Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[Cl:17][C:18]1[CH:31]=[CH:30][C:21]([CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]2)=[CH:20][C:19]=1[O:32][CH2:33][CH3:34]>CN(C=O)C>[Cl:17][C:18]1[CH:31]=[CH:30][C:21]([CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([NH:29][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:25][CH2:24]2)=[CH:20][C:19]=1[O:32][CH2:33][CH3:34]
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1Cl
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOc1cc(CN2CCC(NC(=O)c3ccccc3)CC2)ccc1Cl
Yield: 59 %

Procedure:
Benzoyl chloride (17 mg, 0.11 mmol), Et3N (20 μL, 0.15 mmol) and 1-(4-chloro-3-ethoxy-benzyl)piperidin-4-ylamine (27 mg, 0.1 mmol) were shaken in DMF (0.5 ml) for 16 h, after which time the solvent was evaporated and the residue purified by reversed phase HPLC (MeCN:H2O) affording the title compound (22 mg, 60%). MS: 373.4 (MH+)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=2)[N:3]=1.N1(C2C=C[C:24]([CH:25]=[O:26])=CC=2)C=CC=N1>>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[CH:24][CH:25]=[O:26])=[CH:10][CH:9]=2)[N:3]=1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Reactant: Cc1ccnc(-c2ccc(C=O)cc2)n1
Product: Cc1ccnc(-c2ccc(C=CC=O)cc2)n1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-(4-methyl-2-pyrimidinyl)benzaldehyde (prepared as described in Reference Example 14) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 225 (M+H)+.
Reaction SMILES: [NH:1]([C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[C@H:2]([C:6]([NH:8][C@H:9]([C:18](OC)=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14](O)=[CH:13][CH:12]=1)=[O:7])C(C)C.[NH:32](C(OCC1C=CC=CC=1)=O)[C@H:33]([C:37]([NH:39][C@H](C(OC)=O)CCCCNC(OC(C)(C)C)=O)=[O:38])[CH:34](C)C.N(C(OCC1C=CC=CC=1)=O)[C@H:68](C(N[C@H](C(N[C@@H](C(OC)=O)C)=O)CC1C=CC=CC=1)=O)C.N[C@H](C(O)=O)CC1C=CC(O)=CC=1.N[C@H](C(O)=O)CCCCNC(OC(C)(C)C)=O.N[C@@H](C(O)=O)C>>[NH:1]([C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[C@H:2]([C:6]([NH:8][C@H:9]([C:18]([NH:32][C@@H:33]([C:37]([NH2:39])=[O:38])[CH3:34])=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:7])[CH3:68]
Reactant: COC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Reactant: COC(=O)[C@@H](C)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)NC(=O)OCc1ccccc1
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Agent: CC(C)(C)OC(=O)NCCCC[C@H](N)C(=O)O
Agent: C[C@@H](N)C(=O)O
Agent: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@H](C)C(N)=O

