Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.C(O)=O.[NH2:12][C:13]1[N:18]2[N:19]=[CH:20][C:21]([C:22]3[CH:23]=[N:24][C:25]4[C:30]([CH:31]=3)=[CH:29][CH:28]=[CH:27][CH:26]=4)=[C:17]2[N:16]=[C:15]([N:32]2[CH2:38][CH2:37][C:36](=[O:39])[NH:35][CH2:34][CH2:33]2)[CH:14]=1>CC#N>[NH2:12][C:13]1[N:18]2[N:19]=[CH:20][C:21]([C:22]3[CH:23]=[N:24][C:25]4[C:30]([CH:31]=3)=[CH:29][CH:28]=[CH:27][CH:26]=4)=[C:17]2[N:16]=[C:15]([N:32]2[CH2:38][CH2:37][C:36](=[O:39])[NH:35][CH2:34][CH2:33]2)[C:14]=1[Br:8]
Reactant: Nc1cc(N2CCNC(=O)CC2)nc2c(-c3cnc4ccccc4c3)cnn12
Reactant: O=C1CCC(=O)N1Br
Solvent: O=CO
Solvent: CC#N
Product: Nc1c(Br)c(N2CCNC(=O)CC2)nc2c(-c3cnc4ccccc4c3)cnn12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64.9 %

Procedure:
A solution of NBS (14.6 mg, 0.082 mmoL) in CH3CN (0.5 mL) was added to a mixture of 1-(7-amino-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-1,4-diazepan-5-one formic acid salt (32.3 mg, 0.077 mmoL) in CH3CN (3 mL). After stirring at room temperature for 10 min, the solvent was evaporated and the residue was purified by prep-LC to afford titled compound (22.6 mg, 59%). LCMS tR=2.78 Min. Mass calculated for, M+ 451.0, observed LC/MS m/z 452.0 (M+H).
Reaction SMILES: [CH3:1][C:2]12[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][C:10]1([CH3:18])[C:9]1[CH:8]=[C:7]([CH3:19])[CH:6]=[CH:5][C:4]=1[NH:3]2.C(=O)(O)[O-].[Na+].[C:25](OC(=O)C)(=[O:27])[CH3:26]>>[C:25]([N:3]1[C:4]2[CH:5]=[CH:6][C:7]([CH3:19])=[CH:8][C:9]=2[C@@:10]2([CH3:18])[CH2:11][C:12]3[C:17]([C@@:2]12[CH3:1])=[CH:16][CH:15]=[CH:14][CH:13]=3)(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc2c(c1)C1(C)Cc3ccccc3C1(C)N2
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(=O)N1c2ccc(C)cc2[C@@]2(C)Cc3ccccc3[C@@]12C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4b,5,9b,10-Tetrahydro-4b,8,9b-trimethylindeno[1,2-b]indole (0.25 g, 1.00 mmol) was dissolved in acetic anhydride (1 cm3) and stirred at room temperature for 16 hours. The reaction mixture was poured into saturated sodium bicarbonate solution (25 cm3) and stirred for 1/2 hour. The mixture was extracted with diethyl ether (3×10 cm3) and the combined organic extracts were washed with brine, dried (Na2SO4) and evaporated. The crude material was purified by flash chromatography on silica gel eluting with 4% ethyl acetate/60°-80° petrol to yield a pale yellow gum. Yield: 0.15 g, 53%. 1H NMR (CDCl3) δ: 7.84 (1H, s), 6.90-7.23 (6H, m), 3.26 (1H, d, J=15.9 Hz), 2.96 (1H, d, J =15.9 Hz), 2.40 (3H, s), 2.31 (3H, s), 1.77 (3H, s), 1.32 (3H, s).
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:25]=[CH:24][C:9]2[C:10](=[O:23])[O:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([OH:22])=[O:21])=[CH:16][CH:15]=3)=[N:13][C:8]=2[CH:7]=1)(=[O:4])[CH2:2][CH3:3].CN(C)C=[O:29].O.Cl>C(N(CC)CC)C>[C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:12]([NH:13][C:8]2[CH:7]=[C:6]([NH:5][C:1](=[O:4])[CH2:2][CH3:3])[CH:25]=[CH:24][C:9]=2[C:10]([OH:11])=[O:23])=[O:29])=[CH:15][CH:16]=1)([OH:22])=[O:21]
Reactant: CN(C)C=O
Reactant: CCC(=O)Nc1ccc2c(=O)oc(-c3ccc(C(=O)O)cc3)nc2c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CCC(=O)Nc1ccc(C(=O)O)c(NC(=O)c2ccc(C(=O)O)cc2)c1

