Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:25](=[O:33])[C:26]5[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=5)[C:19]=4[CH3:34])=[CH:8][CH:9]=[C:10]([C:15]([NH2:17])=[O:16])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C(Cl)Cl.C1COCC1>[F:32][C:29]1[CH:28]=[CH:27][C:26]([C:25]([NH:24][C:20]2[C:19]([CH3:34])=[C:18]([C:7]3[C:6]4[C:5]5[C:13](=[CH:14][C:2]([NH:1][S:36]([CH3:35])(=[O:38])=[O:37])=[CH:3][CH:4]=5)[NH:12][C:11]=4[C:10]([C:15]([NH2:17])=[O:16])=[CH:9][CH:8]=3)[CH:23]=[CH:22][CH:21]=2)=[O:33])=[CH:31][CH:30]=1
Reactant: Cc1c(NC(=O)c2ccc(F)cc2)cccc1-c1ccc(C(N)=O)c2[nH]c3cc(N)ccc3c12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1c(NC(=O)c2ccc(F)cc2)cccc1-c1ccc(C(N)=O)c2[nH]c3cc(NS(C)(=O)=O)ccc3c12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 7-amino-4-(3-(4-fluorobenzamido)-2-methylphenyl)-9H-carbazole-1-carboxamide (Example 54-5, 30 mg, 0.066 mmol) and TEA (0.018 mL, 0.133 mmol) in DCM-THF (2:1, 3 mL) was treated with methanesulfonyl chloride (10 μL, 0.133 mmol). The mixture was stirred at rt for 1.5 h, and was concentrated and purified by preparative HPLC to provide 4-(3-(4-fluorobenzamido)-2-methylphenyl)-7-(methylsulfonamido)-9H-carbazole-1-carboxamide as a white solid (Example 59-1, 3.5 mg, 9%). 1H NMR (500 MHz, methanol-d4) δ 7.91-8.01 (2 H, m), 7.83 (1 H, d, J=7.8 Hz), 7.45 (1 H, d, J=1.7 Hz), 7.42 (1 H, d, J=7.8 Hz), 7.34 (1 H, t, J=7.8 Hz), 7.12-7.20 (3 H, m), 6.95 (1 H, d, J=7.8 Hz), 6.88 (1 H, d, J=8.6 Hz), 6.73 (1 H, dd, J=8.5, 2.1 Hz), 2.85 (3 H, s), 1.90 (3 H, s). Mass spectrum m/z 531.0 (M+H)+. Also obtained was 4-(3-(4-fluorobenzamido)-2-methylphenyl)-7-(N-(methylsulfonyl)methylsulfonamido)-9H-carbazole-1-carboxamide as a white solid (Example 59-2, 14 mg, 28%). 1H NMR (400 MHz, DMSO-d6) δ 11.67 (1 H, s), 10.08 (1 H, s), 8.21 (1 H, br. s.), 7.97-8.08 (3 H, m), 7.79 (1 H, d, J=1.8 Hz), 7.53 (1 H, br. s.), 7.48 (1 H, d, J=7.3 Hz), 7.26-7.39 (3 H, m), 7.15 (1 H, d, J=6.5 Hz), 6.93-7.03 (2 H, m), 6.86 (1 H, d, J=8.3 Hz), 3.46 (6 H, d, J=9.0 Hz), 1.86 (3 H, s). Mass spectrum m/z 607.2 (M−H)−.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9](/[CH:13]=[CH:14]/[CH:15]([O:24][Si:25]([C:38]([CH3:41])([CH3:40])[CH3:39])([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[N:8]=1.CN(C)[CH:44]=[O:45].Cl>C(OCC)C.O1CCCC1>[Si:25]([O:24][CH:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])/[CH:14]=[CH:13]/[C:9]1[N:8]=[C:7]([CH:44]=[O:45])[CH:12]=[CH:11][CH:10]=1)([C:38]([CH3:41])([CH3:40])[CH3:39])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CN(C)C=O
Reactant: CCCCCCCCC(/C=C/c1cccc(Br)n1)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCCCCC(/C=C/c1cccc(C=O)n1)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: -40 °C
Reaction time: 0.25 h
Yield: 84.6 %