Procedure:
With the exception of Z-Val-Tyr-OMe, Z-Val-Lys(Boc)-OMe and Z-Ala-Phe-D-Ala-OMe, all substrate peptides were quantitatively converted into products, i.e. the corresponding amide peptide and free carboxylic acid peptide, in 4 h reaction time. At longer reaction times also the methyl ester peptides ending with Tyr and Lys(Boc) were totally converted. Surprisingly, the methyl ester of the tripeptide with a C-terminal D-Ala residue was also converted. The HPLC analysis at 75 h reaction time showed conversion of 54 ala % of substrate to yield about 36 a/a % of the product Z-Ala-Phe-D-Ala-NH2.
Reaction SMILES: [Br:1][CH:2]1[C:6]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13]([Cl:18])[CH:12]=2)([C:7]([F:10])([F:9])[F:8])[O:5][N:4]=[C:3]1[C:19]1[CH:31]=[CH:30][C:22]([C:23]([NH:25][CH:26]2[CH2:29][S:28][CH2:27]2)=[O:24])=[C:21]([CH3:32])[CH:20]=1.C(=O)([O-])[OH:34].[Na+].ClC1C=C(C=CC=1)C(OO)=O>ClCCl.O>[Br:1][CH:2]1[C:6]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13]([Cl:18])[CH:12]=2)([C:7]([F:8])([F:9])[F:10])[O:5][N:4]=[C:3]1[C:19]1[CH:31]=[CH:30][C:22]([C:23]([NH:25][CH:26]2[CH2:29][S:28](=[O:34])[CH2:27]2)=[O:24])=[C:21]([CH3:32])[CH:20]=1
Reactant: O=C([O-])O
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2Br)ccc1C(=O)NC1CSC1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2Br)ccc1C(=O)NC1CS(=O)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-[4-bromo-5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N-thietan-3-yl-benzamide (145 mg) (Example A22) in dichloromethane (8 ml) was added a solution of sodium hydrogen carbonate (128 mg) in water (4 ml). A solution of 3-chloroperoxybenzoic acid (“MCPBA”) (48 mg) in dichloromethane (1 ml) was added dropwise. The reaction mixture was stirred at ambient temperature for 4 hours. Dichloromethane was evaporated and the residue partitioned between aqueous sodium carbonate (1M) and ethyl acetate. The phases were separated and the aqueous phase extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated. The residue was purified by preparative HPLC to give Compound No. A25 of Table A (101 mg) and Compound No. A26 of Table A (17 mg) as colorless solids.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH:12]=[CH:11][S:10]/[C:9]/1=[N:13]\[C:14]([C:16]12[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]3)[CH2:17]1)[CH2:23]2)=[O:15])(=O)=O.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(Cl)Cl>[N:26]1([CH2:6][CH2:7][N:8]2[CH:12]=[CH:11][S:10]/[C:9]/2=[N:13]\[C:14]([C:16]23[CH2:23][CH:22]4[CH2:21][CH:20]([CH2:19][CH:18]([CH2:24]4)[CH2:17]2)[CH2:25]3)=[O:15])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: C1COCCN1
Reactant: CS(=O)(=O)OCCn1ccs/c1=N\C(=O)C12CC3CC(CC(C3)C1)C2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: O=C(/N=c1\sccn1CCN1CCOCC1)C12CC3CC(CC(C3)C1)C2
Reaction time: 16 h
Yield: 28 %

Procedure:
To a solution of Example 79A (0.22 g, 0.57 mmol) in 3 mL of acetonitrile was added morpholine (50 μL, 0.63 mmol), potassium iodide (0.11 g, 0.63 mmol), and potassium carbonate (0.17 g, 1.3 mmol). The mixture stirred for 16 hours and then diluted with methylene chloride and was washed with water, saturated aqueous potassium carbonate and brine. The organic phase was dried over anhydrous potassium carbonate, filtered and concentrated tinder reduced pressure. Purification by preparative HPLC afforded 60 mg (28%) of the title compound. 1H NMR (CDCl3, 400 MHz) δ ppm 1.69-1.79 (m, 6 H), 1.96 (d, J=2.8 Hz, 6 H), 2.03 (s, 3 H), 2.48-2.58 (m, 4 H), 2.75 (t, J=6.3 Hz, 2 H), 3.64-3.72 (m, 4 H), 4.28 (t, J=6.3 Hz, 2 H), 6.55 (d, J=4.6 Hz, 1 H), 6.99 (d, J=4.6 Hz, 1 H); MS (DCI/NH3) m/z 376 (M+H)+. Anal. Calculated for C20H29N3O2S: C, 63.97; H, 7.78; N, 11.19. Found: C, 63.85; H, 7.42; N, 10.91.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[N:9]=[CH:8][NH:7][C:6]2=O.S(Cl)([Cl:19])=O>CN(C=O)C>[ClH:19].[Cl:19][C:6]1[C:5]2[C:10](=[CH:11][C:12]([N+:13]([O-:15])=[O:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc2c(=O)[nH]cnc2cc1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)ncnc2cc1[N+](=O)[O-]
Product: Cl
Yield: 75 %

Procedure:
A suspension of 6-methoxy-7-nitro-3,4-dihydroquinazolin-4-one (8 g, 36 mmol) in thionyl chloride (150 ml) and DMF (0.8 ml) was heated at reflux for 3 hours. Excess thionyl chloride was removed by evaporation and the residue azeotroped with toluene. The resulting solid was triturated with ether, collected by filtration and dried under vacuum to give 4-chloro-6-methoxy-7-nitroquinazoline hydrochloride(7.5 g, 75%).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=2)[NH:12][CH:11]=[CH:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19]([N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C:27]1=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C[O-].[Na+]>CO>[C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=2)[NH:12][CH:11]=[C:10]3[C:29]2[CH2:30][CH2:31][N:26]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:27][CH:28]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC(=O)c1cc(-c2ccccc2)cc2cc[nH]c12
Reactant: O=C1CCCCN1Cc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1cc(-c2ccccc2)cc2c(C3=CCN(Cc4ccccc4)CC3)c[nH]c12
Temperature: 80 °C
Yield: 54.4 %

