Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(C[N:8]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]3[C:38]4[C:37]5[CH2:36][CH2:35][CH2:34][CH2:33][C:32]=5[C:31](=[O:39])[NH:30][C:29]=4[N:28]([CH3:40])[N:27]=3)[CH:21]=2)C(=O)OCC2C=CC=CC=2)=CC=1>FC(F)(F)C(O)=O>[NH2:8][CH2:19][C:20]1[CH:21]=[C:22]([C:26]2[C:38]3[C:37]4[CH2:36][CH2:35][CH2:34][CH2:33][C:32]=4[C:31](=[O:39])[NH:30][C:29]=3[N:28]([CH3:40])[N:27]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: COc1ccc(CN(Cc2cccc(-c3nn(C)c4[nH]c(=O)c5c(c34)CCCC5)c2)C(=O)OCc2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cn1nc(-c2cccc(CN)c2)c2c3c(c(=O)[nH]c21)CCCC3
Yield: 69.8 %

Procedure:
A solution of EXAMPLE 56F (3.4 g) in trifluoroacetic acid (20 mL) was stirred at 55° C. for 6 hours. The mixture was concentrated and the residue purified by HPLC (Zorbax, C-18, 250×2.54 column, Mobile phase A: 0.1% trifluoroacetic acid in water; B: 0.1% trifluoroacetic acid in acetonitrile; 0-100% gradient) to give the title compound (1.3 g, 50%) as the trifluoroacetate salt. 1H NMR (CD3OD) □ 2.28-2.40 (m, 2H), 2.44-2.57 (m, 2H), 3.08-3.37 (m, 4H), 4.69 (s, 3H), 4.93 (s, 2H), 8.26-8.37 (m, 3H), 8.43 (s, 1H).
Reaction SMILES: [CH3:1][C:2]([CH3:47])([CH3:46])[C@H:3]([NH:32][C:33](=[O:45])[C@@H:34]([N:36]([CH3:44])[C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])[CH3:35])[C:4]([N:6]1[C@H:15]([C:16](=[O:28])[NH:17][C@H:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21][CH2:20][CH2:19]2)[CH2:14][C:13]2[C:8](=[CH:9][C:10]([N+:29]([O-])=O)=[CH:11][CH:12]=2)[CH2:7]1)=[O:5]>CO.[Pd]>[NH2:29][C:10]1[CH:9]=[C:8]2[C:13]([CH2:14][C@@H:15]([C:16](=[O:28])[NH:17][C@H:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21][CH2:20][CH2:19]3)[N:6]([C:4](=[O:5])[C@@H:3]([NH:32][C:33](=[O:45])[C@@H:34]([N:36]([CH3:44])[C:37](=[O:43])[O:38][C:39]([CH3:41])([CH3:42])[CH3:40])[CH3:35])[C:2]([CH3:1])([CH3:46])[CH3:47])[CH2:7]2)=[CH:12][CH:11]=1
Reactant: C[C@@H](C(=O)N[C@H](C(=O)N1Cc2cc([N+](=O)[O-])ccc2C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: C[C@@H](C(=O)N[C@H](C(=O)N1Cc2cc(N)ccc2C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 91.8 %

Procedure:
To a pressure flask containing 10% Pd/C (240 mg, 0.23 mmol) was added a solution of tert-butyl ((S)-1-(((S)-3,3-dimethyl-1-((S)-7-nitro-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-1-oxobutan-2-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate (1.46 g, 2.25 mmol) in MeOH (11.2 mL). The resulting reaction mixture was stirred under H2 at 15 psi for 3 h and then filtered through a pad of CELITE® rinsing with EtOAc. The filtrate was concentrated in vacuo and redissolved in CH2Cl2. The solution was filtered through a 0.45 μM PTFE filter and concentrated in vacuo to give the title compound (1.28 g, 92%) as a yellow solid. MS (ESI+) m/z 620.4 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:9][C:8](=[O:18])[C:4]([C:5]([OH:7])=[O:6])=[C:3]1[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1.[OH-].[Na+:27]>CO>[CH3:1][N:2]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)=[CH:9][C:8](=[O:18])[C:4]([C:5]([O-:7])=[O:6])=[C:3]1[C:19]1[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=1.[Na+:27]
Reactant: Cn1c(-c2ccc(Cl)cc2)cc(=O)c(C(=O)O)c1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1c(-c2ccc(Cl)cc2)cc(=O)c(C(=O)[O-])c1-c1ccc(Cl)cc1
Yield: 96.7 %

