Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][NH:4][C:5]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][N:11]=[C:10]2O)=[O:6].C(N(CC)CC)C.P(Cl)(Cl)([Cl:27])=O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][CH2:3][NH:4][C:5]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][N:11]=[C:10]2[Cl:27])=[O:6]
Reactant: COCNC(=O)c1ccc2ncnc(O)c2c1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COCNC(=O)c1ccc2ncnc(Cl)c2c1
Temperature: 130 °C
Reaction time: 0.5 h

Procedure:
4-Hydroxyquinazoline-6-carboxylic acid methoxymethylamide (XIII-1, 2.9 g) was suspended in toluene (57 ml), and 6.8 ml of triethylamine and 3.4 ml of phosphorus oxychloride were added, followed by stirring at 130° C. for 30 minutes. After completion of the reaction, the reaction mixture was cooled to room temperature, and 50 ml of aqueous saturated sodium bicarbonate solution and ethyl acetate were added. Sodium bicarbonate was added until the aqueous layer exhibited a pH 8, followed by extraction with ethyl acetate. The organic layer was washed with aqueous saturated sodium bicarbonate solution, dried over sodium sulfate. After concentration, the crystalline residue was washed with diethyl ether, and dried to obtain 4-chloroquinazoline-6-carboxylic acid methoxymethylamide (XIV-1, 2.3 g) as a white solid.
Reaction SMILES: C(OC(N1CCC[C@@H]1C(O)=O)=O)(C)(C)C.[Cl:16][C:17]1[CH:18]=[C:19]([CH:34]=[CH:35][C:36]=1[Cl:37])[C:20]([C@H:22]1[CH2:26][CH2:25][CH2:24][N:23]1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=O.BrC1C=CC(Cl)=C(Cl)C=1.CB1N2CCC[C@@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1.[C:68]1(=[O:78])[C:76]2[C:71](=[CH:72][CH:73]=[CH:74][CH:75]=2)[C:70](=[O:77])[NH:69]1>>[Cl:16][C:17]1[CH:18]=[C:19]([C@H:20]([N:69]2[C:70](=[O:77])[C:71]3[C:76](=[CH:75][CH:74]=[CH:73][CH:72]=3)[C:68]2=[O:78])[C@H:22]2[CH2:26][CH2:25][CH2:24][N:23]2[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:34]=[CH:35][C:36]=1[Cl:37]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)c1ccc(Cl)c(Cl)c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Agent: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Agent: Clc1ccc(Br)cc1Cl
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1[C@H](c1ccc(Cl)c(Cl)c1)N1C(=O)c2ccccc2C1=O

Procedure:
(R)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid and be converted to (R)-tert-butyl 2-(3,4-dichlorobenzoyl)-pyrrolidine-1-carboxylate in accord with steps 1 and 2 of example 11, except in step 2,4-bromo-1-(trifluoromethyl)benzene was replaced with 1-bromo-3,4-dichlorobenzene. Reduction of the ketone with (R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole and condensation with isoindoline-1,3 dione can be carried out in accord with procedures in steps 4 and 5 of example 11 to afford (R)-tert-butyl 2-((S)-(3,4-dichlorophenyl)(1,3-dioxoisoindolin-2-yl)methyl)pyrrolidine-1-carboxylate (242).
Reaction SMILES: O[CH2:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.S(Cl)([Cl:19])=O>C(Cl)(Cl)Cl>[Cl:19][CH2:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(c1ccc(CO)cc1)N1CCCCC1
Solvent: ClC(Cl)Cl
Product: O=C(c1ccc(CCl)cc1)N1CCCCC1
Reaction time: 8 h
Yield: 92 %

Procedure:
The alcohol (6.97 mmol) of the preceding paragraph was dissolved in 15 mL CHCl3, followed by the addition of 0.66 mL thionyl chloride. The solution was refluxed for 1 hour and then allowed to stand at room temperature overnight. The volume was then reduced by 50% on a rotary evaporator and the solution was diluted with CCl4 and petroleum ether to induce crystallization. The product 1-(4'-chloromethylbenzoyl)piperidine was isolated in 92% yield and had a melting point of 106°-108° C.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][OH:11].[CH2:16](O)[CH2:17][O:18]CCOCCO>>[Br:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:16][CH2:17][OH:18]
Reactant: OCCOCCOCCO
Reactant: OCCOCCOCc1ccccc1Br
Product: OCCOCCOCCOCc1ccccc1Br