Procedure:
To the solution of 5-phenyl-1H-indole-7-carboxamide (3.11 g, 12 mmol) in methanol (100 mL) was added benzyl piperidone (7.4 g, 36 mmol), followed by 156 mL of NaOMe (0.5 M in MeOH). The reaction mixture was then heated at 80° C. overnight. The solution was cooled to ambient temperature and the solvent removed under reduced pressure, and the resulting residue redisolved in a bilayer of ethyl acetate and 5% sodium hydroxide solution. The organic phase washed with brine, dried over potassium carbonate, and the solvent removed under reduced pressure. The residue was purified by silica gel chromatography (CH2Cl2:MeOH:NH4OH=96:3:1) to provide the desired product (2.66 g, 51%).
Reaction SMILES: [CH2:1]([O:8]C1C(OC)=CC(C(Cl)=O)=CC=1OC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:22]CCN1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].C1(S(O)(=O)=O)C=CC=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:1]([NH2:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCN1CCOCC1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)c1ccccc1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: NC(=O)c1ccccc1

Procedure:
First, 4-benzyloxy-3,5-dimethoxybenzoic acid chloride represented by Formula 85 (61.30 mg, 0.200 mmol) prepared in Preparative Example 1 and 4-(2-aminoethyl)morpholine represented by Formula 99 (31.22 mg, 0.240 mmol) were prepared in 0.2 M solution, respectively, using a toluene solvent. After adding 1M sodium carbonate solution and 0.2 M acyl chloride solution to the above solutions, the mixture was vigorously shaken and agitated at room temperature overnight. After terminating the reaction, an aqueous layer was discarded using a tip while an organic layer was moved to a cartridge tube (6 mL, benzenesulfonic acid, 904030-WJ, UCT) using ethyl acetate. Impurities were removed using methanol (15 mL), while separation and purification using an elute solution (ethyl acetate/methanol/triethylamine, 20:2:1, v/v/v) was conducted to produce a benzamide compound represented by Formula 7 as a desired product (VVZ-006; 79.10 mg, 98.8% yield).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:16]([CH2:21][P:22]([CH:27]([NH:31]C(OCC2C=CC=CC=2)=O)[CH:28]([CH3:30])[CH3:29])([O:24][CH2:25][CH3:26])=[O:23])[C:17]([O:19][CH3:20])=[O:18])[CH:13]=[CH:14][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[CH3:20][O:19][C:17](=[O:18])[CH:16]([C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH:11]=1)[CH2:21][P:22]([CH:27]([NH2:31])[CH:28]([CH3:29])[CH3:30])([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOP(=O)(CC(C(=O)OC)c1cccc(CNC(=O)OC(C)(C)C)c1)C(NC(=O)OCc1ccccc1)C(C)C
Agent: [Pd]
Solvent: CO
Product: CCOP(=O)(CC(C(=O)OC)c1cccc(CNC(=O)OC(C)(C)C)c1)C(N)C(C)C
Reaction time: 2.5 h
Yield: 86.7 %

Procedure:
To a solution of 2-(3-(t-butoxycarbonylamino)methylphenyl)-3-((1-(benzyloxycarbonyl)amino-2-methylpropyl)(ethoxy)phosphinoyl)propanoic acid, methyl ester (10.6 g, 18.0 mmol) in 200 mL methanol was added Pd/C (10%) (2.1 g). The reaction mixture was hydrogenated in H2 (50 psi) for 2 to 3 hours. The catalyst was filtered over a celite pad. The solvent was removed in vacuo to afford 2-(3-(t-butoxycarbonylamino)methylphenyl)-3-((1-amino-2-methylpropyl)(ethoxy)-phosphinoyl)propanoic acid methyl ester (7.1 g, 15.6 mmol, 87%) as white solid, NMR (DMSO-d6) 0.80-0.91 (m, 6), 1.05-1.18 (m, 3), 1.37 (s, 9), 1.46 (m, 1), 1.90 (m, 1), 2.00-2.90 (m, 1), 2.56-2.64 (m, 1), 3.56 (s, 3), 3.70-3.95 (m, 3), 4.08 (d, 2), 7.10-7.20 (3, m), 7.24 (m, 1), 7.38 (t, 1) ppm.
Reaction SMILES: C(N(CC)[CH2:4][CH2:5][C:6](=[O:18])[CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1)C.C(NCC)C>>[CH3:17][O:16][C:12]1[CH:11]=[C:10]([CH2:9][CH2:8][CH2:7][C:6](=[O:18])[CH:5]=[CH2:4])[CH:15]=[CH:14][CH:13]=1.[CH:11]([C:12]([CH:13]=[CH2:14])=[O:16])=[CH2:10]
Reactant: CCN(CC)CCC(=O)CCCc1cccc(OC)c1
Solvent: CCNCC
Product: C=CC(=O)C=C
Product: C=CC(=O)CCCc1cccc(OC)c1

