Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[C:6]([CH:17]=O)[C:7]3[C:12]([C:13]=2[CH:15]=O)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[CH3:19][N:20]([CH3:25])[CH2:21][CH2:22][NH:23][NH2:24]>C(O)(=O)C.C(O)C>[CH3:19][N:20]([CH3:25])[CH2:21][CH2:22][NH:23][N:24]=[CH:15][C:13]1[C:14]2[C:5]([C:6]([CH:17]=[N:24][NH:23][CH2:22][CH2:21][N:20]([CH3:25])[CH3:19])=[C:7]3[C:12]=1[CH:11]=[CH:10][CH:9]=[CH:8]3)=[CH:4][CH:3]=[CH:2][CH:1]=2
Reactant: O=Cc1c2ccccc2c(C=O)c2ccccc12
Reactant: CN(C)CCNN
Solvent: CC(=O)O
Solvent: CCO
Product: CN(C)CCNN=Cc1c2ccccc2c(C=NNCCN(C)C)c2ccccc12
Temperature: 45 °C

Procedure:
A suspension of 4.68 g. of anthracene-9,10-dicarboxaldehyde in 100 ml. of ethanol containing 4.13 g. of [2-(dimethylamino)ethyl]hydrazine [Elslager et al., J. Med. Chem. I, 493 (1964)] containing two drops of acetic acid is stirred and heated under reflux for two hours. The resulting solution is filtered, concentrated, allowed to cool to 45° C., diluted with petroleum ether, then allowed to cool further at 5° C. The desired product separates as an orange solid and is collected by filtration.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[N:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2/[CH:18]=[CH:19]/[C:20]([O:22][CH3:23])=[O:21])[CH:6]=[CH:7][CH:8]=1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[CH:31]=[CH:32][CH:33]=1>>[CH3:26][O:27][C:28]1[CH:29]=[C:30]([N:34]2[CH2:39][CH2:38][N:37]([C:10]3[N:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:24])([F:1])[F:25])[CH:4]=4)[CH:18]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:13]4[CH:14]=[N:15][CH:16]=[CH:17][C:12]=4[N:11]=3)[CH2:36][CH2:35]2)[CH:31]=[CH:32][CH:33]=1
Reactant: COC(=O)/C=C/c1cnccc1N=C=Nc1cccc(C(F)(F)F)c1
Reactant: COc1cccc(N2CCNCC2)c1
Product: COC(=O)CC1c2cnccc2N=C(N2CCN(c3cccc(OC)c3)CC2)N1c1cccc(C(F)(F)F)c1

Procedure:
Starting from 107 mg (0.31 mmol) of the carbodiimide from Example 15A and 59 mg (0.31 mmol) of 3-methoxyphenylpiperazine, general procedure [C] and purification by preparative HPLC result in 40 mg (23% of theory) of product.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][O:7][C:8](=[O:34])/[CH:9]=[CH:10]/[C:11]1[CH:12]=[C:13]2[C:30](=[CH:31][CH:32]=1)[O:29][C:16]1([CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]1)[CH2:15][C:14]2=[O:33]>C(Cl)Cl>[CH3:6][O:7][C:8](=[O:34])/[CH:9]=[CH:10]/[C:11]1[CH:12]=[C:13]2[C:30](=[CH:31][CH:32]=1)[O:29][C:16]1([CH2:17][CH2:18][N:19]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:20][CH2:21]1)[CH2:15][C:14]2=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Solvent: ClCCl
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(S(C)(=O)=O)CC1)O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
TEA (0.185 ml, 1.33 mmol) and methanesulfonyl chloride (0.067 ml, 0.88 mmol) were added to a suspension of (E)-3-{4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester hydrochloride (150 mg, 0.44 mmol, Intermediate 1) in DCM (3 ml), and the mixture was stirred at RT overnight. The solvent was removed under vacuum and the residue was purified by column chromatography (eluent: DCM/MeOH 97:3) to give (E)-3-{1′-methanesulfonyl-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (162 mg).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][O:10][CH2:11][C@@H:12]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O.O>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][O:10][CH2:11][C@@H:12]2[CH2:16][CH2:15][NH:14][CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](COCCCc2ccccc2)C1
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(CCCOC[C@@H]2CCNC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.4 %