Procedure:
1.16 ml of n-butyllithium (1.6 molar in hexane) is instilled in a suspension of 500 mg of 2-bromo-6-[(1E)-(3RS)-3-tert-butyldiphenylsilyloxy-1-undecenyl]-pyridine in 2 ml of diethyl ether and 1 ml of tetrahydrofuran at -80° C. under argon atmosphere. After completion of the addition, the reaction mixture is stirred for 15 minutes at -40° C., cooled to -80° C. and mixed by instillation at this temperature with 140 mg of dimethylformamide. After 4 hours at -80° C., the reaction mixture is hydrolyzed with 3 ml of 2 n hydrochloric acid, the organic phase is separated, dried on sodium sulfate, concentrated by evaporation and the residue is chromatographed on silica gel with hexane/0-10% ethyl acetate. 385 mg of 6-[(1E)-(3RS)-3-tert- butyldiphenylsilyloxy-1-undecenyl]-pyridine-2-carbaldehyde is obtained as yellow oil.
Reaction SMILES: [CH2:1]([N:3]([CH2:39][CH3:40])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=2)[CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([N:21]3[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[NH:23][C:22]3=[O:30])[CH2:17][CH2:16]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[H-].[Na+].[CH2:43](Br)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.O>CN(C)C=O>[CH2:39]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[CH:7]=[CH:8][C:9]([CH:12]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=2)[CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([N:21]3[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]([CH2:43][C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[C:22]3=[O:30])[CH2:17][CH2:16]2)=[CH:10][CH:11]=1)=[O:5])[CH3:40]
Reactant: CCN(CC)C(=O)c1ccc(C(CCN2CCC(n3c(=O)[nH]c4ccccc43)CC2)c2cccc(OC)c2)cc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)c1ccc(C(CCN2CCC(n3c(=O)n(Cc4ccccc4)c4ccccc43)CC2)c2cccc(OC)c2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 57 %

Procedure:
The 1-[3-(4-diethylcarbamoylphenyl)-3-(3-methoxyphenyl)propyl]-4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine (50 mg) obtained in Example 1 was dissolved in N,N-dimethylformamide (1 ml), added with sodium hydride (60% in oil, 7.4 mg) and stirred at room temperature for 1.5 hours. The reaction mixture was added with benzyl bromide (22 μl) and further stirred at 60° C. for 2 hours. The reaction mixture was added with water (5 ml) and extracted twice with ethyl acetate (5 ml). The organic layer was washed with water (10 ml) and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by preparative thin layer silica gel column chromatography (developing solvent: ethyl acetate:methanol=10:1) to obtain 33 mg of the title compound. Yield: 57%.
Reaction SMILES: [N:1]1([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@H:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][C@H:2]1[C:3]([OH:5])=O.[C:24]([NH2:28])([CH3:27])([CH3:26])[CH3:25].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[N:1]1([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@H:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][C@H:2]1[C:3]([NH:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:5]
Reactant: CC(C)(C)N
Reactant: CC(C)(C)OC(=O)N1C[C@H](OCc2ccccc2)C[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)[C@@H]1C[C@@H](OCc2ccccc2)CN1C(=O)OC(C)(C)C

Procedure:
In a DMF solution containing 100 mg of Boc-Hyp(Bzl)-OH, 33 μl of t-butylamine, 48 mg of HOBt and 71 mg of EDC hydrochloride were added and the resultant mixture was stirred for 14 hr. The reaction mixture was treated similarly to that in Example 33 (Process3) to give 88 mg of the title compound.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[Br:17][C:18]1[CH:19]=[C:20]([C:28]([C:30]2[O:31][C:32]([CH3:35])=[N:33][N:34]=2)=O)[CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1.Cl>C1COCC1.O>[CH2:15]([O:14][C:12](=[O:13])/[CH:11]=[C:28](/[C:20]1[CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=[C:18]([Br:17])[CH:19]=1)\[C:30]1[O:31][C:32]([CH3:35])=[N:33][N:34]=1)[CH3:16]
Reactant: Cc1nnc(C(=O)c2cc(Br)cc(C(F)(F)F)c2)o1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)/C=C(/c1cc(Br)cc(C(F)(F)F)c1)c1nnc(C)o1
Temperature: -78 °C
Reaction time: 1 h
Yield: 82.3 %