Procedure:
Referring now to FIG. 1, wherein the compounds are assigned Roman numerals for identification schematically, the sequence of reactions involved in the synthesis of a specific embodiment, namely, 13β,17α-diethyl-17β-hydroxygon-4-en-3-one, is illustrated. 3-(m-Methoxyphenyl)propanol (I) is heated with phosphorus tribromide in benzene after dropwise addition in the cold to form 3-(m-methoxyphenyl)propyl bromide (II). This halogen compound (II) dissolved in tetrahydrofuran is condensed with sodium acetylide in liquid ammonia to obtain 5-(m-methoxyphenyl)-1-pentyne (III). Compound III is allowed to stand under nitrogen with water, 30% formalin, acetic acid, diethylamine, dioxan, and cuprous chloride at 70° C for about 12 hours, whereby there is obtained 1-diethylamino-6-(m-methoxyphenyl)-2-hexyne (IV), which is in turn hydrated in the presence of a mercury salt and sulfuric acid to form 1-diethylamino-6-(m-methoxyphenyl)-3-hexanone (V). The ketamine (V) may eliminate diethylamine on distillation to give the vinyl ketone 6-(m-methoxyphenyl)-1-hexen-3-one (VI). Either the ketamine (V) or the ketone (VI), or mixtures thereof, is then reacted with 2-ethyl-1,3-cyclopentanedione (VII) under Michael condensation conditions, e.g. refluxing in methanolic potassium hydroxide to form 2-ethyl-2-[6-(m-methoxyphenyl)-3-oxohexyl]-1,3-cyclopentanedione (VIII).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19](=O)[CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1.O.[NH2:29][NH2:30]>C(O)C>[C:12]1([N:5]2[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]3[NH:29][N:30]=[C:19]([CH2:20][C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[C:3]=3[C:4]2=[O:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cc1cccnc1)c1c(O)c2cccnc2n(-c2ccccc2)c1=O
Reactant: NN
Solvent: O
Solvent: CCO
Product: O=c1c2c(Cc3cccnc3)n[nH]c2c2cccnc2n1-c1ccccc1
Yield: 76 %

Procedure:
The procedure of Example 1 was repeated using a suspension of 4-hydroxy-3-[1-oxo-2-(pyridin-3-yl)ethyl]-1-phenyl-1,8-naphthyridin-2 (1H)-one (16 mg, 0.045 mmol, prepared in Synthetic Example 3) in ethanol (5 ml), and hydrazine monohydrate (80%, 10 μl, 0.25 mmol, 5.5 eq.) to obtain 5-phenyl-3-(pyridin-3-yl)methyl-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4 (5H)-one (yield: 76%).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[C:6]2[S:11][CH:10]=[CH:9][C:7]=2[N:8]=1.[Br:16]Br>C(O)(=O)C>[Br:16][C:9]1[C:7]2[N:8]=[C:3]([S:2][CH3:1])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[C:6]=2[S:11][CH:10]=1
Reactant: BrBr
Reactant: CCCn1c(SC)nc2ccsc2c1=O
Solvent: CC(=O)O
Product: CCCn1c(SC)nc2c(Br)csc2c1=O