Procedure:
To a solution of tert-butyl 3(R)-[(3-phenylpropoxy)methyl]pyrrolidine-1-carboxylate (600 mg, 1.88 mmol) in CH2Cl2 (15 mL) was added a mixture of CF3COOH (4.62 g, 40.5 mmol, 21.6 equiv.) and water (0.3 mL) at 0° C. under N2. The solution was stirred overnight at room temperature. After concentration in vacuo, water was added, and the solution was washed with hexane. The water phase was basified with saturated aqueous NaHCO3 solution and extracted with EtOAc. The combined organic phases were dried and concentrated to obtain the product (220 mg, 53%) as a yellow oil. LC-MS (ESI) m/z 220 (M+H+).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Mg].[CH3:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH:16]=[O:17]>C1COCC1>[CH3:12][C:13]1[CH:14]=[C:15]([CH:16]([OH:17])[CH2:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: BrCCCc1ccccc1
Reactant: COc1ccc(C=O)cc1C
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1ccc(C(O)CCCc2ccccc2)cc1C
Temperature: 25 °C
Yield: 58.7 %

Procedure:
3-Phenyl-1-1-propyl magnesium bromide was prepared from the reaction of 3-phenyl-1-bromopropane (8.0 mL. 52.6 mmol) and magnesium turnings (1.40 g, 57.6 mmol) in THF. This solution was added dropwise to an ice-water cooled solution of 3-methyl-para-anisaldehyde (7.70 mL. 52.6 mmol) in THF. The resulting reaction was allowed to warm to room temperature, and after 1h was partitioned between aqueous ammonium chloride and ether. The organic phase was dried over magnesium sulfate, concentrated, and purified by chromatography over silica gel eluted with 15% ethyl acetate in hexanes to afford 8.35 g of 2-methyl-4-(1-hydroxy-4-phenyl-1-butyl) anisole as a clear oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[Na+].[Br:12][C:13]1[C:14]([O:32][CH3:33])=[C:15]([C:21]([CH2:24]SC2C=CC=CC=2)=[CH:22][CH:23]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17].C(=O)(O)[O-].[Na+]>CC(N(C)C)=O.O>[Br:12][C:13]1[C:14]([O:32][CH3:33])=[C:15]([C:21]([CH2:24][S:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])=[CH:22][CH:23]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: O=S([O-])c1ccc(F)cc1
Reactant: CCOC(=O)c1c(CSc2ccccc2)ccc(Br)c1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1c(CS(=O)(=O)c2ccc(F)cc2)ccc(Br)c1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.8 %

Procedure:
Sodium 4-fluorobenzenesulphinate (0.517 g) was added to a suspension of ethyl 3-bromo-6-bromomethyl-2-methoxybenzoate (Intermediate 87, 0.4 g) and sodium bicarbonate (0.24 g) in dimethylacetamide (8 ml) and water (2 ml) and the mixture was stirred at room temperature for 3 hours. The resultant mixture was diluted with water and loaded onto a C-18 SPE column. The column was flushed with water then eluted with DCM and ethyl acetate. The organic eluent was dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of t-butyl methyl ether and cyclohexane with a gradient of 0-60% to give ethyl 3-bromo-6-(4-fluorobenzenesulphonyl-methyl)-2-methoxybenzoate (0.37 g) as a colourless gum.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.CN(C)C=O.F[C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=1[N+:27]([O-:29])=[O:28]>O>[N+:27]([C:18]1[CH:19]=[C:20]([C:23]([F:24])([F:25])[F:26])[CH:21]=[CH:22][C:17]=1[N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1)([O-:29])=[O:28]
Reactant: c1ccc2c(c1)CCNC2
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1N1CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 99.9 %