Procedure:
To a suspension of NaH (60%, 1.13 g, 28.35 mmol) in dry THF (20 mL) was added ethyl 2-(diethoxyphosphoryl)acetate (6.49 g, 28.35 mmol) at −78° C. After being stirred at −78° C. for 1 hour, a solution of (3-Bromo-5-trifluoromethyl-phenyl)-(5-methyl-[1,3,4]oxadiazol-2-yl)-methanone (9.047 g, 27 mmol) in 20 ml THF was added drop wise over 30 min. The mixture was stirred at −78° C. for 30 min and then warmed to room temperature followed by stirring overnight. The mixture was cooled to 0° C. and treated with water (50 mL), pH value was adjusted to 6 with HCl (0.5N) and extracted with EtOAc (50 mL×3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a petroleum ether/EtOAc mixture to afford 9 g of the desired product (Yield: 90%).
Reaction SMILES: [CH2:1]([C:3]1[CH2:4][CH2:5][CH2:6][N:7]2[C:12]=1[C:11]1[NH:13][C:14]3[C:19]([C:10]=1[CH2:9][CH2:8]2)=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH3:2].[CH2:20]=[O:21].O>CC(C)=O>[CH2:1]([C:3]1([CH2:20][OH:21])[C:12]2[N:7]([CH2:8][CH2:9][C:10]3[C:11]=2[N:13]=[C:14]2[C:19]=3[CH:18]=[CH:17][CH:16]=[CH:15]2)[CH2:6][CH2:5][CH2:4]1)[CH3:2]
Reactant: C=O
Reactant: CCC1=C2c3[nH]c4ccccc4c3CCN2CCC1
Solvent: O
Solvent: CC(C)=O
Product: CCC1(CO)CCCN2CCC3=c4ccccc4=NC3=C21
Temperature: 25 °C

Procedure:
37.8 g (0.15 moles) of 1-ethyl-2,3,4,6,7,12-hexahydro-indolo[2,3-a]quinolizine are dissolved in 100 ml of acetone, 5 g of paraformaldehyde are added thereto and the mixture is stirred at room temperature for an hour and a half. Then 30 ml of distilled water are added to the mixture within 15 minutes and the stirring is continued for another hour at O° C. The precipitated title compound obtained in the form of orange-colored crystals is filtered off and washed in two portions under altogether 20 ml of acetone, at 0° C. Weight: 34.13 g (80.7%), melting point: 111°-113° C.
Reaction SMILES: BrC[CH2:3][CH2:4][N:5]1[C:9](=O)[C:8]2=CC=[CH:13][CH:14]=[C:7]2[C:6]1=O.C(#[N:18])C>>[CH2:6]([N:5]1[CH2:9][CH2:8][NH:18][CH2:3][CH2:4]1)[CH2:7][CH2:14][CH3:13]
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: CC#N
Product: CCCCN1CCNCC1
Yield: 80 %