Procedure:
A mixture of 5 g of 7-(propionamido)-2-(4-carboxyphenyl)-4H-3,1-benzoxazine-4-one, 50 ml of dimethylformamide, 10 ml of water and 8 ml of triethylamine was heated at 80°-90° C. for a period of 10 hours. After being allowed to cool, the mixture was treated with dilute hydrochloric acid to adjust its pH between 2 and 3. The precipitating crystal was filtered, washed with water, and recrystallized from isopropyl alcohol to produce 4.1 g of 2-(4-carboxybenzamido)-4-propionamidobenzoic acid having a melting point in the range of 284° to 286° C. (decompose).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:35])[C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[NH:24][C:25]([C:27]2[S:28][CH:29]=[C:30]([CH2:33]Cl)[C:31]=2[Cl:32])=[O:26])=[CH:11][CH:10]=1>CN(C=O)C>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:35])[C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[NH:24][C:25]([C:27]2[S:28][CH:29]=[C:30]([CH2:33][N:1]3[CH:5]=[N:4][CH:3]=[N:2]3)[C:31]=2[Cl:32])=[O:26])=[CH:13][CH:14]=1
Reactant: c1nc[nH]n1
Reactant: O=C(Nc1ccc(Cl)cc1)c1cc(Cl)ccc1NC(=O)c1scc(CCl)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Cl)cc1)c1cc(Cl)ccc1NC(=O)c1scc(Cn2cncn2)c1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 102.8 %

Procedure:
To a solution of 1,2,4-triazole (0.40 g, 5.7 mmol) in DMF (10 mL) was added NaH (60% dispersion in mineral oil, 0.23 g, 5.7 mmol) and the mixture stirred at ambient temperature. After 10 min, N-(4-chlorophenyl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide (0.90 g, 1.9 mmol) in DMF (5 mL) was added and stirring continued. After 18 hours, the mixture was poured onto water and extracted with methylene chloride. The organic layer was dried over MgSO4 and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 0.99 g (77% yield) of N-(4-chlorophenyl)-2-[((3-chloro-4-((1,2,4-triazol-1-yl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide; as a white solid; NMR (DMSO-dr/TFA) 11.2 (s, 1), 10.7 (s, 1), 9.3 (s, 1), 8.5 (s, 1), 8.3 (d, 1), 8.0 (s, 1), 7.9 (d, 1), 7.7 (d, 2), 7.6 (dd, 1), 7.4 (d, 2), 5.5 (s, 2) ppm.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([CH2:14][O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(O)[CH:11]=[CH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:25])=O>C(Cl)Cl.CN(C=O)C>[CH2:1]([O:8][CH2:9][C:10]([CH2:14][O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:11][CH2:12][Cl:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: C=CC(O)(COCc1ccccc1)COCc1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: ClCC=C(COCc1ccccc1)COCc1ccccc1
Reaction time: 0.5 h

