Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[CH:5]=[CH:4][C:3]=1[NH:13]C(=O)OC(C)(C)C.CN(C)[C@@H]1CCN(CC2C=CC(C(O)=O)=CC=2)C1.[N:39]1[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][O:46][C:47]([NH:49][C:50]2[CH:58]=[CH:57][C:53]([C:54](O)=[O:55])=[CH:52][CH:51]=2)=[O:48])[CH:40]=1>>[NH2:13][C:3]1[CH:4]=[CH:5][C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[CH:7][C:2]=1[NH:1][C:54]([C:53]1[CH:52]=[CH:51][C:50]([NH:49][C:47](=[O:48])[O:46][CH2:45][C:41]2[CH:40]=[N:39][CH:44]=[CH:43][CH:42]=2)=[CH:58][CH:57]=1)=[O:55]
Reactant: O=C(Nc1ccc(C(=O)O)cc1)OCc1cccnc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1N
Agent: CN(C)[C@@H]1CCN(Cc2ccc(C(=O)O)cc2)C1
Product: Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(NC(=O)OCc2cccnc2)cc1
Yield: 31 %

Procedure:
Following the same procedure as described in Example 1, steps 6 and 7 (scheme 1), using compound 4 but substituting compounds 7 & 8 for compounds 281 & 282, the title compound 283 was obtained (step 2: 31% yield, step 3: 23% yield).
Reaction SMILES: [CH3:1][CH:2]([C@H:4]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:5]([OH:7])=O)[CH3:3].CN1CCOCC1.[NH2:23][C@H:24]([C:29]([N:31]1[CH2:45][CH2:44][CH2:43][C@H:32]1[C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])=[O:30])[CH2:25][CH:26]([CH3:28])[CH3:27].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CCOC(C)=O>[NH:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:4]([C:5]([NH:23][C@H:24]([C:29]([N:31]1[CH2:45][CH2:44][CH2:43][C@H:32]1[C:33]([O:35][CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)=[O:34])=[O:30])[CH2:25][CH:26]([CH3:27])[CH3:28])=[O:7])[CH:2]([CH3:1])[CH3:3]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)C[C@H](NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: 23 °C
Reaction time: 0.25 h

Procedure:
To a flask containing Boc-Valine-OH (652 mg, 3 mmol) in DCM (6 ml) at 0° C. was added NMM (0.35 ml, 3.15 mmol). After stirring for 15 min, A5 (1.065 g, 3 mmol), HOBt (405 mg, 3.0 mmol) and DCC (650 mg, 3.15 mmol) were added in portions. The reaction mixture was allowed to warm to 23° C. and stirred for 14 h. The suspension was diluted with DCM (25 ml) and washed successively with aq KHSO4 (2×10 ml, 10%), aq NaHCO3 (2×10 ml, sat) and brine (10 ml) dried over Na2SO4 filtered and concentrated under reduced pressure. The residue was purified by flash LC (silica, gradient hex-EtOAc 2:1 to 1:1) to give SVPLA4 (1.48 g, 93%) as a white solid. Rf=0.57 (hex-EtOAc 1:2).
Reaction SMILES: [CH2:1]([O:8][C:9]1C=CC(Br)=CC=1C(C)(C)C)[C:2]1C=CC=CC=1.[F:20][C:21]1[C:26]([F:27])=[CH:25][C:24](Br)=[CH:23][C:22]=1[OH:29].CC[OH:32]>>[CH2:1]([O:8][C:9](=[O:32])[C:24]1[CH:23]=[C:22]([OH:29])[C:21]([F:20])=[C:26]([F:27])[CH:25]=1)[CH3:2]
Reactant: CCO
Reactant: CC(C)(C)c1cc(Br)ccc1OCc1ccccc1
Reactant: Oc1cc(Br)cc(F)c1F
Product: CCOC(=O)c1cc(O)c(F)c(F)c1