Procedure:
1,2,3,4-tetrahydroisoquinoline (909 μl, 7.26 mmol, commercially available product) was added at 0° C. to an N,N-dimethylformamide (DMF; 4 ml) solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (506 g, 2.42 mmol, commercially available product). The resulting mixture was warmed to room temperature and stirred for 3.5 hours. Water was added to the mixture, and the resulting mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30 g, hexane/ethyl acetate=10/1). Thus, 1,2,3,4-tetrahydro-2-[2-nitro-4-(trifluoromethyl)phenyl]isoquinoline (779 mg, 99.9%) was yielded as an orange-colored solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:8][CH2:9][NH2:10])[CH:4]=[C:5]([CH3:7])[N:6]=1.[Cl:11][C:12]1[CH:13]=[C:14]([CH2:18][CH2:19][CH:20]=O)[CH:15]=[CH:16][CH:17]=1>>[Cl:11][C:12]1[CH:13]=[C:14]([CH2:18][CH2:19][CH:20]2[NH:10][CH2:9][CH2:8][N:3]3[C:2]([CH3:1])=[N:6][C:5]([CH3:7])=[C:4]23)[CH:15]=[CH:16][CH:17]=1
Reactant: O=CCCc1cccc(Cl)c1
Reactant: Cc1cn(CCN)c(C)n1
Product: Cc1nc(C)n2c1C(CCc1cccc(Cl)c1)NCC2

Procedure:
Prepared according to the previously described general procedure (GP11) by reaction of 2-(2,4-dimethyl-imidazol-1-yl)-ethylamine with 3-(3-chloro-phenyl)-propionaldehyde. LC-MS: tR=0.59 min.; [M+H]+=290 g/mol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18]C)=[CH:4][C:3]=1[NH:20][C:21](=[O:23])[CH3:22].B(Br)(Br)Br.Cl.O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[OH:18])=[CH:4][C:3]=1[NH:20][C:21](=[O:23])[CH3:22]
Reactant: COc1ccccc1Oc1cc(NC(C)=O)c(F)cc1[N+](=O)[O-]
Agent: BrB(Br)Br
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CC(=O)Nc1cc(Oc2ccccc2O)c([N+](=O)[O-])cc1F
Reaction time: 2 h
Yield: 62 %

Procedure:
First, 5.4 g of N-[2-fluoro-5-(2-methoxyphenoxy)-4-nitrophenyl]acetamide was dissolved in 50 ml of methylene chloride, to which 4.7 g of boron tribromide was added under ice cooling. After stirring at the same temperature for 2 hours, concentrated hydrochloric acid was added, and the mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, and then concentrated. The resulting crystals were washed with t-butyl methyl ether to give 3.2 g of N-[2-fluoro-5-(2-hydroxyphenoxy)-4-nitrophenyl]acetamide.
Reaction SMILES: N1C[CH:3]([CH2:5][N:6]2[CH:10]=[C:9]([C:11]3[C:19]4[C:14](=[CH:15][C:16]([F:20])=[CH:17][CH:18]=4)[NH:13][CH:12]=3)[CH:8]=[N:7]2)C1.CN(C([O:28]N1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CC[N:47]([CH2:50]C)CC.CN>C1COCC1.O>[F:20][C:16]1[CH:15]=[C:14]2[C:19]([C:11]([C:9]3[CH:8]=[N:7][N:6]([CH2:5][C:3]([NH:47][CH3:50])=[O:28])[CH:10]=3)=[CH:12][NH:13]2)=[CH:18][CH:17]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCN(CC)CC
Reactant: Fc1ccc2c(-c3cnn(CC4CNC4)c3)c[nH]c2c1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)Cn1cc(-c2c[nH]c3cc(F)ccc23)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.3 %