Procedure:
Crude 1-benzyloxy-2-benzyloxymethylbut-3-en-2-ol (1.42 g, 3.16 mmol) in 10 ml of CH2Cl2 was added to 0.71 g thionyl chloride (6 mmol) and 2 drops of DMF in 10 ml of CH2Cl2, and the solution was stirred for 0.5 h and evaporated in vacuum. Toluene was added and the mixture was evaporated in vacuum to yield crude 1-benzyloxy-2-benzyloxymethyl-4-chlorobut-2-ene.
Reaction SMILES: C(C1N=C(N2CCOCC2)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.[C:28]([C:32]1[N:33]=[C:34](Cl)[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29].[CH3:50][C:51]1[CH:55]=[C:54]([CH:56]2[CH2:60][CH2:59][CH2:58][NH:57]2)[O:53][N:52]=1>>[C:28]([C:32]1[N:33]=[C:34]([N:57]2[CH2:58][CH2:59][CH2:60][CH:56]2[C:54]2[O:53][N:52]=[C:51]([CH3:50])[CH:55]=2)[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: Cc1cc(C2CCCN2)on1
Agent: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Product: Cc1cc(C2CCCN2c2nc(C(C)(C)C)nc3c2nnn3Cc2ccccc2Cl)on1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chlorobenzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-methyl-5-(pyrrolidin-2-yl)isoxazole. MS(m/e): 452.4
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1.[Cl:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[Cl:25]>>[Cl:18][C:19]1[CH:20]=[C:21]([N:1]2[CH:5]=[C:4]([C:6]3[C:7]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)=[N:8][O:9][C:10]=3[CH3:11])[N:3]=[CH:2]2)[CH:22]=[CH:23][C:24]=1[Cl:25]
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: Cc1onc(-c2ccccc2)c1-c1c[nH]cn1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc(Cl)c(Cl)c2)cn1
Yield: 10 %

Procedure:
As described for Example 3, 4-(1H-imidazol-4-yl)-5-methyl-3-phenyl-isoxazole (112.6 mg, 0.5 mmol) was converted, using 3,4-dichlorophenylboronic acid instead of 4-fluorophenylboronic acid, to the title compound (18 mg, 10%) which was obtained as a white solid. MS (ESI): m/e=369.9 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:4][C:3]=1[C:15](=[O:22])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].C(N(CC)CC)C.C1(C)C(S([N:39]=[N+:40]=[N-])(=O)=O)=CC=CC=1>CC#N>[N+:39](=[C:16]([C:15]([C:3]1[CH:4]=[C:5]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][C:2]=1[F:1])=[O:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N-:40]
Reactant: Cc1ccccc1S(=O)(=O)N=[N+]=[N-]
Reactant: CCOC(=O)CC(=O)c1cc(CN2CCOCC2)ccc1F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)C(=[N+]=[N-])C(=O)c1cc(CN2CCOCC2)ccc1F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 86.3 %