Procedure:
N-(3-Bromopropyl)phthalimide (15.1 g) was dissolved in acetonitrile (100 ml), and 1-n-butylpiperazine (5.33 g) obtained in Preparation Example 1 and 50% potassium fluoride-Celite (21.8 g) were added at room temperature. After stirring overnight, the reaction solution was filtered off with Celite, and the solvent was distilled off under reduced pressure. The residue obtained was purified by silica gel column chromatography (methylene chloride:methanol=95:5) to give the title compound (9.83 g) as a yellow oily substance. Yield=80%.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15]([C:19](Cl)=[O:20])=[CH:14][CH:13]=[CH:12]3)[CH:5]=[CH:4][N:3]=1.[F:22][C:23]([F:32])([F:31])[C:24]1[CH:25]=[C:26]([NH2:30])[CH:27]=[CH:28][CH:29]=1>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15]([C:19]([NH:30][C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([C:23]([F:22])([F:31])[F:32])[CH:25]=2)=[O:20])=[CH:14][CH:13]=[CH:12]3)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: O=C(Cl)c1cccc2cc(Oc3ccnc(Cl)n3)ccc12
Solvent: C1CCOC1
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1cccc2cc(Oc3ccnc(Cl)n3)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of the hydrochloride salt of 6-(2-chloropyrimidin-4-yloxy)-1-naphthoyl chloride (step b, 0.122 g, 0.34 mmol) in THF (3 mL) was added 3-(trifluoromethyl)benzenamine (0.047 mL, 0.38 mmol). The reaction was stirred at RT overnight. The mixture was concentrated and partitioned between EtOAc and 2N aqueous NaOH. Extraction with several portions of EtOAc was followed by washing of the organic layer with brine and drying with MgSO4. The solution was filtered and concentrated to afford the desired compound.
Reaction SMILES: C1(CCN2C3C(=CC=CC=3)C(O)(C3C(O)=CC4OCOC=4C=3)C2=O)CC1.[CH2:27]([O:29][C:30](=[O:54])[CH2:31][N:32]1[C:40]2[C:35](=[C:36]([Cl:41])[CH:37]=[CH:38][CH:39]=2)[C:34](O)([C:42]2[C:43]([OH:51])=[CH:44][C:45]3[O:49][CH2:48][CH2:47][C:46]=3[CH:50]=2)[C:33]1=[O:53])[CH3:28]>>[CH2:27]([O:29][C:30](=[O:54])[CH2:31][N:32]1[C:40]2[C:35](=[C:36]([Cl:41])[CH:37]=[CH:38][CH:39]=2)[CH:34]([C:42]2[C:43]([OH:51])=[CH:44][C:45]3[O:49][CH2:48][CH2:47][C:46]=3[CH:50]=2)[C:33]1=[O:53])[CH3:28]
Reactant: CCOC(=O)CN1C(=O)C(O)(c2cc3c(cc2O)OCC3)c2c(Cl)cccc21
Agent: O=C1N(CCC2CC2)c2ccccc2C1(O)c1cc2c(cc1O)OCO2
Product: CCOC(=O)CN1C(=O)C(c2cc3c(cc2O)OCC3)c2c(Cl)cccc21

Procedure:
Following the procedure as described in PREPARATION 2C, and making non-critical variations to replace 1-(2-cyclopropylethyl)-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one with ethyl[4-chloro-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate, the title compound was obtained (75%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.33-7.27 (m, 2H), 7.12 (d, 1H), 6.71 (d, 1H), 6.50-6.48 (m, 1H), 5.10 (s, 1H), 4.54-4.42 (m, 4H), 4.19 (q, 2H), 3.11-2.90 (m, 2H), 1.23 (t, 3H); MS (ES+) m/z 388.8 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]3)[N:9]=[C:10](I)[C:3]=12.CC1(C)C(C)(C)OB([C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:39]3[O:40][C:41]4[C:47]([CH3:48])=[CH:46][C:45]([CH3:49])=[CH:44][C:42]=4[N:43]=3)=[CH:34][CH:33]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]3)[N:9]=[C:10]([C:32]3[CH:33]=[CH:34][C:35]([NH:38][C:39]4[O:40][C:41]5[C:47]([CH3:48])=[CH:46][C:45]([CH3:49])=[CH:44][C:42]=5[N:43]=4)=[CH:36][CH:37]=3)[C:3]=12
Reactant: Cc1cc(C)c2oc(Nc3ccc(B4OC(C)(C)C(C)(C)O4)cc3)nc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(n2nc(I)c3c(N)ncnc32)C1
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1cc(C)c2oc(Nc3ccc(-c4nn(C5CCN(C(=O)OC(C)(C)C)C5)c5ncnc(N)c45)cc3)nc2c1
Temperature: 80 °C
Yield: 198.7 %