Procedure:
The compound was prepared and worked up as described in the preparation of compound 415, using triethylenglycol (16.0 mL, 120 mmol) instead of diethylenglycol. The crude product was purified by flash chromatography using DCM/acetone 6:1–3:1 as the eluent to afford the title compound as a pale yellow oil.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH:9]=O)=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1.[NH2:12][C@@H:13]([CH3:16])[CH2:14][OH:15]>>[Cl:11][C:6]1[C:7]2[CH:8]=[CH:9][N:12]([C@@H:13]([CH3:16])[CH2:14][OH:15])[C:2]=2[N:3]=[CH:4][N:5]=1
Reactant: C[C@H](N)CO
Reactant: O=CCc1c(Cl)ncnc1Cl
Product: C[C@@H](CO)n1ccc2c(Cl)ncnc21

Procedure:
The title compound was prepared according to the method described for Preparation 1 using (4,6-dichloropyrimidin-5-yl)acetaldehyde and (S)-2-amino-1-propanol to afford the title compound as a cream solid in 98% yield, 10.9 g.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](OS(C(F)(F)F)(=O)=O)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:24])[CH:11]=2)[CH:6]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.B(O)(O)[C:46]1[CH:51]=[CH:50][C:49]([S:52]([NH:55][CH:56]2[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]2)(=[O:54])=[O:53])=[CH:48][CH:47]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:46]2[CH:47]=[CH:48][C:49]([S:52](=[O:53])(=[O:54])[NH:55][CH:56]3[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]3)=[CH:50][CH:51]=2)[C:8]2[C:7](=[CH:12][CH:11]=[C:10]([Cl:24])[CH:9]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(OS(=O)(=O)C(F)(F)F)c1C
Reactant: O=S(=O)(NC1CCCCC1)c1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(S(=O)(=O)NC3CCCCC3)cc2)c1C
Temperature: 25 °C
Yield: 49.4 %

Procedure:
A stirred solution of (6-chloro-3-methyl-4-trifluoromethanesulfonyloxy-naphthalen-2-yl)-acetic acid methyl ester (0.10 g, 0.25 mmol) in dimethoxyethane (5 mL) was purged with argon for 5 minutes at room temperature. Triphenylphosphine (0.015 g, 0.055 mmol), palladium (II) acetate (0.006 g, 0.027 mmol), 4-N-cyclohexylsulfamoylphenylboronic acid (0.096 g, 0.33 mmol) and a 2 M aqueous solution of sodium carbonate (0.6 mL, 1.2 mmol) were added simultaneously to the reaction mixture at room temperature under argon. The reaction mixture was refluxed for 2 hours and then cooled to room temperature. Water was added and the mixture was extracted twice with ethyl acetate. The collected organic extracts were washed with water and then brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product, which was finally purified using flash chromatography (Biotage, 5-10% ethyl acetate-hexane) to afford [6-chloro-4-(4-cyclohexylsulfamoyl-phenyl)-3-methyl-naphthalen-2-yl]-acetic acid methyl ester (0.06 g, 50%) as a solid. MS calcd. for C26H27ClNO4S [(M−H)−] 484, obsd. 484.4.
Reaction SMILES: C([O:5][C:6](=[O:34])[CH2:7][C@H:8]([NH:11][S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH2:22][CH2:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[N:26][CH:25]=1)(=[O:14])=[O:13])[CH:9]=[O:10])(C)(C)C.ClCCl.[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41].O>C1(C)C=CC=CC=1>[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41].[CH:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:24]([CH2:23][CH2:22][O:21][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[S:12]([NH:11][CH:8]([CH:9]=[O:10])[CH2:7][C:6]([OH:34])=[O:5])(=[O:13])=[O:14])=[CH:25][N:26]=1
Reactant: CC(C)(C)OC(=O)C[C@@H](C=O)NS(=O)(=O)c1ccccc1OCCc1cncc2ccccc12
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: O=CC(CC(=O)O)NS(=O)(=O)c1ccccc1OCCc1cncc2ccccc12
Reaction time: 2 h