Procedure:
The title compound was synthesized by substituting 1-benzyloxy-4-bromo-2-tert-butyl-benzene in Example 47C with 2,3-difluoro-5-bromophenol in EtOH. MS (DCI) m/z 220 (M+NH4)+.
Reaction SMILES: [O:1]=[C:2](Cl)[O:3][C:4](Cl)(Cl)Cl.[F:9][C:10]([F:19])([F:18])[C:11]1[CH:16]=[CH:15][N:14]=C(O)[N:12]=1.[Cl:20][C:21]1[CH:22]=[C:23]([NH:27][CH3:28])[CH:24]=[CH:25][CH:26]=1>O1CCCC1>[F:9][C:10]([F:19])([F:18])[C:11]1[CH:16]=[CH:15][N:14]=[C:4]([O:3][C:2](=[O:1])[N:27]([C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([Cl:20])[CH:22]=2)[CH3:28])[N:12]=1
Reactant: Oc1nccc(C(F)(F)F)n1
Reactant: CNc1cccc(Cl)c1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: CN(C(=O)Oc1nccc(C(F)(F)F)n1)c1cccc(Cl)c1
Reaction time: 1 h
Yield: 40 %

Procedure:
At 0° C. diphosgene (0.99 g, 5.00 mmol) was added to a stirred solution of 4-trifluoromethyl-2-hydroxypyrimidine (1.64 g, 10.0 mmol) in tetrahydrofuran (25 ml). The cooling bath was removed and stirring was continued at room temperature for 1 hour. (3-Chlorophenyl)-methylamine (0.35 g, 2.50 mmol) was added to one-fourth of the solution. After stirring overnight at room temperature the solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane (20:80)) followed by preparative HPLC, yielding the title compound (332 mg, 40%) as a colourless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][C:17]([NH:20][C:21]3[N:22]=[CH:23][C:24]4[C:30]([CH3:31])=[C:29](Br)[C:28](=[O:33])[N:27]([CH:34]5[CH2:38][CH2:37][CH2:36][CH2:35]5)[C:25]=4[N:26]=3)=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:44]([O:46][CH2:47][CH3:48])=[CH2:45])CCC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][C:17]([NH:20][C:21]3[N:22]=[CH:23][C:24]4[C:30]([CH3:31])=[C:29]([C:44]([O:46][CH2:47][CH3:48])=[CH2:45])[C:28](=[O:33])[N:27]([CH:34]5[CH2:38][CH2:37][CH2:36][CH2:35]5)[C:25]=4[N:26]=3)=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)ncc12
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=C(OCC)c1c(C)c2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n(C2CCCC2)c1=O
Yield: 78.2 %

Procedure:
A suspension of 4-[6-(6-bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (5.93 g, 0.010 mol, prepared as in Example 1A), tetrakis(triphenylphosphine)palladium(0) (1.40 g, 0.00121 mol), and tributyl(1-ethoxyvinyl)tin (5.32 mL, 0.0157 mol) in toluene (30 mL) was heated under reflux for 3.5 hours. The mixture was cooled and filtered to give a solid. Purification of the solid by silica gel chromatography using a gradient of 5%-66% ethyl acetate/hexane over 15 minutes gave 4-{6-[8-cyclopentyl-6-(1-ethoxy-vinyl)-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-pyridin-3-yl}-piperazine-1-carboxylic acid tert-butyl ester as a yellow foam (4.50 g, 78%). MS (APCI) M++1: calc'd 576.2, found, 576.3.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([NH:19][C@H:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH3:21])=[N:5][C:6]([NH:10][C:11]2[CH:15]=[C:14]([CH:16]3[CH2:18][CH2:17]3)[NH:13][N:12]=2)=[C:7]([F:9])[CH:8]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:53]=[C:54]1[NH:58][C@@H:57]([C:59](O)=[O:60])[CH2:56][CH2:55]1.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[CH:16]1([C:14]2[NH:13][N:12]=[C:11]([NH:10][C:6]3[N:5]=[C:4]([NH:19][C@H:20]([C:22]4[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=4)[CH3:21])[C:3]([CH2:2][NH:1][C:59]([C@H:57]4[CH2:56][CH2:55][C:54](=[O:53])[NH:58]4)=[O:60])=[CH:8][C:7]=3[F:9])[CH:15]=2)[CH2:18][CH2:17]1
Reactant: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1CN)c1ccc(F)cc1
Reactant: O=C1CC[C@H](C(=O)O)N1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1CNC(=O)[C@H]1CCC(=O)N1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.1 %