Procedure:
3.32 gms of 1-methyl-2,6-di(4'-chlorophenyl)-4-oxonicotinic acid, 0.39 gms of NaOH and 50 mls of methanol were mixed. Evaporation of the solvent provided 3.4 gms of sodium 1-methyl-2,6-di(4'-chlorophenyl)-4-oxonicotinate as a glass solid.
Reaction SMILES: Cl.[CH2:2]([O:4][CH:5]([O:11][CH2:12][CH3:13])[C@@H:6]1[CH2:10][CH2:9][CH2:8][NH:7]1)[CH3:3].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][C:25](Cl)=[O:26])=[CH:18][CH:17]=1.C(N(CC)CC)C.CCOCC>C(Cl)Cl>[CH2:12]([O:11][CH:5]([O:4][CH2:2][CH3:3])[C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:25](=[O:26])[CH2:24][CH2:23][CH2:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][CH3:14])=[CH:21][CH:20]=1)[CH3:13]
Reactant: CCOC(OCC)[C@@H]1CCCN1
Reactant: COc1ccc(CCCC(=O)Cl)cc1
Agent: Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(OCC)[C@@H]1CCCN1C(=O)CCCc1ccc(OC)cc1
Reaction time: 0.5 h
Yield: 58 %

Procedure:
L-prolinal diethyl acetal hydrochloride is dissolved, together with 4-(p-methoxyphenyl)butyryl chloride (686 mg, 4.02 mmol) prepared in the same manner as described in Example 5, in methylene chloride (12 ml) and triethylamine (1.7 ml, 12.2 mmol) is added dropwise thereto under ice-cooling and agitation. After the dropwise addition, stirring is further continued for 30 minutes under cooling, and then for one hour at room temperature. Ether (40 ml) is added to the reaction mixture, and the ethereal layer is separated, washed with a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of edible salt, dried over sodium sulfate and filtered. The filtrate is concentrated to dryness under reduced pressure. The residue is purified by column chromatography on silica gel (n-hexane-ethyl acetate, 2:1) to give 805 mg (58%) of the title compound as a pale yellow syrup.
Reaction SMILES: [CH2:1]1[N:6]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2F)[CH2:5][CH2:4][N:3]([C:17]([C:19]2[C:24]3[NH:25][CH:26]=[C:27]([C:28]#[N:29])[C:23]=3[CH:22]=[CH:21][CH:20]=2)=[O:18])[CH2:2]1.O.[ClH:31]>CC(C)=O>[ClH:31].[F:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][CH2:7][N:6]2[CH2:5][CH2:4][N:3]([C:17]([C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:24]=3[NH:25][CH:26]=[C:27]4[C:28]#[N:29])=[O:18])[CH2:2][CH2:1]2)=[CH:10][CH:11]=1
Reactant: N#Cc1c[nH]c2c(C(=O)N3CCN(CCc4ccc(F)cc4F)CC3)cccc12
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: N#Cc1c[nH]c2c(C(=O)N3CCN(CCc4ccc(F)cc4)CC3)cccc12
Yield: 69 %

Procedure:
2.1 g of the free base of EMD281014 are heated in 50 ml of acetone, and water is added until a clear solution is formed. A mixture of 0.6 ml of hydrochloric acid (w=37%) and 1.2 ml of acetone is then stirred in. The mixture is subsequently evaporated to half the volume in a rotary evaporator. The precipitated hydrochloride is filtered off with suction, washed with acetone and diethyl ether and dried, giving 1.6 g of 7-{4-[2-(4-fluorophenyl)ethyl]-piperazine-1-carbonyl}-1H-indole-3-carbonitrile, hydrochloride (69% of theory), decomposition range 314-319°.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl[CH2:17][CH:18]([OH:22])[CH2:19][CH2:20][Cl:21]>O>[Cl:21][CH2:20][CH2:19][CH:18]([OH:22])[CH2:17][O:13][C:10]1[CH:9]=[CH:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:12][CH:11]=1
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: OC(CCl)CCCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: OC(CCCl)COc1ccc(-c2ccccc2)cc1
Temperature: 40 °C