Procedure:
To a solution of 2-(4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)acetic acid (Example 6; 120 mg; 0.46 mmol) in THF (25 mL) was added HATU (350 mg; 0.92 mmol) and Et3N (279 mg; 2.76 mmol) under nitrogen. The reaction mixture was stirred for 10 minutes before methylamine (0.5 mL; 1.0 mmol; 2 M in THF) was added dropwise. The reaction mixture was stirred at r.t. overnight, diluted with water (20 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were concentrated, and purified by preparative TLC (EtOAc) to afford 33 mg (26%) of the title product as a white solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:5][C:6]1[S:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[C:17](=[C:18]([C:20]([NH2:22])=[O:21])[CH:19]=2)[NH:16][CH:15]=[C:14]3[CH:23]2[CH2:28][CH2:27][N:26]([S:29]([CH2:32][CH3:33])(=[O:31])=[O:30])[CH2:25][CH2:24]2)[CH:7]=1)[CH3:4])[CH3:2].[CH2:34](C1CCCN1)CC>>[CH2:32]([S:29]([N:26]1[CH2:27][CH2:28][CH:23]([C:14]2[C:13]3[C:17](=[C:18]([C:20]([NH2:22])=[O:21])[CH:19]=[C:11]([C:8]4[CH:7]=[C:6]([CH2:5][N:3]([CH3:4])[CH2:1][CH2:2][CH3:34])[S:10][CH:9]=4)[CH:12]=3)[NH:16][CH:15]=2)[CH2:24][CH2:25]1)(=[O:30])=[O:31])[CH3:33]
Reactant: CCCC1CCCN1
Reactant: CCN(C)Cc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cs1
Product: CCCN(C)Cc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cs1
Yield: 63.7 %

Procedure:
The title compound was prepared according to the general procedure of 5-(5-{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, substituting methyl(propyl)amine (73 mg, 1.0 mmol) for 2-propylpyrrolidine to afford 32.0 mg of the title compound (63.7%).
Reaction SMILES: P(=O)(O)(O)O.[CH3:6][C:7]1[CH2:12][CH2:11][C:10]([CH3:15])([CH:13]=[CH2:14])[CH2:9][CH:8]=1>C1(C)C=CC=CC=1>[CH3:6][C:7]1[CH:12]2[CH2:11][C:10]([CH3:15])([CH2:9][CH:8]=1)[CH2:13][CH2:14]2
Reactant: C=CC1(C)CC=C(C)CC1
Agent: O=P(O)(O)O
Solvent: Cc1ccccc1
Product: CC1=CCC2(C)CCC1C2

Procedure:
Phosphoric acid (145 g, 1.48 mol) was added to a solution of 1,4-dimethyl-4-vinyl-cyclohexene (403 g, 2.96 mol, commercially available from Evonik Industries) in toluene (500 mL) and refluxed for 6 hours. The reaction mixture was subsequently quenched with a solution of sodium hydroxide (NaOH). The organic layer was separated, dried over sodium sulfate (Na2SO4), and fractionated to provide 2,5-dimethyl-bicyclo[3.2.1]oct-2-ene (280 g) having a boiling point of 87° C. at a pressure of 27 mmHg.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH:3]=[C:4]([CH3:6])[CH3:5].[C-:9]#[N:10].S(=O)(=O)(O)O.[OH2:16]>>[F:1][C:2]([F:8])([F:7])[CH2:3][C:4]([NH:10][CH:9]=[O:16])([CH3:6])[CH3:5]
Reactant: O
Reactant: CC(C)=CC(F)(F)F
Reactant: [C-]#N
Agent: O=S(=O)(O)O
Product: CC(C)(CC(F)(F)F)NC=O
Temperature: 43 °C
Reaction time: 0.2 h