Procedure:
To (S)-3-[2-(2-isoquinolin-4-yl-ethoxy)-benzenesulfonylamino]-4-oxo-butyric acid tert-butyl ester was added 3:1 dichloromethane/trifluoroacetic acid (20 mL) and water (200 μL). After 2 h at room temperature, toluene (20 ml) was added and the solvent was removed under reduced pressure to give 3-[2-(2-isoquinolin-4-yl-ethoxy)-benzenesulfonylamino]-4-oxo-butyric acid trifluoro-acetate salt as a colorless foam (36 mg). MS (APCI) m/z 429.1 (M+1).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][CH:6](O)[CH2:7][O:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH3:16])[CH:10]=1>C1(C)C=CC=CC=1>[CH3:16][C:11]1[CH:10]=[C:9]([CH:14]=[C:13]([CH3:15])[CH:12]=1)[O:8][CH2:7][CH:6]([Cl:3])[CH3:5]
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(C)cc(OCC(C)O)c1
Solvent: Cc1ccccc1
Product: Cc1cc(C)cc(OCC(C)Cl)c1
Yield: 92.8 %

Procedure:
3.3 Milliliter (45 mmol) of thionyl chloride was added dropwise to a solution prepared by dissolving 7.38 g (41 mmol) of 1-methyl-2-(3,5-dimethylphenoxy)ethanol in 20 ml of toluene, and the resultant mixture was refluxed in an oil bath at 100° to 110° C. for 4 hours. The reaction solution was cooled, and then washed consecutively with 50 ml of a saturated sodium hydrogencarbonate aqueous solution and 50 ml of a saturated common salt water. The resultant organic layer was dried over 10 g of anhydrous sodium sulfate, and toluene was removed under reduced pressure to give 7.56 g of oily 1-(3,5-dimethylphenoxy)-2-chloropropane (yield 92.9%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[F:16][C:17]1[CH:29]=[CH:28][C:20]([CH2:21][N:22]2[CH:26]=[CH:25][C:24]([NH2:27])=[N:23]2)=[CH:19][CH:18]=1>>[F:16][C:17]1[CH:29]=[CH:28][C:20]([CH2:21][N:22]2[CH:26]=[CH:25][C:24]([NH:27][C:2]3[CH:3]=[CH:4][C:5]([N:10]4[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]4)=[C:6]([CH:9]=3)[C:7]#[N:8])=[N:23]2)=[CH:19][CH:18]=1
Reactant: Cc1cn(-c2ccc(Br)cc2C#N)cn1
Reactant: Nc1ccn(Cc2ccc(F)cc2)n1
Product: Cc1cn(-c2ccc(Nc3ccn(Cc4ccc(F)cc4)n3)cc2C#N)cn1

Procedure:
Prepared in analogy to example 1b) starting with 5-bromo-2-(4-methyl-imidazol-1-yl)-benzonitrile and 1-(4-fluoro-benzyl)-1H-pyrazol-3-ylamine. The title compound was obtained as a yellowish oil (Yield=75%). MS ISP (m/e): 373.2 (100) [(M+H)+].
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([C:10]2[N:15]=[N:14][C:13]([N:16]([CH3:27])[CH:17]3[CH2:22][C:21]([CH3:24])([CH3:23])[NH:20][C:19]([CH3:26])([CH3:25])[CH2:18]3)=[CH:12][CH:11]=2)=[C:4]([F:28])[CH:3]=1.BrC1C=C(C2C(OC)=CC=CC=2F)N=N[C:31]=1[N:45](C)[CH:46]1CC(C)(C)[NH:49][C:48](C)(C)[CH2:47]1.BrC1C=C(F)C(C2N=NC(N(C)C3CC(C)(C)NC(C)(C)C3)=CC=2)=C(O)C=1.CC1(C)C(C)(C)OB(C2C=NN(C(OC(C)(C)C)=O)C=2)O1>>[F:28][C:4]1[CH:3]=[CH:2][CH:7]=[C:6]([O:8][CH3:9])[C:5]=1[C:10]1[N:15]=[N:14][C:13]([N:16]([CH3:27])[CH:17]2[CH2:22][C:21]([CH3:24])([CH3:23])[NH:20][C:19]([CH3:25])([CH3:26])[CH2:18]2)=[C:12]([C:47]2[CH:48]=[N:49][N:45]([CH3:31])[CH:46]=2)[CH:11]=1
Reactant: COc1cccc(F)c1-c1cc(Br)c(N(C)C2CC(C)(C)NC(C)(C)C2)nn1
Reactant: COc1cc(Br)cc(F)c1-c1ccc(N(C)C2CC(C)(C)NC(C)(C)C2)nn1
Agent: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: CN(c1ccc(-c2c(O)cc(Br)cc2F)nn1)C1CC(C)(C)NC(C)(C)C1
Product: COc1cccc(F)c1-c1cc(-c2cnn(C)c2)c(N(C)C2CC(C)(C)NC(C)(C)C2)nn1