Procedure:
The method of claim 14 wherein 7-bromo-2-(methylthio)-3-propylthieno[3,2-d]pyrimidin-4(3H)-one is prepared by treating 2-(methylthio)-3-propylthieno[3,2-d]pyrimidin-4(3H)-one with bromine in acetic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH:12]=[CH:13][C:14]([NH2:16])=[O:15].[Cl:17][CH2:18][C:19]([CH2:21]Cl)=O>C1(C)C=CC=CC=1>[Cl:17][CH2:18][C:19]1[N:16]=[C:14]([CH:13]=[CH:12][C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]=2[F:1])[O:15][CH:21]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=O)C=Cc1ccc(C(F)(F)F)cc1F
Solvent: Cc1ccccc1
Product: Fc1cc(C(F)(F)F)ccc1C=Cc1nc(CCl)co1
Temperature: 25 °C
Yield: 23 %

Procedure:
4.00 g (17.1 mmol) 3-(2-Fluoro-4-trifluoromethyl-phenyl)-acrylamide, 2.60 g (21.3 mmol) 1,3-dichloroacetone and 40 ml toluene were kept at reflux temperature for 16 h with continuous removal of water by use of a Dean-Stark trap. After cooling to room temperature, two extractions with 100 ml water, the organic phase was dried over sodium sulphate and the solvent removed in vacuo. Chromatography on silica gel (eluent: n-heptane/ethyl acetate 5:1) gave 1.20 g (23%) 4-chloromethyl-2-[2-(2-fluoro-4-trifluoromethyl-phenyl)-vinyl]-oxazole.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:34])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][OH:21])[CH:19]=[C:15]3[N:14]=[C:13]([CH3:22])[C:12]=2[C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[CH2:35]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1O)[CH:36]=[CH2:37].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.CCOCC>[CH2:1]([O:4][C:5]1([CH3:34])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][O:21][C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=4[CH2:35][CH:36]=[CH2:37])[CH:19]=[C:15]3[N:14]=[C:13]([CH3:22])[C:12]=2[C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCc1ccccc1O
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(CO)nn23)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(COc4ccccc4CC=C)nn23)CC1
Temperature: 25 °C
Yield: 19.7 %

Procedure:
To a stirred solution of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(hydroxymethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.190 g, 0.320 mmol), 2-allylphenol (0.084 ml, 0.641 mmol) and Ph3P (0.126 g, 0.480 mmol) in THF (5 mL) was added DEAD (0.101 ml, 0.641 mmol) at 0° C. The reaction was slowly warming to rt over 3 h and after 1 h at rt, diluted with Et2O (50 mL), washed with water (2×10 mL), brine (10 mL), dried (MgSO4), filtered, concentrated and the resulting yellow residue purified by flash chromatography using 10 and 20% EtOAc/Hex to afford (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-((2-allylphenoxy)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.0374 g, 0.063 mmol, 19.77% yield) as colorless paste. 1H NMR (500 MHz, CDCl3) δ 7.17-7.23 (m, 2H), 7.08 (d, J=7.9 Hz, 1H), 6.94 (t, J=7.4 Hz, 1H), 6.63 (s, 1H), 6.00-6.10 (m, 2H), 5.88-5.98 (m, 1H), 5.44-5.55 (m, 1H), 5.31 (s, 2H), 5.22 (dd, J=1.3, 10.4 Hz, 1H), 4.15-4.27 (m, 2H), 4.00-4.06 (m, 2H), 3.47 (d, J=6.5 Hz, 2H), 2.62 (s, 3H), 1.88-2.06 (m, 3H), 1.68-1.77 (m, 2H), 1.37 (br. s., 3H), 1.21-1.28 (m, 12H). LCMS (M+H)=591.6.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[C:4]([F:11])[CH:3]=1.[N:12]([Si](C)(C)C)=[N+:13]=[N-:14].C1(C)C=CC=CC=1>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9](=[O:10])[NH:14][N:13]=[N:12]2)=[C:4]([F:11])[CH:3]=1
Reactant: O=C=Nc1ccc(Cl)cc1F
Reactant: C[Si](C)(C)N=[N+]=[N-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=c1[nH]nnn1-c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred solution of 17.1 g (0.10 mole) of 4-chloro-2-fluorophenyl isocyanate and 20.0 g (0.17 mole) of azidotrimethylsilane was heated under reflux for 16 hours. The reaction mixture was cooled to ambient temperature and 60 ml of toluene and 100 ml of water were added. The mixture was allowed to stand for two hours and the resultant solid collected by filtration. The filter cake was washed with petroleum ether to yield 14.5 g of 1-(4-chloro-2-fluorophenyl-1,4-dihydro-5H-tetrazol-5-one; m.p. 185°-187° C. The reaction was repeated several times.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[Cl:42][C:43]1[C:44]([F:54])=[CH:45][C:46]([F:53])=[C:47]([S:49](Cl)(=[O:51])=[O:50])[CH:48]=1>C(#N)C>[F:53][C:46]1[CH:45]=[C:44]([F:54])[C:43]([Cl:42])=[CH:48][C:47]=1[S:49]([O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34])(=[O:51])=[O:50]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: O=S(=O)(Cl)c1cc(Cl)c(F)cc1F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)c3cc(Cl)c(F)cc3F)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 28.4 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0283 g, 0.0613 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0540 mL, 0.390 mmol) and 5-chloro-2,4-difluorobenzenesulfonyl chloride (0.0482 g, 0.195 mmol) to obtain 4-(2,4-difluoro-5-chlorobenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0117 g, yield 28%).
Reaction SMILES: [NH2:1][NH2:2].[CH2:3]1[CH:10]2[C:6]3([C:12]4[O:13][C:14](=O)[C:15]5[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=5[N:17]=4)[CH2:7][CH:8]([CH2:11][CH:4]1[CH2:5]3)[CH2:9]2>C1(C)C=CC=CC=1>[NH2:1][N:2]1[C:14](=[O:13])[C:15]2[C:16](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:17]=[C:12]1[C:6]12[CH2:7][CH:8]3[CH2:11][CH:4]([CH2:3][CH:10]1[CH2:9]3)[CH2:5]2
Reactant: O=c1oc(C23CC4CC(CC2C4)C3)nc2ccccc12
Reactant: NN
Solvent: Cc1ccccc1
Product: Nn1c(C23CC4CC(CC2C4)C3)nc2ccccc2c1=O
Temperature: 22.5 °C
Reaction time: 10 h
Yield: 99.9 %