Procedure:
To a solution of ethyl 3-(2-fluoro-5-(4-morpholinylmethyl)phenyl)-3-oxopropanoate (Preparation 9, 5.00 g) and triethylamine (2.48 mL) in 50 mL CH3CN cooled to 0° C. is added toluenesulfonyl azide (3.51 g, prepared according to Org. Prep. Proc. Intl., 1981, 13, 112) in 10 mL CH3CN. The reaction is stirred at 0° C. for 15 min then at room temperature for 2 h. The reaction is concentrated (below 50° C.). 2N NaOH (25 mL) is added. The aqueous layer is extracted with CHCl3 (3×). The combined organic layers are washed, dried and concentrated to yield 4.68 g (86%) of the desired product as a yellow oil. Physical characteristics are as follows: 1H NMR (CDCl3) δ7.52, 7.44, 7.06, 4.24, 3.75, 3.55, 2.50, 1.24; MS (ESI+) for C16H18FN3O4 m/z 336.1 (M+H)+.
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[CH:67]([C:69]1[CH:88]=[CH:87][C:72]([CH2:73][N:74]2[CH2:79][CH2:78][N:77]([C:80]([O:82][C:83]([CH3:86])([CH3:85])[CH3:84])=[O:81])[CH2:76][CH2:75]2)=[CH:71][CH:70]=1)=O>C(O)C.CN(C=O)C>[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]2[N:43]=[C:67]([C:69]3[CH:70]=[CH:71][C:72]([CH2:73][N:74]4[CH2:75][CH2:76][N:77]([C:80]([O:82][C:83]([CH3:84])([CH3:86])[CH3:85])=[O:81])[CH2:78][CH2:79]4)=[CH:87][CH:88]=3)[NH:42][C:39]2=[N:40][CH:41]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(C=O)cc2)CC1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3cccnc3)CC2)c1[N+](=O)[O-]
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(-c3nc4c(N5CCN(Cc6cccnc6)CC5)c(Br)cnc4[nH]3)cc2)CC1
Reaction time: 6 h
Yield: 26.1 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-bromo-3-nitro-4-(4-(pyridin-3-ylmethyl)piperazin-1-yl)pyridin-2-amine (50 mg, 0.13 mmol), DMF (0.3 mL), ethanol (1.2 mL), 1M Na2S2O4 (3 eq, 0.38 mmol, 0.38 mL) and tert-butyl 4-(4-formylbenzyl)piperazine-1-carboxylate (1.1 eq, 0.14 mmol, 45 mg). After 6 h, concentration in vacuo and purification by preparative tlc (CH2Cl2-MeOH, 95:5) gave the product (22 mg, 27%) as a pale yellow solid; δH (500 MHz, DMSO-d6) 1.39 (s, 9H, C(CH3)3), 2.34 (t, J=5.0 Hz, 4H, piperazine N(CH2)2), 2.62 (s, br, 4H, piperazine N(CH2)2), 3.32 (s, br, 4H, piperazine N(CH2)2), 3.55 (s, 2H, CH2), 3.62 (s, 2H, CH2), 3.67 (t, J=4.8 Hz, 4H, piperazine N(CH2)2), 7.39 (dd, J=7.8, 4.8 Hz, 1H, pyridine H-5), 7.46 (d, J=8.1 Hz, 2H, phenyl H-3 & H-5), 7.78 (d, br, J=8.0 Hz, 1H, pyridine H-4), 8.14 (d, J=8.1 Hz, 2H, phenyl H-2 & H-6), 8.23 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.50 (dd, J=4.8, 1.6 Hz, 1H, pyridine H-6), 8.56 (d, J=1.7 Hz, 1H, pyridine H-2), 13.46 (s, br, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11](O)=[O:12].S(Cl)([Cl:19])=O>CN(C)C=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([Cl:19])=[O:12]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cccc(Oc2ccccn2)c1
Solvent: CN(C)C=O
Product: O=C(Cl)c1cccc(Oc2ccccn2)c1

Procedure:
To a suspension of 3-(2-pyridyloxy)benzoic acid (1.80 g) in thionyl chloride (5.4 ml), dimethylformamide (0.2 ml is added, and the resultant mixture is stirred at room temperature for 2.5 hours. The reaction mixture is evaporated under reduced pressure to remove the excessive thionyl chloride, and the residue is combined with anhydrous pyridine (0.73 g) and anhydrous benzene (40 ml). The precipitated pyridine hydrochloride is filtered off. The filtrate is evaporated to remove the benzene, and the residue is dissolved in anhydrous ether (20 ml). The ether solution is filtered to remove the insoluble substance. The filtrate is evaporated to remove the ether, whereby 3-(2-pyridyloxy)benzoyl chloride is obtained. IR (CCl4): 1774 cm-1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][C:3]=1[F:9].[H-].[Na+].IC.Cl[CH2:15]Cl>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:15])=[CH:4][C:3]=1[F:9]
Reactant: Fc1cc(S)ccc1Br
Reactant: ClCCl
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CSc1ccc(Br)c(F)c1
Reaction time: 0.08 h
Yield: 86 %

Procedure:
A solution of 4-bromo-3-fluoro-benzenethiol (225 mg, 1.09 mmol) in tetrahydrofuran (3 ml) was cooled to 0° C. Sodium hydride (60% dispersion in mineral oil, 52 mg, 1.31 mmol) was added and the mixture was stirred for 5 minutes. Iodomethane (78 μl, 1.25 mmol) was then added and the mixture was allowed to return to room temperature with stirring over 20 minutes. Dichloromethane (10 ml) was added and the reaction was quenched with 1 M aqueous hydrochloric acid. The layers were separated and the organic layer was washed with water, dried (MgSO4), then concentrated in vacuo. The residue was purified by flash chromatography (Si-PPC, pentane:diethyl ether, gradient 100:0 to 90:10) to afford the title compound as a bright yellow oil (208 mg, 86%). 1H NMR (CDCl3, 400 MHz) 7.43 (1H, dd, J=8.4, 7.2), 7.00 (1H, dd, J=9.4, 2.3), 6.91 (1H, ddd, J=8.4, 2.1, 0.7), 2.48 (3H, s).
Reaction SMILES: [CH2:1](O)[C:2]#[C:3][CH2:4][CH2:5][CH2:6][CH2:7]/[CH:8]=[CH:9]\[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].P(Br)(Br)[Br:17]>CCOCC.N1C=CC=CC=1>[Br:17][CH2:1][C:2]#[C:3][CH2:4][CH2:5][CH2:6][CH2:7]/[CH:8]=[CH:9]\[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: BrP(Br)Br
Reactant: CCCCC/C=C\CCCCC#CCO
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCCCC/C=C\CCCCC#CCBr
Yield: 219.3 %

