% ethyl acetate in hexane afforded 1-benzyl-3,5-diethyl-3-methylpiperidin-4-one. Yield 12.0 g (19%), C17H25NO, m/z 260 (M+1).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([O:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH2:7][N:6]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=O.[BH4-].[Na+].CO>O1CCCC1>[C:18]([O:17][C:15]([N:6]1[CH2:7][C@H:8]([O:10][S:11]([CH3:14])(=[O:12])=[O:13])[CH2:9][C@H:5]1[CH2:3][OH:2])=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: COC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CO
Temperature: 60 °C
Reaction time: 0.42 h
Yield: 80.5 %

Procedure:
To a solution of (2S,4R)-1-t-butoxycarbonyl-4-methanesulfonyloxypyrrolidine-2-carboxylic acid methyl ester (8.11 g) in tetrahydrofuran (49 ml) stirring under ice cooling, sodium borohydride (2.36 g) and methanol (20 ml) are added. The mixture is stirred at room temperature for 25 minutes and at 60° C. for 25 minutes. The mixture is cooled with ice and filtered. The filtrate is concentrated, diluted with ethyl acetate, washed with water, dried over sodium sulfate, and concentrated in vacuo. The residue is recrystallized from petroleum ether-ether to give (2S,4R)-1-t-butoxycarbonyl-4-methanesulfonyloxypyrrolidine-2-methanol (5.96 g). Colorless crystals. Yield: 80%. mp. 95° to 96° C. NMR δ(CDCl3) ppm: 1.48(s, 9H), 1.78 to 2.02(m, 1H), 2.3 to 2.48(m, 1H), 3.05(s, 3H), 3.5 to 3.65(m, 2H), 3.65 to 4.0(m, 2H), 4.03 to 4.25(m, 1H), 5.2(s, 1H). IR ν (CHCl3) cm-1 : 3460, 1680.