Procedure:
To a DCM (10 ml) solution of (S)-3-(aminomethyl)-N6-(5-cyclopropyl-1H-pyrazol-3-yl)-5-fluoro-N2-(1-(4-fluorophenyl)ethyl)pyridine-2,6-diamine (Example 3; 0.45 g, 1.17 mmol) and HBTU (0.44 g, 1.17 mmol) cooled at 0° C. was added a solution of (R)-5-oxopyrrolidine-2-carboxylic acid (0.15 g, 1.17 mmol) in DMF (5 ml), followed by the addition of DIEA (0.14 g, 1.17 mmol). The reaction was then stirred at room temperature for 1 hour and quenched with 20 ml aqueous NaHCO3, and extracted with DCM (2×30 ml). The combined organic fractions were dried over Na2SO4, filtered, and then concentrated. The resulting oil was purified by column chromatography (DCM-MeOH=20:1) to give the title compound (0.25 g, 43%). 1H NMR (400 MHz, CD3OD) δ 7.37-7.34 (m, 2H), 7.14 (d, J=10.9 Hz, 1H), 7.02-6.97 (m, 2H), 5.80-5.65 (br s, 1H), 5.07 (br s, 1H), 4.33-4.16 (m, 3H), 2.46-2.22 (m, 3H), 2.05-1.98 (m, 1H), 1.88-1.81 (m, 1H), 1.51 (d, J=6.8 Hz, 3H), 0.93-0.92 (m, 2H), 0.66-0.62 (m, 2H). MS: Calcd.: 495. Found: [M+H]+ 496.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:49]=[CH:50][CH:51]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[C:22]([N:26]5[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]5)[CH:23]=[CH:24][CH:25]=4)[CH:18]=3)[N:13]([S:39]([C:42]3[CH:48]=[CH:47][C:45]([CH3:46])=[CH:44][CH:43]=3)(=[O:41])=[O:40])[CH:12]=2)[CH:8]=[N:7]1.CO.[ClH:54]>O1CCOCC1>[ClH:54].[F:1][C:2]1[CH:3]=[C:4]([CH:49]=[CH:50][CH:51]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([N:26]5[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]5)[CH:21]=4)[CH:18]=3)[N:13]([S:39]([C:42]3[CH:48]=[CH:47][C:45]([CH3:46])=[CH:44][CH:43]=3)(=[O:40])=[O:41])[CH:12]=2)[CH:8]=[N:7]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4cccc(N5CCN(C(=O)OC(C)(C)C)CC5)c4)cnc32)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4cccc(N5CCNCC5)c4)cnc32)cc1
Yield: 72.8 %