Procedure:
To a solution of 1 mole (158 g.) of 4-phenylphenol 100 g. of sodium hydroxide and 500 ml. of water was added 1 mole (143.02 g.) of 1,4-dichloro-2-butanol with stirring at 40° C. The resulting mixture was heated at 68° C. in a steam bath for 6 hr., cooled and extracted with 300 ml. of chloroform. The chloroform extract was washed with water to neutrality, dried over sodium sulfate and concentrated to dryness. The solid residue was recrystallized with isopropanol and yielded 180 g. of a white crystalline solid which melted at 123°-124° C.
Reaction SMILES: [H-].[Na+].O1CCCC1.[C:8]([CH2:10]P(=O)(OCC)OCC)#[N:9].[Br:19][C:20]1[C:28]2[O:29][CH2:30][CH2:31][C:27]=2[C:26]2[C:25](=O)[CH2:24][CH2:23][C:22]=2[CH:21]=1>O>[Br:19][C:20]1[C:28]2[O:29][CH2:30][CH2:31][C:27]=2[C:26]2/[C:25](=[CH:10]/[C:8]#[N:9])/[CH2:24][CH2:23][C:22]=2[CH:21]=1
Reactant: O=C1CCc2cc(Br)c3c(c21)CCO3
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#C/C=C1\CCc2cc(Br)c3c(c21)CCO3
Reaction time: 0.33 h
Yield: 43.1 %

Procedure:
60% Sodium hydride (0.17 g, 4.35 mmols) was added to a tetrahydrofuran (20 ml) solution of diethyl cyanomethylphosphonate (0.77 g, 4.35 mmols) while cooling with ice, and the mixture was stirred for 20 minutes. To this was added a tetrahydrofuran (10 ml) solution of 4-bromo-1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one (1.00 g, 3.95 mmols), and the mixture was stirred at room temperature further for 2 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The extract was washed with a saturated saline solution, then dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified through silica-gel column chromatography (hexane/ethyl acetate=from 85/15 to 8/2) and then recrystallized from ethyl acetate/isopropyl ether to obtain 0.47 g (yield: 43%) of the target compound.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH:7]=[CH:8][O:9][C:4]=2[CH:3]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH:18]=O.Cl.CO>O>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:18]=[C:7]2[C:6](=[O:10])[C:5]3[CH:11]=[CH:12][C:2]([OH:1])=[CH:3][C:4]=3[O:9][CH2:8]2)[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: COc1ccc(C=O)cc1OC
Reactant: O=c1ccoc2cc(O)ccc12
Agent: Cl
Solvent: O
Solvent: CO
Product: COc1ccc(C=C2COc3cc(O)ccc3C2=O)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
After 7-hydroxy-4(4H)-benzopyranone 1.0 g and 3,4-dimethoxybenzaldehyde 1.22 g were added to a mixture of concentrated hydrochloric acid 50 ml and methanol 40 ml, the mixture was refluxed for 1.5 hours and cooled to room temperature, water 100 ml was added and the mixture was allowed to stand for 30 minutes. The precipitated crystals were filtered.
Reaction SMILES: Cl[S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[F:14][C:15]1[CH:22]=[CH:21][C:18]([NH:19][CH3:20])=[CH:17][CH:16]=1>>[F:14][C:15]1[CH:22]=[CH:21][C:18]([N:19]([CH3:20])[S:2]([C:5]2[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=2)(=[O:4])=[O:3])=[CH:17][CH:16]=1
Reactant: CNc1ccc(F)cc1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Product: CN(c1ccc(F)cc1)S(=O)(=O)c1ccc(C(=O)O)cc1

Procedure:
4-(chlorosulfonyl)benzoic acid (0.5 g, 2.27 mmol) was treated with 4-fluoro-N-methylaniline (851 mg, 6.80 mmol) using method A to give 4-(N-(4-fluorophenyl)-N-methylsulfamoyl)benzoic acid as a white solid. Yield: 534 mg (76%). 1H-NMR: 8.10 (d, J=8.5 Hz, 2H), 7.62 (d, J=8.5 Hz, 2H), 7.23-7.11 (m, 4H), 3.15 (s, 3H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[CH:4]=[O:5].[CH3:12][CH2:13][OH:14]>>[CH2:13]([O:14][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[CH:4]=[O:5])[CH3:12]
Reactant: CCO
Reactant: COc1cccc(F)c1C=O
Product: CCOc1cccc(OC)c1C=O
Temperature: 55 °C