Procedure:
1,1,1-Trifluoro-3-methyl-2-butene (16.1 g, 130 mmol), sodim cyanide (6.7 g, 133 mmol), and water (3.1 g) were stirred together in a flask, and cooled in an ice-salt mixture to 1°-6° C. internal temperature. Sulphuric acid (35.3 g of 98%, 353 mmol) was added from a dropping funnel over 45 minutes. After the addition, the cooling bath was removed, and the reaction mixture allowed to warm. A temperature of 35° C. was reached in 12 minutes, and cooling was applied to give 25° C. When the heat of reaction had subsided, the mixture was heated in a water bath to 43° C. during 2 hours and kept at 43° C. for 1.75 hours. The mixture was allowed to cool to 20° C., and the apparatus was then evacuated to 15 mmHg through a -78° C. trap. The mixture was then cooled to 5°-10° C. in a bath of ice and salt, while water (46 ml) was added over 10 minutes from the dropping funnel. The mixture at 25° C. was stirred vigorously and again evacuated to 15 mmHg, to collect unreacted olefin and other volatile products in the -78° C. trap.
Reaction SMILES: C([CH2:4][NH:5][C:6]1[S:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C@H:18]([O:23][CH2:24][CH3:25])[C:19]([O:21]C)=[O:20])=[CH:13][CH:12]=2)=[CH:9][N:10]=1)(=O)C.[OH-].[Na+]>CO.O>[CH2:24]([O:23][C@@H:18]([CH2:17][C:14]1[CH:13]=[CH:12][C:11]([C:8]2[S:7][C:6]([NH:5][CH3:4])=[N:10][CH:9]=2)=[CH:16][CH:15]=1)[C:19]([OH:21])=[O:20])[CH3:25]
Reactant: CCO[C@@H](Cc1ccc(-c2cnc(NCC(C)=O)s2)cc1)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCO[C@@H](Cc1ccc(-c2cnc(NC)s2)cc1)C(=O)O

Procedure:
0.6 g (1.6 mmol) of methyl 3-{4-[2-(acetylmethylamino)thiazol-5-yl]phenyl}-2(S)-ethoxypropanoate in 25 ml of methanol and 2.4 ml (2.4 mmol) of aqueous 1M sodium hydroxide solution are heated at 60° C. for 18 hours. The reaction medium is cooled, diluted with water, acidified to pH 4-5 and then extracted with ethyl acetate and n-butanol. The organic phase is washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated. The residue obtained is used in step h without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1.Cl>C1COCC1.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)[C:7]#[N:8])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: N#CCc1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: N#CC(c1ccc(Cl)cc1)c1ccc([N+](=O)[O-])cc1
Reaction time: 0.17 h

Procedure:
To a solution of 4-chlorobenzylcyanide (5.909 g, 38.979 mmol, 1.1 equip) in THF (100 mL) was added potassium t-butoxide (9.941 g, 88.589 mmol, 2.5 equip) and the solution was stirred for 10 minutes. 4-Fluoronitrobenzene (5.000 g, 35.435 mmol, 1 equip) was added and the reaction mixture stirred at room temperature overnight. The resulting mixture was acidified to pH 7 with 1N HCl, ethyl acetate and water were added, and the layers were separated. The aqueous layer was extracted 1× with ethyl acetate, and the organic layers were combined, dried (Na2SO4), and concentrated. The residue was purified by MPLC using an ethyl acetate-heptane gradient to yield 2-(4-chlorophenyl)-2-(4-nitrophenyl)acetonitrile as an orange-yellow solid.
Reaction SMILES: ClC1C=CN=CC=1C=O.[C:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][O:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=1[C:30]1[C:35](/[CH:36]=[C:37](\[CH2:43][C:44]2[CH:49]=[C:48]3[O:50][CH2:51][O:52][C:47]3=[CH:46][C:45]=2[O:53][CH3:54])/[C:38]([O:40]CC)=[O:39])=[CH:34][CH:33]=[CH:32][N:31]=1)([O:12]C)=[O:11].CCCCCC.C(O)(C(F)(F)F)=O>C(O)C>[C:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][O:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=1[C:30]1[C:35](/[CH:36]=[C:37](\[CH2:43][C:44]2[CH:49]=[C:48]3[O:50][CH2:51][O:52][C:47]3=[CH:46][C:45]=2[O:53][CH3:54])/[C:38]([OH:40])=[O:39])=[CH:34][CH:33]=[CH:32][N:31]=1)([OH:12])=[O:11]
Reactant: CCOC(=O)/C(=C/c1cccnc1-c1ccc(OC)cc1OCc1ccccc1C(=O)OC)Cc1cc2c(cc1OC)OCO2
Agent: O=Cc1cnccc1Cl
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCCC
Product: COc1ccc(-c2ncccc2/C=C(\Cc2cc3c(cc2OC)OCO3)C(=O)O)c(OCc2ccccc2C(=O)O)c1