Procedure:
Using similar reaction conditions as described in step-iii of example-33, tert-butyl 4-(3-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazine-1-carboxylate (compound of step-i of example-33) (130 mg, 0.184 mmol) was deprotected using methanol/HCl in dioxane (5/5 mL) to give 86 mg, (72.8%) of the titled compound.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7](=O)[C:8]([CH3:13])=[CH:9]N(C)C)=[CH:4][CH:3]=1.[NH2:15][C:16]([NH2:18])=[S:17].[CH3:19]C(C)([O-])C.[K+].IC>C(O)(C)C.O1CCCC1>[Br:1][C:2]1[S:6][C:5]([C:7]2[C:8]([CH3:13])=[CH:9][N:18]=[C:16]([S:17][CH3:19])[N:15]=2)=[CH:4][CH:3]=1
Reactant: CC(=CN(C)C)C(=O)c1ccc(Br)s1
Reactant: NC(N)=S
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Solvent: CC(C)O
Product: CSc1ncc(C)c(-c2ccc(Br)s2)n1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
1-(5-Bromothiophen-2-yl)-3-(dimethylamino)-2-methylprop-2-en-1-one (6.39 g, 23 mmol) was dissolved in isopropyl alcohol (30 mL) at room temperature. Thiourea (1.748 g, 23 mmol) followed by potassium tert-butoxide (23 mL of a 1.0 M solution in tetrahydrofuran) was added to the mixture, which was then heated to reflux overnight. The reaction was cooled to rt and iodomethane (2.86 mL, 46 mmol) was added to the reaction in one portion. The mixture was subsequently stirred for an additional 6 h. The volatiles were removed in vacuo and the residue was dissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate, water and brine. The organic layer was then dried with sodium sulfate, reduced in vacuo and purified by column chromatography on silica gel using a gradient of 10 to 40% of ethyl acetate in hexanes to yield a yellow solid (5 g). MS (M+H)+ 302.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.C[N:8]([CH3:11])C=O.[F:12]/[CH:13]=[C:14](\[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)/CO.[Cl-].[Na+]>C1(C)C=CC=CC=1>[NH2:8][CH2:11]/[C:14](=[CH:13]/[F:12])/[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1
Reactant: CN(C)C=O
Reactant: OC/C(=C/F)CCc1ccc(F)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: NC/C(=C/F)CCc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Combine oxalyl chloride (2.71 g, 21.4 mmol) and toluene (20 mL). Cool to 0° C. Add N,N-dimethylformamide (1.62 g, 22.2 mmol) as a solution in toluene (2 mL). Warm to ambient temperature. After 10 minutes, cool to 0° C. Add (E)-2-(fluoromethylene)-4-(p-fluorophenyl)butan-1-ol (4.0 g, 20.2 mmol). Warm to ambient temperature. After 18 hours, pour the reaction mixture into a saturated sodium chloride solution (100 mL). Extract the aqueous layer 3 times with toluene. Dry the combined organic layers over Na2SO4, filter, and evaporate in vacuo to give the title compound. 1H NMR (CDCl3, 300 MHz) δ 2.52 (m, 2H), 2.75 (m, 2H), 3.91 (d, J=6Hz, 2H), 6.65 (d, J=82.5Hz, 1H), 6.95 (m, 2H), 7.15 (m, 2H).
Reaction SMILES: N#N.[CH:3]([N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1)=[CH2:4].C([Li])C[CH2:12][CH3:13].[C:15](=[O:20])(OC)OC.[Na+].[Cl-]>C1COCC1>[CH:3]([N:5]1[CH:9]=[CH:8][N:7]=[C:6]1[C:15]([C:6]1[N:5]([CH:12]=[CH2:13])[CH:9]=[CH:8][N:7]=1)=[O:20])=[CH2:4]
Reactant: COC(=O)OC
Reactant: C=Cn1ccnc1
Reactant: [Li]CCCC
Agent: N#N
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=Cn1ccnc1C(=O)c1nccn1C=C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A flame-dry round-bottom flask with magnetic stir bar is cooled under N2 flow. 180 mLs anhydrous THF is added via canula and positive N2 pressure is established. 7.39 g (78.5 mmol) of 1-vinylimidazole (a light yellow liquid) is added via syringe. The vessel is then cooled to -78° C. by immersion is a CO2 /EtOH bath. Once cool, 32 mLs of 2.5M n-butyllithium is carefully added via syringe. The reaction is allowed to stir for approximately 1 hour while -78° C. is maintained. Meanwhile a second 500 mL flame-dry round-bottom flask is cooled under N2 flow and 100 mLs of anhydrous THF are added to it via canula. Positive N2 pressure is established. This is followed by syringe addition of 3.54 g (39.3 mmol) dimethyl carbonate. The second flask is cooled to -78° C. in a CO2 /EtOH bath. After the 1 hour has elapsed in the first vessel's reaction, the contents of the first flask (a greenish/orange solution) are transferred via canula to the second flask. The transfer is done dropwise over a 1 hour period. No signs of a color change occur in the destination flask. The reaction mixture is allowed to stir overnight while warming to 25° C. In the morning the reaction mixture is quenched by lifting of the septum and adding excess solid CO2. This is done slowly. Yellow solids precipitate out of the solution. The solvents are then removed in vacuo with a 25° C. water bath. The white residue is dissolved in 250 mLs of saturated NaCl solution. Much of the solid residue does not dissolve. The brine solution is filtered through a Buchner funnel to collect the light yellow crystals- The brine solution is then extracted with three aliquots of 100 mLs methylene chloride- The extract is dried over anhydrous sodium sulfate and filtered through a fluted filter. The methylene chloride is removed in vacuo with a 25° C. water bath to leave light yellow crystals. The light yellow crystals are washed with diethyl ether to leave a white solid; or they can be recrystallized from boiling diethyl ether to isolate clear crystals. 1HNMR (300 MHz, CDCl3): δ7.7167, 7.6179, 7.6645, 7.6355 (q, CNH, 2H, J=8.705 Hz and 7.001 Hz), 7.4710, 7.4671 (d, CH, 2H, J=1.16 Hz), 7.3457, 7.3423 (d, CH, 2H, J=1.01 Hz), 5.3940, 5.3888, 5.3418, 5.3365 (d of d, CH2, 2H, J=14.08 Hz and 1.59 Hz), 5.0751, 5.0698, 5.0462, 5.0408 (d of d, CH2, 2H, J=7.08 Hz and 1.59 Hz). 13C NMR (300 MHz, CDCl3): δ173.9390, 141.9383, 131.3468, 130.9122, 121.2263, 105.4057, IR (NaCl, cm-1): 3167.87-2994.581 m); 1723.84(s); 1660.31(s); 1510.13, 1440.82, 1394.01(m); 1313.75, 1279.09, 1300(m); 1140.46 (m); 1094.25(s); 1059.59(s); 967.18,944.07, 886.31(m). M.P.=133.0° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([C:7]1[CH:8]=[C:9]([NH:13][C:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[O:15])[CH:10]=[CH:11][CH:12]=1)[CH2:5][CH3:6].[OH-].[K+]>CO.O>[Cl:1][CH2:2][CH2:3][N:4]([C:7]1[CH:8]=[C:9]([NH:13][C:14]([C:16]2[CH:17]=[CH:18][C:19]([C:22]([OH:24])=[O:23])=[CH:20][CH:21]=2)=[O:15])[CH:10]=[CH:11][CH:12]=1)[CH2:5][CH3:6]
Reactant: CCN(CCCl)c1cccc(NC(=O)c2ccc(C(=O)[O-])cc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCN(CCCl)c1cccc(NC(=O)c2ccc(C(=O)O)cc2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 75 %