Procedure:
Following GENERAL METHOD 1-6 for Suzuki cross-coupling, a mixture of 6-(4-bromo-2-fluoro-6-methoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine, 4-bromo-6-(2-fluoro-6-methoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine (Intermediate 8-1, Step 2, 0.10 g, 0.22 mmol, total amount of the 2 regioisomers) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (0.14 g, 0.67 mmol) were reacted. The crude product was purified by column chromatography using silica gel and a gradient elution of 1-15% 7 N ammonia in MeOH, in CH2Cl2. An inseparable mixture of the desired product (6-(2-fluoro-6-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6 tetramethylpiperidin-4-yl)pyridazin-3-amine) and 6-(2-fluoro-6-methoxyphenyl)-N-methyl-4-(1-methyl-1H-pyrazol-4-yl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine was afforded as a colorless solid (80 mg, 80%). [M+H]: 453.4.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.[CH3:11][Si](C=[N+]=[N-])(C)C.CCOCC>C1C=CC=CC=1.CO>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1
Reactant: Nc1ccc(C(=O)O)nc1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCOCC
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)c1ccc(N)cn1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
5-Amino-pyridine-2-carboxylic acid 1 (5.4 mmol) is dissolved in benzene:MeOH 3:1 (40 mL) and cooled in an ice-bath to 0° C. To the solution is slowly added 2M TMSCH2N2 in Et2O solution (6.5 mmol). After the addition is complete, the reaction mixture is warmed to it and stirred for 6 h. After removing the solvent in vacuum, methyl 5-aminopicolinate 2 is obtained and used in the next step without further purification. MS (m/z) (M+1)+: 153.1.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:37][C:38]1[CH:43]=[C:42]([F:44])[C:41]([F:45])=[CH:40][C:39]=1[F:46])[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:18]([C:33]([F:36])([F:35])[F:34])=[N:19][C:20]([C:21]([N:23]3[CH2:28][CH2:27][N:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:25][CH2:24]3)=[O:22])=[C:14]2[CH2:13]1)=[O:11])(C)(C)C.[ClH:48]>C(OCC)(=O)C>[ClH:48].[NH2:7][C@H:8]([CH2:37][C:38]1[CH:43]=[C:42]([F:44])[C:41]([F:45])=[CH:40][C:39]=1[F:46])[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:18]([C:33]([F:36])([F:34])[F:35])=[N:19][C:20]([C:21]([N:23]3[CH2:28][CH2:27][N:26]([S:29]([CH3:32])(=[O:30])=[O:31])[CH2:25][CH2:24]3)=[O:22])=[C:14]2[CH2:13]1)=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)N3CCN(S(C)(=O)=O)CC3)c2C1)Cc1cc(F)c(F)cc1F
Agent: Cl
Solvent: CCOC(C)=O
Product: CS(=O)(=O)N1CCN(C(=O)c2nc(C(F)(F)F)n3c2CN(C(=O)C[C@H](N)Cc2cc(F)c(F)cc2F)CC3)CC1
Yield: 99 %

Procedure:
(R)-[3-[1-(4-Methanesulfonyl-piperazine-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 22a (0.19 g, 0.27 mmol) and 2 mL of ethyl acetate were added into the reaction flask. A solution of 2.7 N hydrochloric acid in 4 mL of ethyl acetate was then added to the flask. The reaction mixture was reacted at room temperature for 3 hours and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure to obtain the title compound (R)-3-amino-1-[1-(4-methanesulfonyl-piperazine-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-4-(2,4,5-trifluoro-phenyl)-butan-1-one hydrochloride 22 (170 mg, yield 99%) as a white solid.
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:17]=[C:16]([C:18]([NH2:20])=[O:19])[O:15][N:14]=2)=[CH:9][CH:8]=1)(C)(C)C.C([O-])([O-])=O.[K+].[K+].C1OCCOCCOCCOCCOCCOC1.[F-].[K+].[Cl:49][C:50]1[CH:51]=[C:52]([CH:55]=[CH:56][CH:57]=1)[CH2:53]Cl>CN(C=O)C.O>[Cl:49][C:50]1[CH:51]=[C:52]([CH:55]=[CH:56][CH:57]=1)[CH2:53][O:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:17]=[C:16]([C:18]([NH2:20])=[O:19])[O:15][N:14]=2)=[CH:11][CH:12]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2cc(C(N)=O)on2)cc1
Reactant: ClCc1cccc(Cl)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [F-]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1cc(-c2ccc(OCc3cccc(Cl)c3)cc2)no1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 76.8 %