Procedure:
A mixture of commercially available 2-fluoro-6-methoxybenzaldehyde (3.372 g; 21.90 mmol) and sodium hydroxide NaOH (10.208 g; 255.00 mmol) in EtOH (525 ml) was heated to 55° C. for 1 h. After cooling to rt, the reaction mixture was concentrated under reduced pressure. Water and DCM were added, and the aq. layer was further extracted with DCM. The mixed organic layers were dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure affording 2-ethoxy-6-methoxybenzaldehyde as a yellow oil. LC-MS (conditions A): tR=0.61 min.; [M+H]+: 181.13 g/mol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[NH:10][C:11](=[O:15])[O:12][CH2:13][CH3:14].C(=O)([O-])[O-].[K+].[K+].[CH:22]1(Br)[CH2:26][CH2:25][CH2:24][CH2:23]1>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:4][C:3]=1[NH:10][C:11](=[O:15])[O:12][CH2:13][CH3:14]
Reactant: CCOC(=O)Nc1cc(O)c(Cl)cc1F
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)Nc1cc(OC2CCCC2)c(Cl)cc1F
Reaction time: 7 h
Yield: 98.3 %

Procedure:
Then, a solution of the resulting ethyl N-(2-fluoro-4-chloro-5-hydroxyphenyl)carbamate (10.0 g, 42.8 mmol) and potassium carbonate (8.87 g, 64.2 mmol) in acetonitrile (150 ml) was stirred for 1 hour at 80° C. Then, cyclopentyl bromide (9.57 g, 84.2 mmol) was added dropwise thereto, followed by reacting for further 7 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was made acidic by adding 1N hydrochloric acid (100 ml) and extracted with ethyl acetate (100 ml×8 times). The organic layer was washed with water, dried, and the solvent was distilled off under reduced pressure to obtain ethyl N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)carbamate (12.7 g, 98% yield).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8](Cl)=[O:9])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([NH:19][C:20](=[O:37])[C:21]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH:22]=2)[CH:15]=[CH:16][C:17]=1[CH3:18]>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:11][C:12]2[CH:13]=[C:14]([NH:19][C:20](=[O:37])[C:21]3[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=[C:23]([N:31]4[CH2:32][CH2:33][O:34][CH2:35][CH2:36]4)[CH:22]=3)[CH:15]=[CH:16][C:17]=2[CH3:18])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: Cc1ccc(NC(=O)c2cc(N3CCOCC3)cc(C(F)(F)F)c2)cc1N
Product: Cc1ccc(NC(=O)c2cc(N3CCOCC3)cc(C(F)(F)F)c2)cc1NC(=O)c1ccc(Cl)nc1
Temperature: 100 °C
Yield: 63 %

Procedure:
Using an analogous procedure to that described in Example 2 except that the reaction mixture was heated to 100° C. for 2 hours, 6-chloropyridine-3-carbonyl chloride was reacted with N-(3-amino-4-methylphenyl)-3-morpholino-5-trifluoromethylbenzamide. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was dried over magnesium sulphate and evaporated. The residue was triturated under a mixture of isohexane and diethyl ether. There was thus obtained the title compound in 63% yield; NMR Spectrum: (DMSOd6): 2.2 (s, 3H), 3.3 (m, 4H) 3.75 (t, 4H), 7.25 (d, 1H), 7.35 (s, 1H), 7.55-7.65 (m, 1H), 7.65 (s, 1H), 7.7-7.75 (m, 2H), 7.8 (d, 1H), 8.35-8.4 (m, 1H), 8.95 (d, 1H), 10.15 (s, 1H), 10.33 (s, 1H); Mass Spectrum M+H+ 519 and 521.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[N:7][CH:6]=[CH:5][N:4]=1)=[CH2:2].[CH3:9][SH:10].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>>[CH3:9][S:10][CH2:2][CH2:1][C:3]1[CH:8]=[N:7][CH:6]=[CH:5][N:4]=1
Reactant: CS
Reactant: C=Cc1cnccn1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: CSCCc1cnccn1