Procedure:
By the procedure of example 14, 3.82 g (18.34 mmol) of (Z)-8-tetradecen-2-yn-1-ol, 72 mg of dry pyridine, and 1.66 g (6.12 mmol) of phosphorous tribromide were reacted in 20 ml of ether under reflux for 2.0 h. It was worked up as described in example 14 to give 3.83 g of crude product. It was purified by evaporative distillation at 105° C.-120° C./0.25 mm to yield 3.64 g (73% by weight yield) of (Z)-1-bromo-8-tetradecen-2-yne as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O=[C:17]1[CH2:21][CH2:20][CH2:19][CH:18]1[C:22]([O:24][CH3:25])=[O:23].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH3:25][O:24][C:22]([C:18]1[CH2:19][CH2:20][CH2:21][C:17]=1[O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])=[O:23]
Reactant: COC(=O)C1CCCC1=O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1=C(OS(=O)(=O)C(F)(F)F)CCC1
Reaction time: 72 h
Yield: 72.9 %

Procedure:
Trifluoromethanesulfonic anhydride (1.5 mL, 8.9 mmol) was slowly added to a solution of methyl 2-oxocyclopentanecarboxylate (1.0 mL, 8.1 mmol) and N,N-diisopropylethylamine (2.2 mL, 13.0 mmol) in methylene chloride (30 mL) under a nitrogen atmosphere at room temperature. The reaction was stirred for 72 h, and then partitioned between methylene chloride and water. The organic layer was washed with 1 N HCl, aqueous NaHCO3, and brine; dried over magnesium sulfate; and concentrated to give an oil. The product was purified by FCC on silica gel eluting ethyl ether:hexane (5:95) to give 2-trifluoromethanesulfonyloxy-cyclopent-1-enecarboxylic acid methyl ester (1.62 g, 73%) as a yellow oil.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13](=[O:26])[C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[N:16][CH:15]=3)[CH:10]=2)[CH:5]=[CH:4]1)[CH3:2].Br[C:28]1[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[C:30]([Cl:37])[CH:29]=1.C(C1C=C(NC(C2C=CC(N3CCN(C4C=CC(C(O)=O)=CC=4)CC3)=C(F)C=2)=O)C=CC=1)(C)(C)C>>[Cl:37][C:30]1[CH:29]=[C:28]([N:23]2[CH2:24][CH2:25][N:20]([C:17]3[CH:18]=[CH:19][C:14]([C:13](=[O:26])[NH:12][C:9]4[CH:10]=[C:11]5[C:6]([CH:5]=[CH:4][N:3]5[CH2:1][CH3:2])=[CH:7][CH:8]=4)=[CH:15][N:16]=3)[CH2:21][CH2:22]2)[CH:36]=[CH:35][C:31]=1[C:32]([OH:34])=[O:33]
Reactant: CCn1ccc2ccc(NC(=O)c3ccc(N4CCNCC4)nc3)cc21
Reactant: O=C(O)c1ccc(Br)cc1Cl
Agent: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCN(c4ccc(C(=O)O)cc4)CC3)c(F)c2)c1
Product: CCn1ccc2ccc(NC(=O)c3ccc(N4CCN(c5ccc(C(=O)O)c(Cl)c5)CC4)nc3)cc21