Procedure:
3-[4-(tert-Butyl-dimethyl-silanyloxy)-phenyl]-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 13; 40 mg, 0.126 mmol) was dissolved in DMF (1.5 mL). K2CO3 (19 mg, 0.14 mmol), 18-crown-6 (6 mg, 0.02 mmol), KF (8 mg, 0.14 mmol), and 3-chlorobenzyl chloride (20 μL, 0.129 mmol) were added. The reaction mixture was stirred at room temperature for 10 min and then at 40° C. for 12 h. H2O (2.5 mL) was added and the mixture was extracted with EtOAc. The organic layer was evaporated to give 3-[4-(3-chloro-benzyloxy)-phenyl]-isoxazole-5-carboxylic acid amide (31.8 mg, 77%) as an off-white powder. HRMS Calcd. for C17H13ClN2O3 (M+), 328.0615. Found: 328.0612.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[N:19]([CH3:20])[N:18]=[C:17]([O:21][CH2:22][CH2:23][OH:24])[C:16]=2[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:35]1[N:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][N:36]=1>C1COCC1.CC(N(C)C)=O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:15]2[N:19]([CH3:20])[N:18]=[C:17]([O:21][CH2:22][CH2:23][O:24][C:35]3[N:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][N:36]=3)[C:16]=2[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1cnc(Cl)nc1
Reactant: Cc1ccc(-c2c(OCCO)nn(C)c2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: Cc1ccc(-c2c(OCCOc3ncc([N+](=O)[O-])cn3)nn(C)c2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 146.5 %

Procedure:
To a solution of 4-(tert-butyl)-N-[3-(2-hydroxyethoxy)-1-methyl-4-(4-methylphenyl)-1H-pyrazol-5-yl]-benzenesulphonamide (Example 2) (1838 mg) in anhydrous THF (18 ml) at 0° C. stirred under an atmosphere of nitrogen was added sodium hydride (60% dispersion in oil, 348 mg) A precipitate began to form which was stirred at 0° C. for 15 min. 2-Chloro-5-nitropyrimidine (Wempen, I.; Blank, H. U.; Fox, J. J. J. Heterocyclic Chem. 1969, 6, 593. Hurst, D. T.; Heterocycles 1984, 22, 79; Heterocycles, 1977, 6, 1999-2004.) (661 mg) in anhydrous DMA (3 ml) was added dropwise and the solution was allowed to warm to room temperature. The reaction was quenched after 130 min by cautiously pouring the mixture onto a vigorously stirred mixture of ethyl acetate (300 ml) and saturated ammonium chloride solution (300 ml). The ethyl acetate layer was separated off, dried (MgSO4) and evaporated to dryness. This afforded a yellow residue (3.44 g) which was purified by column chromatography on silica gel (256 g), eluting with a gradient of ethyl acetate:hexane (4:5 to 5:4).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8](=[O:25])[NH:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(OCC)(=O)C.C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8](=[O:25])[N:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1n[nH]c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCCc1nn(-c2ccccc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 57 %