Procedure:
h. 2-Pyrazinyl-ethyl methyl sulfide was prepared by reacting vinylpyrazine [c.f. J. Org. Chem. 27, 1363 (1962] with methylmercaptan by the action of ultra violet light and in the presence of benzoyl peroxide by the method described in Acta Chem. Scand. 8, 295 (1954). The product was identified by mass spectrometry. It has a b.p. of 57°-69°C. at 0.05 mm. Hg.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[NH:19][N:18]=3)[N:15]=2)[N:10]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:39][CH2:40][CH2:41][N:42]1[CH2:45][CH:44]([C:46]#[N:47])[CH2:43]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:28])[F:29])[CH:24]=4)[N:19]([CH2:39][CH2:40][CH2:41][N:42]4[CH2:45][CH:44]([C:46]#[N:47])[CH2:43]4)[N:18]=3)[N:15]=2)[N:10]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#CC1CN(CCCCl)C1
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4ccc(OC(F)F)cc34)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CCCN4CC(C#N)C4)c4ccc(OC(F)F)cc34)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 73.1 %

Procedure:
In a 2-5 mL Biotage microwave vial were mixed N-tert-butyl-2-(5-(difluoromethoxy)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (50 mg, 94.2 μmol), 1-(3-chloropropyl)azetidine-3-carbonitrile (44.8 mg, 283 μmol, Eq: 3.0) and Cs2CO3 (123 mg, 377 μmol) in DMF (2.00 mL). The mixture was stirred ˜10 min at 25° C. then heated to 100° C. in the Biotage microwave reactor for 30 min. LCMS showed complete reaction, diluted with 10 mL of dichloromethane and filtered through a celite pad, filtrate concentrated under high vacuum at 65° C. and residue dissolved in dichloromethane and purified by chromatography (spherical silica 20-45 μm, 23 g, Versaflash Supelco) eluting with 0 to 5% over 20 min (MeOH containing 10% ammonium hydroxide)/dichloromethane to give N-tert-butyl-2-(1-(3-(3-cyanoazetidin-1-yl)propyl)-5-(difluoromethoxy)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (45 mg, 68.9 μmol, 73.2%) as a white solid. MS (M+H)+=653.1; 1H NMR (CDCl3) δ: 9.22 (s, 1H), 8.36 (s, 1H), 8.31 (d, J=2.3 Hz, 1H), 8.04 (s, 1H), 7.58 (d, J=9.1 Hz, 1H), 7.36 (dd, J=8.9, 2.1 Hz, 1H), 6.56 (t, J=73.7 Hz, 1H), 5.75 (s, 2H), 4.57 (t, J=6.6 Hz, 2H), 3.24-3.40 (m, 3H), 2.50 (t, J=6.6 Hz, 2H), 2.08 (quin, J=6.5 Hz, 2H), 1.65 (s, 9H), 0.91-1.03 (m, 2H), 0.00 (s, 9H).
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[C:11]([C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([F:22])[CH:21]=1)[C:16](O)=O)#[N:12].N>>[F:22][C:20]1[CH:21]=[C:13]([CH:14]=[C:15]([C:16]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[N:10]=2)[CH:19]=1)[C:11]#[N:12]
Reactant: N#Cc1cc(F)cc(C(=O)O)c1
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: N#Cc1cc(F)cc(-c2nc(-c3cccnc3)no2)c1