Procedure:
Anhydrous hydrazine (0.30 mL, 9.56 mmol) was added to a solution of the product of Example 2A (0.79 g, 2.81 mmol) in toluene (10 mL). The solution was stirred at 20-25° C. for 10 hours, then diluted with toluene (15 mL) and heated at reflux under a Dean-Stark trap for 33 hours. The solution was cooled to room temperature and concentrated under vacuum to leave a white solid residue. The residue was purified by flash chromatography (silica gel, eluted with hexanes-EtOAc 70:30-50:50) to provide the title compound as a white solid (0.79 g, 72% yield). 1H NMR (300 MHz, CDCl3) δ ppm 1.64-1.78 (m, 4H), 2.05 (dd, J=10.5, 2.7 Hz, 2H), 2.08-2.18 (m, 2H), 2.40 (br s, 2H), 2.45-2.55 (m, 2H), 2.96 (t, J=6.6 Hz, 1H), 4.73 (s, 2H), 7.44 (ddd, J=8.1, 6.4, 1.7 Hz, 1H), 7.66-7.77 (m, 2H), 8.24 (ddd, J=8.0, 1.4, 0.7 Hz, 1H); MS (DCI) m/z 282 (M+H)+.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C(=O)N([Br:39])C(=O)C1>CN(C=O)C>[Br:39][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: C=CCCCCCCCCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=CCCCCCCCCCBr
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82.3 %

Procedure:
To a solution of undec-10-en-1-ol (0.86 g, 5.0 mmol) in DMF (15 mL) was added triphenylphosphine (1.46 g, 5.6 mmol). The solution was cooled to 0° C. and NBS (0.96 g, 5.4 mmol) was added in portions. After stirring for 30 min at room temperature, the reaction was quenched with methanol (0.5 mL). The solution was diluted with ether (80 mL), washed with water, saturated aqueous NaHCO3 and brine successively. The organic layer was dried and concentrated. The residue was purified by flash chromatography on silica gel, eluting with hexane to afford 11-bromo-undec-1-ene (0.96 g, 82%) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 5.79 (1H, m), 4.93 (2H, m), 3.38 (2H, t, J=6.9 Hz), 2.02 (2H, m), 1.83 (2H, m), 1.20–1.55 (12H, m); 13C NMR (75 MHz, CDCl3) δ 139.36, 114.33, 34.27, 33.99, 33.01, 29.57×2, 29.27, 29.09, 28.94, 28.35.