Procedure:
To a solution of rac-tert-butyl 3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-pyrrolidinecarboxylate (0.412 g, 0.958 mmol) in ethylene glycol dimethyl ether (6 mL) and water (3 mL) was added N2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-5,7-dimethyl-1,3-benzoxazol-2-amine (0.436 g, 1.20 mmol), tetrakis(triphenylphosphine)palladium (0) (0.055 g, 0.048 mmol), and sodium carbonate (0.254 g, 2.39 mmol). The solution was heated at 80° C. for 18 h, and then cooled to room temperature. The reaction mixture was partitioned between ethyl acetate (10 mL) and water (10 mL). The organic layer was separated and washed with brine (10 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated to afford rac-tert-butyl 3-(4-amino-3-{4-[(5,7-dimethyl-1,3-benzoxazol-2-yl)amino]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-pyrrolidinecarboxylate as an orange solid (1.029 g), which was used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]2[CH2:14][NH:13][C:12](=[O:15])[CH2:11]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:16]1([CH2:22][CH2:23][CH2:24]Br)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:16]1([CH2:22][CH2:23][CH2:24][O:1][C:2]2[CH:3]=[C:4]([CH:10]3[CH2:14][NH:13][C:12](=[O:15])[CH2:11]3)[CH:5]=[CH:6][C:7]=2[O:8][CH3:9])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCCCc1ccccc1
Reactant: COc1ccc(C2CNC(=O)C2)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C2CNC(=O)C2)cc1OCCCc1ccccc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 72.2 %

Procedure:
A mixture of 4-(3-hydroxy-4-methoxyphenyl)-2-pyrrolidone (42 mg, 0.2 mmol), 3-phenylpropyl bromide (44 mg, 0.22 mmol), potassium carbonate (83 mg, 0.6 mmol) and N,N-dimethylformamide (3 ml) is allowed to stir at 100° C. After 18 hours, the reaction mixture is cooled to 25° C. The solid is filtered off and the filtrate is concentrated under vacuum. The same working up procedure gives 47 mg (72%) of 4-(3-(3-phenylpropoxy)-4-methoxyphenyl)-2-pyrrolidone: 1H NMR (300 MHz, CDCl3) δ 7.34-7.17 (m, 5H), 6.82 (d, J=8.4 Hz, 1H), 6.78 (d, J=12 Hz, 1H), 6.70 (s, 1H), 6.02 (b, 1H), 4.03 (t, J=7.2 Hz, 2H), 3.84 (s, 3H), 3.75 (t, J=8.8 Hz, 1H), 3.63-3.55 (m, 1H), 3.36 (t, J=8.8 Hz, 1H), 2.82 (t, J=8.0 Hz, 2H), 2.71 (dd, J=16.8, 8.8 Hz, 2H), 2.47 (dd, J=16.6, 8.8 Hz), 2.20-2.13 (m, 2H).
Reaction SMILES: Cl[C:2]1[NH:7][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][N:11]([CH2:12]C)[C:4]=2[CH:3]=1.[F:14][C:15]([F:26])([F:25])[C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)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>[CH3:12][N:11]1[C:4]2[CH:3]=[C:2]([C:19]3[CH:20]=[CH:21][C:16]([C:15]([F:26])([F:25])[F:14])=[CH:17][CH:18]=3)[NH:7][C:6](=[O:8])[C:5]=2[CH:9]=[CH:10]1
Reactant: CCn1ccc2c(=O)[nH]c(Cl)cc21
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
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: [Na+]
Solvent: CCO
Product: Cn1ccc2c(=O)[nH]c(-c3ccc(C(F)(F)F)cc3)cc21
Temperature: 140 °C
Yield: 109.5 %