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 3-cyano-5-fluorobenzoic acid (Aldrich). 1H NMR (300 MHz, CD3OD) δ 7.65 (ddd, J=8.0, 5.1, 0.8 Hz, 1H), 7.95 (ddd, J=8.1, 2.6, 1.6 Hz, 1H), 8.32 (ddd, J=8.7, 2.6, 1.4 Hz, 1H), 8.46 (t, J=1.4 Hz, 1H), 8.58 (ddd, J=8.1, 2.0, 1.8 Hz, 1H), 8.76 (dd, J=5.2, 1.6 Hz, 1H), 9.31 (dd, J=2.0, 0.8 Hz, 1H) ppm; MS (DCl/NH3) m/z 267 (M+H)+.
Reaction SMILES: Br[C:2]1[S:10][C:5]2[C:6](=[O:9])[NH:7][CH2:8][C:4]=2[CH:3]=1.[CH:11]1([B-](F)(F)F)[CH2:13][CH2:12]1.[K+].C(=O)([O-])[O-].[Cs+].[Cs+].C(P(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2)CCC>C(OCC)(=O)C.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[CH:11]1([C:2]2[S:10][C:5]3[C:6](=[O:9])[NH:7][CH2:8][C:4]=3[CH:3]=2)[CH2:13][CH2:12]1
Reactant: O=C1NCc2cc(Br)sc21
Reactant: F[B-](F)(F)C1CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCCP(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1NCc2cc(C3CC3)sc21
Temperature: 100 °C
Yield: 34.4 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a reflux condenser, magnetic stirrer and nitrogen inlet was charged with 116f (900 mg, 4.12 mmol), potassium cyclopropyltrifluoroborate (733 mg, 4.95 mmol), cesium carbonate (4.03 g, 12.4 mmol), toluene (18 mL), water (1 mL). After bubbling nitrogen through the resulting suspension for 30 min, palladium(II) acetate (279 mg, 0.412 mmol) and n-butyldi-1-adamantylphosphine (222 mg, 0.618 mmol) were added, and the reaction mixture was heated at 100° C. for 14 h. After this time, the mixture was cooled to room temperature and diluted with ethyl acetate (150 mL) and water (30 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3×150 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 0% to 5% methanol/methylene chloride) to afford a 35% yield (254 mg) of 116g as an off-white solid: mp 109-110° C.; 1H NMR (300 MHz, CDCl3) δ 6.72 (s, 1H), 6.08 (br s, 1H), 4.28 (s, 2H), 2.16 (m, 1H), 1.09 (m, 2H), 0.84 (m, 1H); MS (ESI+) m/z 180.1 (M+H).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[N:7](C(OCC)=O)[C:6]=1[C:20](=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=1)(=O)C.[C:29](OCC)(=[O:31])[CH3:30]>>[C:29]([N:4]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:20](=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=1)[CH3:1])(=[O:31])[CH3:30]
Reactant: CCOC(=O)n1c(C(=O)c2cccc(Cl)c2)c(NC(C)=O)c2ccc(Cl)cc21
Reactant: CCOC(C)=O
Product: CC(=O)N(C)c1c(C(=O)c2cccc(Cl)c2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared from 3-acetylamino-6-chloro-2-(3-chlorobenzoyl)-1-(ethoxycarbonyl)indole (Example 31, step 1) according to the procedure described in Example 146. m.p.: 202-203° C. (ethyl acetate)
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:25])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[Br:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]Br.Cl>CCCCCC.C1(C)C=CC=CC=1>[CH2:3]([O:25][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][Br:26])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCCCCCCCCCCCCCO
Reactant: BrCCCCCCCCCCCCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCCCCCCCCCCCCCCCCCCCCCOCCCCCCCCCCCCBr
Temperature: 85 °C
Reaction time: 48 h
Yield: 78 %

Procedure:
Sodium hydride (60%, 0.98 g, 24.5 mmol) washed with hexane was suspended in toluene (16 ml), 1-docosanol (4.00 g, 12.2 mmol) was added, 1,12-dibromododecane (8.04 g, 24.5 mmol) was added, and the mixture was stirred at 85° C. for 2 days. The reaction mixture was cooled to room temperature, 1N hydrochloric acid (30 ml) was added dropwise thereto in a water bath to quench the reaction. The mixture was extracted with chloroform (100 ml), and washed 3 times with 1N hydrochloric acid (30 ml), 3 times with 5% aqueous sodium hydrogen carbonate solution (30 ml), and once with 20% aqueous sodium chloride solution (30 ml). The organic layer was dried over sodium sulfate, and the solvent of the filtrate was evaporated. The residue was isolated and purified by silica gel column chromatography and precipitated with methanol (70 ml) to give 12-docosyloxy-dodecyl bromide (yield 78%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([C:21]([OH:23])=O)=[N:19][CH:20]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[N:6][CH:7]=1.[NH2:25][C:26]([CH3:30])([CH3:29])[CH2:27][OH:28]>>[OH:28][CH2:27][C:26]([NH:25][C:21]([C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=3)=[N:9][O:10][C:11]=2[CH3:24])=[CH:20][N:19]=1)=[O:23])([CH3:30])[CH3:29]
Reactant: CC(C)(N)CO
Reactant: Cc1onc(-c2ccc(F)cn2)c1COc1ccc(C(=O)O)nc1
Product: Cc1onc(-c2ccc(F)cn2)c1COc1ccc(C(=O)NC(C)(C)CO)nc1
Yield: 66 %

Procedure:
As described for example 23f, 5-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-pyridine-2-carboxylic acid (75 mg, 0.23 mmol) was converted, using 2-amino-2-methyl-1-propanol instead of isopropylamine, to the title compound (60 mg, 66%), which was obtained as a light-bluish solid. MS: m/e=401.4 [M+H]+.