Procedure:
A suspension of (XIV; R=Z=H) (2.88 g, 8 mmol) in MeOH (100 mL) containing KOH (5.6 g) was stirred at 25° C. until homogeneous, andthen for a further 5 h. The mixture was diluted with water, filtered, and acidified with AcOH to give 4-[3-(N-(2-chloroethyl)-N-ethylamino) phenyl]carbamoylbenzenecarboxylic acid (XV; R=Z=H) (2.08 g, 75%), mp (EtOAc) 203° C. (dec.). 1H NMR (CD3SOCD3) 13.3 (br s, 1 H, COOH), 10.21 (s, 1 H, CONH), 8.05 (q, J=8.50, 4 H, H-2',3',5'6'), 7.16 (m, 3 H, H-2,4,6 ), 6.48 (m, 1 H, H-5), 3.72 (t, J=7.1Hz, 2 H, NCH2CH2Cl), 3.60 (t, J=7.1 Hz, 2 H, CH2Cl), 3.40(g, J=7.0 Hz, NCH2CH3)-, 1.12 (t, J=7.0 Hz, 3 H, CH3). Anal. (C18H19ClN2O3) C,H,N,Cl.
Reaction SMILES: B1([C:7]2[C:12]([C:13]#[N:14])=[CH:11][CH:10]=[CH:9][CH:8]=2)OCCCO1.Br[C:16]1[CH:22]=[C:21]([CH:23]([CH3:25])[CH3:24])[CH:20]=[CH:19][C:17]=1[NH2:18].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[CH:23]([C:21]1[CH:20]=[CH:19][C:17]2[C:16](=[C:7]3[C:12](=[C:13]([NH2:14])[N:18]=2)[CH:11]=[CH:10][CH:9]=[CH:8]3)[CH:22]=1)([CH3:25])[CH3:24]
Reactant: CC(C)c1ccc(N)c(Br)c1
Reactant: N#Cc1ccccc1B1OCCCO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)c1ccc2nc(N)c3ccccc3c2c1
Temperature: 25 °C