Procedure:
A microwave reaction vial was charged with 6-chloro-1-methyl-1,5-dihydro-pyrrolo[3,2-c]pyridine-4-one (Intermediate G) (16 mg, 0.08 mmol), 4-(trifluoromethyl)phenylboronic acid (20 mg, 0.10 mmol), tetrakis(triphenylphosphine)palladium(0) (5.06 mg, 0.004 mmol), and 2M aqueous sodium carbonate solution (0.13 mL) in ethanol (2 mL). The vial was sealed and then heated in a microwave at 140° C. for 10 min. At this time, the resulting mixture was filtered through a pad of Celite® and concentrated in vacuo. Flash chromatography (20/1 methylene chloride/methanol) afforded 1-methyl-6-(4-trifluoromethyl-phenyl)-1,5-dihydro-pyrrolo[3,2-c]pyridin-4-one (25.6 mg, 39.1%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.8 (s, 3H) 6.5 (d, J=3.01 Hz, 1H) 7.0 (s, 1H) 7.1 (d, J=3.01 Hz, 1H) 7.8 (d, J=8.28 Hz, 2H) 8.0 (d, J=8.28 Hz, 2H) 11.1 (br. s., 1H). LC-MS calcd. for C15H12F3N2O [(M+H)+] 293, obsd. 293.0.
Reaction SMILES: N#N.[OH-].[K+].[CH3:5][O:6][C:7]12[CH2:14][CH2:13][CH:10]([CH:11]=[CH:12]1)[CH2:9][CH:8]2[C:15]([O:17]C)=[O:16]>CO.O>[CH3:5][O:6][C:7]12[CH2:14][CH2:13][CH:10]([CH:11]=[CH:12]1)[CH2:9][CH:8]2[C:15]([OH:17])=[O:16]
Reactant: COC(=O)C1CC2C=CC1(OC)CC2
Agent: N#N
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC12C=CC(CC1)CC2C(=O)O
Yield: 87.8 %

Procedure:
In a 3 liter flask equipped with a mechanical stirrer, thermometer, reflux condenser, addition funnel and N2 atmosphere, potassium hydroxide (4.59 mole) was dissolved in methanol (1 L). To the resulting hot solution was added, over a five minute period, methyl 1-methoxybicyclo[2.2.2]oct-5-ene-2-carboxylate (1.53 mole) and the resulting light brown solution was heated to reflux for 5 hours. The reaction was then diluted with H2O (700 ml) and stripped under reduced pressure to a tan slimy solid. This solid was dissolved in fresh H2O (1 L) and washed with methylene chloride (1×500 ml). The separated aqueous layer was acidified to pH 1.5 with 420 ml conc. HCl at reduced temperature and extraced with methylene chloride (3×500 ml). The combined organic layers were washed with H2O (1 L) and brine. Drying and stripping under reduced pressure yielded 87.8% of title product as brown solids; mp 77°-81°; pnmr/CDCl3 /TMS/delta 1.65-2.0 (m,6,C3H,C7H,C8H), 2.6-2.8 (m,2,C4H, C2H), 3.4 (s, 3,OCH3), 6.2 (m,2,C5H,C6H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH:17]=O)=[CH:11][C:10]=1[O:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([CH:24]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(=[O:23])[CH3:22]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH:17]=[CH:22][C:21](=[O:23])[CH3:24])=[CH:11][C:10]=1[O:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(CCC=O)ccc1OCc1ccccc1
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: COc1cc(CCC=CC(C)=O)ccc1OCc1ccccc1
Yield: 56.4 %