Procedure:
Following the procedures in Example 4(b)-(c) except substituting 2-chloro-3-formyl-pyridine for 4chloro-3-formyl-pyridine and for the preparation of E-Ethyl 3-[2-[(2-Carbomethoxyphenyl)methoxy-4-methoxyphenyl]-pyridin-3-yl]-2-[2-methoxy4,5-methylenedioxybenzyl]prop-2-enoate shown in Example 6 (b), the title compound was prepared as a tan solid. (58 mg, 10% ) (400 MHz, CDCl3) δ 8.67 (d, J=3.5 Hz, 1H), 8.14 (d, J=7.8 Hz, 1H) 7.72 (s, 1H), 7.49-7.37 (m, 4H), 7.14 (dd, J=8.4 Hz, 4.8 Hz 1H), 6.71 (d, J=7.8 Hz, 1H), 6.70 (s, 1H), 6.48 (s, 1H), 6.43 (s, 1H), 5.85 (s, 2H), 5.49 (s, 2H), 3.89 (s, 3H), 3.71 (s, 3H), 2.87 (s, 2H); MS(ESP) m/e 570 [M+H]+ ; MS(ESN) m/e 568 [M-H]- ; mp 135-140°; Anal. (C32H27NO9.0.5H2O) calcd. C, 66.43; H, 4.88; N, 2.42: found. C, 66.47; H, 4.89; N, 2.40; HPLC tR 11.8 min, (Bakerbond Chiracel OC®; 25 cm×4.6 mm; hexane:ethanol, 80% with0.1%TFA;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:21]=[C:20]([CH2:22][C:23]([NH2:25])=O)[CH:19]=[C:18]([CH2:26][O:27][CH2:28][C:29]([F:32])([F:31])[F:30])[N:17]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.P(Cl)(Cl)(Cl)=O.CN(C)C1C=CC=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1)[NH:15][C:16]1[N:21]=[C:20]([CH2:22][C:23]#[N:25])[CH:19]=[C:18]([CH2:26][O:27][CH2:28][C:29]([F:32])([F:31])[F:30])[N:17]=1
Reactant: COc1cc(Nc2nc(COCC(F)(F)F)cc(CC(N)=O)n2)ccc1-n1cnc(C)c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: COc1cc(Nc2nc(CC#N)cc(COCC(F)(F)F)n2)ccc1-n1cnc(C)c1
Reaction time: 0.17 h

Procedure:
2-(2-{[3-Methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]amino}-6-[(2,2,2-trifluoroethoxy)-methyl]pyrimidin-4-yl)acetamide (68 mg, 0.15 mmol, 1.0 eq) was added to a solution of Phosphorus oxychloride (4 mL) and dimethylaniline (0.033 mL, 0.26 mmol, 1.75 eq). The reaction mixture was immersed in a pre-heated oil bath at 120° C. for 10 min. The reaction mixture, still hot, was rapidly poured into ice/DCM slurry and stirred for 16 h. The layers were separated and the aqueous layer was extracted twice with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified on a silica gel cartridge eluting with a gradient of methanol, DCM and EtOAc. The residue was further purified on a C18 reverse phase cartridge eluting with 30% to 70% MeOH/H2O containing 0.05% TFA to give the title compound, 8 mg (12%).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][C:6]([NH:10][C:11]2[C:12]3[C:19]4[CH2:20][CH2:21][NH:22][CH2:23][C:18]=4[S:17][C:13]=3[N:14]=[CH:15][N:16]=2)=[CH:5][C:4]=1[OH:24].Br[CH2:26]/[CH:27]=[CH:28]/[C:29]([OH:31])=O.[C:32]([NH:36][CH3:37])([CH3:35])([CH3:34])[CH3:33]>>[C:32]([N:36]([CH3:37])[CH2:26]/[CH:27]=[CH:28]/[C:29]([N:22]1[CH2:21][CH2:20][C:19]2[C:12]3[C:11]([NH:10][C:6]4[CH:7]=[C:8]([Cl:9])[C:3]([Cl:2])=[C:4]([OH:24])[CH:5]=4)=[N:16][CH:15]=[N:14][C:13]=3[S:17][C:18]=2[CH2:23]1)=[O:31])([CH3:35])([CH3:34])[CH3:33]
Reactant: CNC(C)(C)C
Reactant: Oc1cc(Nc2ncnc3sc4c(c23)CCNC4)cc(Cl)c1Cl
Reactant: O=C(O)/C=C/CBr
Agent: Cl
Product: CN(C/C=C/C(=O)N1CCc2c(sc3ncnc(Nc4cc(O)c(Cl)c(Cl)c4)c23)C1)C(C)(C)C