Procedure:
A 500 ml round bottom flask was charged with 12.2 grams (65.4 mmol) of 2-cyanophenylboronic acid propanediol ester, 14.0 g (65.4 mmol) of 2-bromo-4-isopropylaniline, 2.27 (2 mmol) tetrakis(triphenylphosphine)palladium, 18.0 g (131 mmol) of potassium carbonate, 150 ml toluene, and 50 ml ethanol. The reaction was heated to reflux under N2 for 18 hours. After cooling to room temperature the reaction was extracted with ethyl acetate and water. The organic was washed with brine and then dried with magnesium sulfate. The solids were collected by filtration and the solvent removed from filtrate. The product was purified by silica gel chromatography using 94.5% dichloromethane, 5% methanol, 0.5% ammonium hydroxide as the eluent. The fractions containing the desired product were combined and the solvent removed. The product was confirmed by NMR and mass spectroscopy.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:14].[S:15]1[CH:19]=[CH:18][CH:17]=[C:16]1/[CH:20]=[CH:21]/[C:22](Cl)=O.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]=[C:22]1/[CH:21]=[CH:20]/[C:16]1[S:15][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1ccccc1Nc1ccccn1
Reactant: O=C(Cl)/C=C/c1cccs1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Product: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1cccs1

Procedure:
The tilled compound was prepared from N-(2-pyridyl)-o-phenylenediamine and (E)-3-(2-thienyl)acryloyl chloride (Aitken, R. A.; Boeters, C.; Morrison, J. J. J. Chem. Soc. Perkin. Trans. 1, 1994, 17, 2473) according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). MW: 303.39; mp: 130.0-131.0° C.; 1H-NMR (CDCl3) δ: 8.77 (1H, ddd, J=4.8, 1.8, 0.7 Hz), 8.12 (1H, d, J=15.8 Hz), 8.02 (1H, ddd, J=8.1,8.1, 1.8 Hz), 7.84-7.79 (1H, m), 7.51 (1H, ddd, J=8.1, 1.1, 0.7 Hz), 7.49-7.43 (2H, m), 7.37-7.18 (3H, m), 7.20 (1H, dd, J=3.7,0.7 Hz), 7.02 (1H, dd, J=4.8, 3.7 Hz), 6.94 (1H, d, J=15.8 Hz).
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].Br[C:6]1[CH:15]=[CH:14][C:13](Br)=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]>C(N(CC)CC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:4][CH2:1][C:2]#[C:3][C:6]1[CH:15]=[CH:14][C:13]([C:3]#[C:2][CH2:1][OH:4])=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: C#CCO
Reactant: COC(=O)c1cc(Br)ccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(C#CCO)ccc1C#CCO
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 72.3 %