Procedure:
A solution of 2.3 g of 3-(p-benzyloxy-m-methoxyphenyl)propionaldehyde and 2.97 g of acetylmethylenetriphenylphosphorane in 22 ml of toluene was heated under reflux for 2 hours, toluene was then evaporated and the residue was purified by a chromatography using 30 g of silica gel and recrystallization from a mixture of ethyl ether and n-hexane (1:5) afforded 1.49 g of the desired compound melting at 59.5°-60.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:29](=[O:30])[N:28]([CH3:31])[C:12]2[N:13]([CH3:27])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[N:21]=[C:22]([CH2:25]O)[S:23][CH:24]=1)=[CH:16][CH:15]=3.C(N(S(F)(F)[F:38])CC)C.O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:29](=[O:30])[N:28]([CH3:31])[C:12]2[N:13]([CH3:27])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[N:21]=[C:22]([CH2:25][F:38])[S:23][CH:24]=1)=[CH:16][CH:15]=3
Reactant: CCN(CC)S(F)(F)F
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4csc(CO)n4)ccc3n(C)c21
Solvent: ClCCl
Solvent: O
Product: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4csc(CF)n4)ccc3n(C)c21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
150 mg (0.319 mmol) of compound from Example 9, 3-(2,4-dichlorophenyl)-6-(2-hydroxymethylthiazol-4-yl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one, are dissolved in 3 ml of CH2Cl2. 51 μl of (diethylamino)sulphur trifluoride (DAST) are added at 0° C. The mixture is stirred at 0° C. for 2 hours. A further 100 μl of DAST are added (presence of starting product) and the mixture is left to stir at ambient temperature for a further 16 hours. H2O is added, the mixture is extracted with CH2Cl2, and the organic phase is dried over MgSO4, filtered and concentrated to dryness, adsorbing onto silica. Purification is carried out on a silica column, elution being carried out with EtOAc/40% cyclohexane and then with EtOAc/30% cyclohexane. The residue is taken up in MeOH and the precipitate is filtered off, and washed with MeOH and then with a minimum amount of Et2O.
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])=[CH:14][CH:13]=3)[N:8]=[C:7]([NH:24][C:25]3[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=3)[N:6]2[CH:31]=1.[CH3:32][NH2:33]>>[CH3:30][C:28]1[NH:27][N:26]=[C:25]([NH:24][C:7]2[N:6]3[CH:31]=[C:3]([CH2:2][NH:33][CH3:32])[N:4]=[C:5]3[CH:10]=[C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])=[CH:14][CH:13]=3)[N:8]=2)[CH:29]=1
Reactant: CN
Reactant: Cc1cc(Nc2nc(Sc3ccc(NC(=O)C4CC4)cc3)cc3nc(CO)cn23)n[nH]1
Product: CNCc1cn2c(Nc3cc(C)[nH]n3)nc(Sc3ccc(NC(=O)C4CC4)cc3)cc2n1

Procedure:
The title compound was synthesized using N-(4-(2-(hydroxymethyl)-5-(5-methyl-1H-pyrazol-3-ylamino)imidazo[1,2-c]pyrimidin-7-ylthio)phenyl)cyclopropanecarboxamide and methyl amine using the procedure described in Example 283. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.82 (d, J=5.56 Hz, 4H) 1.82 (dt, J=12.06, 5.97 Hz, 1H) 2.11 (s, 3H) 3.28 (s, 3H) 4.03 (s, 2H) 5.84 (s, 1H) 6.49 (s, 1H) 7.53 (d, J=8.08 Hz, 2H) 7.75 (d, J=8.08 Hz, 2H) 8.27 (s, 1H) 10.48 (s, 1H) 12.12 (s, 1H); ESI-MS: m/z calc'd for C22H24N8OS 448.54; found 449.4 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:20])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=1.Cl[C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[Cl:11][C:7]1[CH:6]=[C:5]2[C:10]([C:2]([NH:1][C:22](=[O:23])[O:24][CH2:25][CH3:26])=[C:3]([C:12](=[O:20])[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=3)[NH:4]2)=[CH:9][CH:8]=1
Reactant: CCOC(=O)Cl
Reactant: Cc1cccc(C(=O)c2[nH]c3cc(Cl)ccc3c2N)c1
Product: CCOC(=O)Nc1c(C(=O)c2cccc(C)c2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 3-amino-6-chloro-2-(3-methylbenzoyl)-1H-indole (step 2) and ethyl chloroformate.