Procedure:
2-Chloro-4-{4-[5-(1-ethyl-1H-indol-6-ylcarbamoyl)-pyridin-2-yl]-piperazin-1-yl}-benzoic acid was synthesized from N-(1-ethyl-1H-indol-6-yl)-6-piperazin-1-yl-nicotinamide and 4-bromo-2-chloro-benzoic acid in a manner similar to the one described in the synthesis of 4-{4-[4-(3-tert-butyl-phenylcarbamoyl)-2-fluoro-phenyl]-piperazin-1-yl}-benzoic acid above. LCMS calcd for C27H26ClN5O3 (m/e) 503, obsd 504 (M+H).
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[CH:23]=[C:21](C)[C:19](=[O:20])[NH:18][C:16]2=[O:17])[CH2:12][C@@H:11]1[OH:24])(C(C)(C)C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:45]1[C:49](=[O:50])[C:48]2=[CH:51][CH:52]=[CH:53][CH:54]=[C:47]2[C:46]1=[O:55].CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.CCOCC>[C:49]1(=[O:50])[N:45]([O:8][CH2:9][C@H:10]2[O:14][C@@H:13]([N:15]3[CH:23]=[CH:21][C:19](=[O:20])[NH:18][C:16]3=[O:17])[CH2:12][C@@H:11]2[OH:24])[C:46](=[O:55])[C:47]2=[CH:54][CH:53]=[CH:52][CH:51]=[C:48]12
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO[Si](C)(C)C(C)(C)C)O2)c(=O)[nH]c1=O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C1c2ccccc2C(=O)N1OC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)C[C@@H]1O
Temperature: 0 °C
Yield: 62 %

Procedure:
To a solution of 5'-O-t-butyldimethylsilylthymidine [1, 21.36 g, 60 mmol, prepared according to the procedure of Nair, et al., Org. Prep. Procedures Int. 1990, 22, 57 in dry THF (750 ml)], triphenylphosphine (17.28 g, 66 mmol) and N-hydroxyphthalimide (10.74 g, 66 mmol) were added. The solution was cooled to 0° C. and diisopropylazodicarboxylate (15.15 g, 75 mmol) was added dropwise over a period of 3 hr while stirring under nitrogen. The reaction mixture was then stirred at room temperature for 12 hr. The solution was evaporated and the residue was dissolved in CH2 Cl2 (750 ml), extracted with sat. NaHCO3 (200 ml), and water (200 ml), dried (MgSO4), filtered and concentrated to furnish yellow oily residue. Silica gel column chromatography (100% hexanes, and then hexanes:Et2O gradient to 90% Et2O) of the residue gave compound 2 as a colorless glass (18.68 g, 62%); 1H NMR (CDCl3) δ 0.05 [2s, 6, (CH3)2 ], 0.91 [s, 9, (CH3)3 ], 2.0 (s, 3, CH3), 2.5-2.65 (m, 2, 2'CH2), 4.05-4.2 (m, 2, 5'CH2), 4.25-4.35 (m, 1, 4'H), 5.0 (m, 1, 3'H) 6.15 (m, 1, 1'H), 8.6 (br s , 1, NH), and aromatic protons. Anal. Calcd. for C24H31 N3O7Si: C, 57.46;H, 6.23; N, 8.37. found: C, 57.20; H, 6.26; N, 8.27.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:3]=1[NH:4][CH2:5][CH:6]=[O:7].C(=O)([O-])[O-].[Na+].[Na+].C1C=CC=CC=1.[Cl:28][CH2:29][C:30](Cl)=[O:31]>O>[Cl:28][CH2:29][C:30]([N:4]([CH2:5][CH:6]=[O:7])[C:3]1[CH:8]=[C:9]([C:12]([F:13])([F:14])[F:15])[CH:10]=[CH:11][C:2]=1[CH3:1])=[O:31]
Reactant: O=C(Cl)CCl
Reactant: Cc1ccc(C(F)(F)F)cc1NCC=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: Cc1ccc(C(F)(F)F)cc1N(CC=O)C(=O)CCl
Temperature: 25 °C