Procedure:
The compound was synthesized in analogy to Example 147 from 2,3-dichloro-5-(5,6,7,8-tetrahydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-ylamino)phenol hydrochloride from Example 69A (85 mg, 0.21 mmol), (2E)-4-bromobut-2-enoic acid (52 mg, 0.32 mmol) and tert-butyl methylamine (29 mg, 0.34 mmol) to yield 18 mg (16%).
Reaction SMILES: [CH2:1]([N:5]1[N:9]=[C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]2=[N:6]1)[CH2:2][C:3]#[CH:4].C([N:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26]C=2N=N1)CC#C>>[N:18]1[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=1[C:4]#[C:3][CH2:2][CH2:1][N:5]1[N:6]=[C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]2=[N:9]1
Reactant: C#CCCn1nnc2ccccc21
Reactant: C#CCCn1nc2ccccc2n1
Product: C(#Cc1ccccn1)CCn1nc2ccccc2n1
Yield: 8 %

Procedure:
The title compounds were prepared in accordance with the general method of Example 108(C), from 90 mg (0.53 mmol) of 2-(but-3-ynyl)-2H-benzo[d][1,2,3]triazole and 1-(but-3-ynyl)-1H-benzo[d][1,2,3]triazole. The crude residue was purified by flash chromatography (DCM/MeOH 99:1 to 98:2) to yield 10 mg (42 mmol, 8%) of 2-(4-(pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole as an orange oil with a purity of 82%. Another fraction yielded after SCX column (DCM, DCM/MeOH 98:2, DCM/MeOH/NH4OH 95:4:1 to 94:4:2) 19 mg (76 μmol, 14%) of 1-(4-(pyridin-2-yl)but-3-ynyl)-1H-benzo[d][1,2,3]triazole as an orange oil.
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:40])[C@@H:15]([NH:25][C:26]([C:28]2[CH:37]=[C:36]([OH:38])[C:35]3[C:30](=[CH:31][C:32]([CH3:39])=[CH:33][CH:34]=3)[N:29]=2)=[O:27])[CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].[CH2:41]([O:48][C:49](=[O:53])[C@H:50]([CH3:52])O)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.O>[CH2:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:40])[C@@H:15]([NH:25][C:26]([C:28]2[CH:37]=[C:36]([O:38][C@@H:50]([C:49]([O:48][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[O:53])[CH3:52])[C:35]3[C:30](=[CH:31][C:32]([CH3:39])=[CH:33][CH:34]=3)[N:29]=2)=[O:27])[CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:12][CH2:13]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: C[C@H](O)C(=O)OCc1ccccc1
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(O)c3ccc(C)cc3n2)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(O[C@H](C)C(=O)OCc3ccccc3)c3ccc(C)cc3n2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2 g 4-{(S)-4-tert-Butoxycarbonyl-2-[(4-hydroxy-7-methyl-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid butyl ester and 647 mg benzyl-L-lactate in 25 ml THF were added 1.4 g triphenylphosphine and 938 mg diethylazodicarboxylate. After stirring for 16 h at RT LCMS indicated complete conversion and water was added to the reaction mixture which was subsequently extracted with ethyl acetate. The residue obtained after evaporation of the solvent was purified by flash chromatography on silica using an ethyl acetate/heptane gradient. Yield: 1.7 g.