Procedure:
A mixture of 4′-[(3-butyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl]biphenyl-2-carbonitrile (1.80 g), phenylboronic acid (1.98 g), molecular sieves 4 A (0.90 g), triethylamine (3.8 mL), pyridine (1.8 mL), copper(II) acetate (1.97 g) and methylene chloride (120 mL) was stirred at room temperature for 24 hr. Ethyl acetate was added to the reaction mixture, and the insoluble solid was filtered off. The solvent of the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (1.26 g, 57%).
Reaction SMILES: C([Li])CCC.[CH3:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9].[C:13]1([CH:19]2[CH2:22][CH:21]([C:23](OC)=[O:24])[CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(O)(=O)C>CCCCCC.O1CCCC1>[O:24]=[C:23]([CH:21]1[CH2:22][CH:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:20]1)[CH2:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9]
Reactant: COP(C)(=O)OC
Reactant: COC(=O)C1CC(c2ccccc2)C1
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COP(=O)(CC(=O)C1CC(c2ccccc2)C1)OC
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
n-Butyl-lithium (16.0ml. of a 1.43M solution in hexane) was added dropwise to a stirred solution of dimethyl methylphosphonate (2.86g.) in dry tetrahydrofuran (25ml.) at -78° C. in an atmosphere of argon. After 10 minutes, a solution of the methyl 3-phenylcyclobutanecarboxylate mixture (2.18g.) in dry tetrahydrofuran (25ml.) was added, and stirred at -78° C. for 2 hours. The reaction mixture was then neutralized by the addition of glacial acetic acid, warmed to room temperature and the tetrahydrofuran was evaporated under reduced pressure. The residue was partitioned between ethyl acetate and water. The ethyl acetate extract was dried over magnesium sulphate and evaporated under reduced pressure, to give dimethyl 2-oxo-2-(3-phenylcyclobutyl)-ethylphosphonate, as a mixture of cis and trans isomers. The n.m.r. spectrum in deuteriochloroform showed the following characteristic features (δ values):-
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13](=[O:40])[N:14]([CH2:26][C:27]([NH:29][CH:30]([CH:37]([CH3:39])[CH3:38])[C:31](=[O:36])[C:32]([F:35])([F:34])[F:33])=[O:28])[CH:15]=[C:16]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([OH:25])[CH:20]=2)[CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1([CH2:47][C:48](Cl)=[O:49])C=CC=CC=1>>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13](=[O:40])[N:14]([CH2:26][C:27]([NH:29][CH:30]([CH:37]([CH3:38])[CH3:39])[C:31](=[O:36])[C:32]([F:35])([F:34])[F:33])=[O:28])[CH:15]=[C:16]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:48](=[O:49])[CH3:47])[CH:20]=2)[CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C(NC(=O)Cn1cc(Cc2cccc(O)c2)cc(NC(=O)OCc2ccccc2)c1=O)C(=O)C(F)(F)F
Reactant: O=C(Cl)Cc1ccccc1
Product: CC(=O)Oc1cccc(Cc2cc(NC(=O)OCc3ccccc3)c(=O)n(CC(=O)NC(C(=O)C(F)(F)F)C(C)C)c2)c1

Procedure:
2-[3-Benzyloxycarbonylamino-5-(3-hydroxybenzyl)-2-oxo-1,2-dihydro-1-pyridyl]-N-(3,3,3-trifluoro-1-isopropyl-2-oxopropyl)acetamide was acylated using conditions similar to those described in Example 14.b., substituting acetic anhydride for phenylacetyl chloride, to give the title compound; NMR: 2.25 (s,3 and m,1), 6.95-7.41 (m,10); MS: m/z=602(M+1).
Reaction SMILES: [N:1]([C@H:4]([CH2:20][O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C@H:5]1[O:10][CH:8]([OH:9])[C@H:7]([OH:11])[C@H:6]1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[N+:2]=[N-:3].[CH3:29]O>C(Cl)Cl>[N:1]([C@H:4]([CH2:20][O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C@H:5]1[O:10][CH:8]([O:9][CH3:29])[C@H:7]([OH:11])[C@H:6]1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=N[C@H](COCc1ccccc1)[C@H]1OC(O)[C@H](O)[C@H]1OCc1ccccc1
Reactant: CO
Solvent: ClCCl
Product: COC1O[C@H]([C@@H](COCc2ccccc2)N=[N+]=[N-])[C@H](OCc2ccccc2)[C@H]1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 85 %

Procedure:
To a solution of 5-azido-3,6-di-O-benzyl-5-deoxy-D-glucofuranose (10.23 g, 26.5 mmol) in methylene chloride (170 ml) was added methanol (11 ml) and borontrifluoroetherate (1.5 ml). The mixture was stirred 24 h at room temperature. The reaction mixture was successively washed with a saturated aqueous solution of sodium bicarbonate and then with brine. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. Flash chromatography on silica gel and elution with a 1:1 mixture of hexane and ethyl acetate afforded methyl 5-azido-3,6-di-O-benzyl-5-deoxy-D-glucofuranoside as a colorless oil (9.15 g, 85%).