Procedure:
The dimethyl acetal of 2-(2-methyl-5-trifluoromethylanilino)acetaldehyde (0.1 mole), sodium carbonate (0.06 mole) dissolved in water (50 ml) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and cooling means. The mixture is cooled to a temperature of about 0° C. and α-chloroacetyl chloride (0.11 mole) is incrementally added with stirring. After the addition is completed stirring is continued and the reaction mixture is permitted to warm to room temperature. After this time the mixture is filtered, washed with dilute hydrochloric acid and stripped of solvent to yield the desired product the dimethyl acetal of 2-(N-α-chloroacetyl-2-methyl-5-trifluoromethylanilino)-acetaldehyde.
Reaction SMILES: C([N:20]1[CH:24]=[C:23]([C:25]2[C:26]([O:31][C:32]3[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=3)=[N:27][CH:28]=[CH:29][CH:30]=2)[CH:22]=[N:21]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.FC(F)(F)C(O)=O>CO>[NH:20]1[CH:24]=[C:23]([C:25]2[C:26]([O:31][C:32]3[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=3)=[N:27][CH:28]=[CH:29][CH:30]=2)[CH:22]=[N:21]1
Reactant: Nc1ccc(Oc2ncccc2-c2cnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: Nc1ccc(Oc2ncccc2-c2cn[nH]c2)cc1
Temperature: 80 °C
Reaction time: 36 h

Procedure:
In a 25 mL sealed tube, was added 4-(3-(1-trityl-1H-pyrazol-4-yl)pyridin-2-yloxy)benzenamine (0.150 g, 0.303 mmol), trifluoroacetic acid (0.23 mL, 3.0 mmol), and methanol (1.0 mL). The mixture was stirred at 80° C. for 36 hours. The mixture was concentrated. The residue was extracted into EtOAc, washed 1×NaHCO3, 1×NaCl, and the organic layers were combined and dried over Mg2SO4, filtered through fritted funnel and concentrated to yield 4-(3-(1H-pyrazol-4-yl)pyridin-2-yloxy)benzenamine as dark brown waxy solid. MS m/z=253 [M+1]+. Calc'd for C14H12N4O: 252.27.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH3:27])[C@@H:12]([C@@H:23]([CH3:26])[CH2:24][CH3:25])[C@H:13]([OH:22])[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28]N(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.F[B-](F)(F)F.C[O+](C)C>ClCCCl>[CH2:1]([O:8][C:9]([N:11]([CH3:27])[C@@H:12]([C@@H:23]([CH3:26])[CH2:24][CH3:25])[C@H:13]([O:22][CH3:28])[CH2:14][C:15]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@H](C)[C@@H]([C@H](O)CC(=O)OC(C)(C)C)N(C)C(=O)OCc1ccccc1
Reactant: CN(C)c1cccc2cccc(N(C)C)c12
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCCl
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)OC(C)(C)C)OC)N(C)C(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
To a solution of #3 (8.4 g, 22 mmol, 1 eq.) in 1,2-dichloroethane (25 mL, 0.88 M) were added molecular sieves (4 Å, 0.7 g) and Proton sponge (1,8-bis(dimethylamino)naphthalene) (13.4 g, 59.2 mmol, 2.7 eq.), followed by trimethyloxonium tetrafluoroborate (9.10 g, 61.6 mmol, 2.8 eq.). After stirring overnight, the reaction mixture was filtered through Celite. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography (Gradient: 0% to 40% 1:1 acetone:ethyl acetate in heptane) to give #@2 (8.7 g, 68%) as a colorless oil. 1H NMR (400 MHz, DMSO-d6), presumed to be a mixture of rotamers: δ 7.28-7.40 (m, 5H), 5.01-5.13 (m, 2H), 3.89-4.08 (br m, 1H), 3.70-3.82 (m, 1H), 3.18 and 3.26 (2 s, total 3H), 2.66 and 2.71 (2 br s, total 3H), 2.44-2.53 (m, 1H, assumed; partially obscured by solvent peak), 2.17-2.24 (m, 1H), 1.71-1.86 (br m, 1H), 1.39 and 1.39 (2 s, total 9H), 1.31-1.40 (m, 1H), 0.94-1.08 (m, 1H), 0.76-0.91 (m, 6H).