Procedure:
Pd(Ph3P)4 (1.95 g), CuBrSMe2 (0.75 g) and propargyl alcohol (5.35 ml, 70.0 mmol) are added successively to a solution of methyl 2,5-dibromobenzoate (10.0 g, 34.0 mmol) in triethylamine (235 ml), and the mixture is stirred at RT for 10 min and then under reflux at 80° C. for 3 h. After cooling, the reaction mixture is filtered off with suction through kieselguhr, and the filter cake is washed with ethyl acetate (50 ml). The organic phase is concentrated under reduced pressure. Further purification is carried out by chromatography [toluene/acetone (8:2)] on a silica gel column. This gives the title compound (6.0 g) as a colorless solid. TLC, silica gel (glass plates), [toluene/acetone (8:2)], Rf=0.16.
Reaction SMILES: [OH:1][C:2]1([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[C:15]([C:20](O)=[O:21])[CH:14]=[CH:13]3)[C:9]2[N:5]([CH:6]=[N:7][CH:8]=2)[CH2:4][CH2:3]1.Cl.C([N:26]=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[OH:1][C:2]1([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[C:15]([C:20]([NH2:26])=[O:21])[CH:14]=[CH:13]3)[C:9]2[N:5]([CH:6]=[N:7][CH:8]=2)[CH2:4][CH2:3]1
Reactant: O=C(O)c1ccc2cc(C3(O)CCn4cncc43)ccc2c1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: NC(=O)c1ccc2cc(C3(O)CCn4cncc43)ccc2c1
Temperature: 25 °C
Yield: 11.8 %

Procedure:
6-(7-Hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)-2-naphthoic acid (449 mg), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (321 mg) and 1-hydroxy-1H-benzotriazole monohydrate (301 mg) were dissolved in DMF (7.6 ml), and diisopropylethylamine (216 mg) was added with stirring under ice-cooling. The reaction mixture was warmed to room temperature and stirred for 18 h. Silica gel (3 g) was added to the reaction mixture and the mixture was concentrated to dryness under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform/methanol containing aqueous ammonia (7%): 19/1) and the eluate was concentrated to dryness. The residue was recrystallized from ethanol to give the title compound (53 mg).
Reaction SMILES: [N:1]1([C:6]2([C:10]#[N:11])[CH2:9]O[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:12]1(=O)CCC1.[CH3:17][N:18]1CCNCC1>>[CH3:17][N:18]1[CH2:4][CH2:5][N:1]([C:6]2([C:10]#[N:11])[CH2:9][CH2:12][CH2:7]2)[CH2:2][CH2:3]1
Reactant: O=C1CCC1
Reactant: N#CC1(N2CCCC2)COC1
Reactant: CN1CCNCC1
Product: CN1CCN(C2(C#N)CCC2)CC1

Procedure:
The title compound, light yellow liquid, MS: m/e=180.2 [(M+H)+], was prepared in accordance with the general method of intermediate A from cyclobutanone and 1-methylpiperazine.
Reaction SMILES: [C:1]([C:5]1[CH:31]=[CH:30][C:8]([C:9]([NH:11][C:12]2[CH:28]=[C:27]([NH2:29])[CH:26]=[CH:25][C:13]=2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[O:15])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:32][O:33][CH2:34][C:35](Cl)=[O:36]>>[C:1]([C:5]1[CH:31]=[CH:30][C:8]([C:9]([NH:11][C:12]2[CH:28]=[C:27]([NH:29][C:35](=[O:36])[CH2:34][O:33][CH3:32])[CH:26]=[CH:25][C:13]=2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[O:15])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCC(=O)Cl
Reactant: COc1ccc(NC(=O)c2ccc(N)cc2NC(=O)c2ccc(C(C)(C)C)cc2)cc1
Product: COCC(=O)Nc1ccc(C(=O)Nc2ccc(OC)cc2)c(NC(=O)c2ccc(C(C)(C)C)cc2)c1
Yield: 74 %

Procedure:
Using the procedure described in Example 59, Part E, 2-(4-tert-butylbenzoylamino)-4-amino-N-(4-methoxyphenyl)benzamide was reacted with methoxyacetyl chloride (0.55 mmol) to yield 175 mg (74%) of the title compound as a solid.