Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:20]2[N:25]([C:26]3[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([F:33])[CH:27]=3)[C:24](=[O:34])[C:23]3=[C:35]([C:38]#[N:39])[CH:36]=[CH:37][N:22]3[N:21]=2)[CH2:10][CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:3]=1I.[F:41][C:42]1[CH:43]=[C:44](B(O)O)[CH:45]=[C:46]([OH:48])[CH:47]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:20]2[N:25]([C:26]3[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([F:33])[CH:27]=3)[C:24](=[O:34])[C:23]3=[C:35]([C:38]#[N:39])[CH:36]=[CH:37][N:22]3[N:21]=2)[CH2:10][CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:3]=1[C:44]1[CH:45]=[C:46]([OH:48])[CH:47]=[C:42]([F:41])[CH:43]=1
Reactant: N#Cc1ccn2nc([C@H](CCOCc3ccccc3)Nc3ncnc(N)c3I)n(-c3cc(F)cc(F)c3)c(=O)c12
Reactant: OB(O)c1cc(O)cc(F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: N#Cc1ccn2nc([C@H](CCOCc3ccccc3)Nc3ncnc(N)c3-c3cc(O)cc(F)c3)n(-c3cc(F)cc(F)c3)c(=O)c12
Yield: 15.7 %

Procedure:
(S)-2-(1-((6-Amino-5-iodopyrimidin-4-yl)amino)-3-(benzyloxy)propyl)-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-5-carbonitrile (12 mg, 0.02 mmol) was treated with (3-fluoro-5-hydroxyphenyl)boronic acid (4.5 mg, 0.03 mmol), sodium carbonate (2 M, 55 μl, 0.11 mmol) and 2′-(dimethylamino)-2-biphenylyl-palladium(II) chloride dinorbornylphosphine complex (2 mg, 0.001 mmol) according to the method described in the Preparation 17. The residue was purified by reverse phase using SP1® Purification System to give 2 mg (18% yield) of the title compound as a white solid. Purity 97%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C@H:8]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl:21]N1C(=O)CCC1=O>C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:20])[NH:7][C@@H:8]1[CH2:9][CH2:10][C:11]2[CH:19]=[C:18]([Cl:21])[CH:17]=[CH:16][C:12]=2[NH:13][C:14]1=[O:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCc2ccccc2NC1=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H]1CCc2cc(Cl)ccc2NC1=O
Temperature: 0 °C
Reaction time: 24 h

Procedure:
A round-bottom flask containing ((R)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-carbamic acid tert-butyl ester (3.09 g, 11.2 mmol) was fitted with a stirbar and septa and flushed with nitrogen. N,N-Dimethylformamide (30 mL) was added, giving a solution that was cooled to 0° C. N-Chlorosuccinimide (2.20 g, 16.5 mmol) was then added, and stirring was continued for 24 hours. The reaction was then poured into ethyl acetate (200 mL) and washed with 1:1 H2O:saturated aqueous NaCl solution (2×100 mL). The organic layer was dried over MgSO4, filtered and concentrated in vacuo to give a solid that was purified via flash chromatography on silica gel (5% to 30% ethyl acetate/hexanes linear gradient) to give the desired product.
Reaction SMILES: [C:1]([CH:3]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH2:5][C:4]1([CH3:11])[CH3:10])#[N:2].[OH2:12]>[OH-].[Na+].CO>[CH3:8][C:7]1([CH3:9])[CH2:6][CH2:5][C:4]([CH3:11])([CH3:10])[CH:3]1[C:1]([NH2:2])=[O:12]
Reactant: O
Reactant: CC1(C)CCC(C)(C)C1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)CCC(C)(C)C1C(N)=O
Temperature: 25 °C
Reaction time: 10 h

Procedure:
760 mg of 1-cyano-2,2,5,5-tetramethylcyclopentane was dissolved in 5 ml of aqueous 3N sodium hydroxide solution and 10 ml of MeOH, and the solution was stirred at room temperature for 10 hours. Then, 10 ml of water was added thereto, and the mixture was twice extracted with 30 ml of chloroform. The organic layers were combined, washed with 50 ml of water and concentrated under reduced pressure. The thus obtained residue was recrystallized from n-hexane, whereby 640 mg of (2,2,5,5-tetramethylcyclopentane-1-yl)carboxamide was obtained (m.p. 97.7° C.).
Reaction SMILES: [C:1]1([C:7]([NH:12][CH3:13])([CH2:10][CH3:11])[CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH2:26]Cl)[CH:19]=[C:20]([O:24][CH3:25])[C:21]=1[O:22][CH3:23]>>[CH3:25][O:24][C:20]1[CH:19]=[C:18]([CH:17]=[C:16]([O:15][CH3:14])[C:21]=1[O:22][CH3:23])[CH2:26][O:9][CH2:8][C:7]([NH:12][CH3:13])([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:10][CH3:11]
Reactant: CCC(CO)(NC)c1ccccc1
Reactant: COc1cc(CCl)cc(OC)c1OC
Product: CCC(COCc1cc(OC)c(OC)c(OC)c1)(NC)c1ccccc1

Procedure:
Prepared by the process of Example 3 from 2-phenyl-2-methylamino-1-butanol and from 3,4,5-trimethoxy-α-chlorotoluene; the product is obtained in the form of a colourless and viscous oil which is analytically pure and appropriate.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:26])=[N+:7]([O-])[C:8]([CH:11]([O:21][C:22](=[O:24])[CH3:23])[CH2:12][N:13]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:14](=[O:16])[CH3:15])=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[C:27]([O:30]C(=O)C)(=[O:29])[CH3:28].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[C:1]([O:4][C:5]1[C:6]([CH2:26][O:30][C:27](=[O:29])[CH3:28])=[N:7][C:8]([CH:11]([O:21][C:22](=[O:24])[CH3:23])[CH2:12][N:13]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:14](=[O:16])[CH3:15])=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)Oc1ccc(C(CN(C(C)=O)C(C)(C)C)OC(C)=O)[n+]([O-])c1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(=O)OCc1nc(C(CN(C(C)=O)C(C)(C)C)OC(C)=O)ccc1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 27 %

Procedure:
A solution of 1.0 g. (0.0027 mole) of 3-acetoxy-2-methyl-6-[1-acetoxy-2-(N-tert-butylacetamido)ethyl]-pyridine N-oxide in 10 ml. of acetic anhydride was heated at the reflux temperature for 2.5 hours, then was allowed to cool to room temperature and stirred at this temperature overnight. The reaction mixture was poured into a two phase mixture of ethyl acetate and aqueous sodium bicarbonate and stirred for 1 hour. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness in vacuo to give a brown oil which was purified by column chromatography on silica gel with ether as the eluant to give 300 mg. (27%) of the desired product; m.p. 60°-64° C.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27]([C:30]2[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=2)[C:33](O)=[O:34])(=[O:29])=[O:28])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH2:39]([NH2:45])[C:40]1[O:44][CH:43]=[CH:42][CH:41]=1>>[O:44]1[CH:43]=[CH:42][CH:41]=[C:40]1[CH2:39][NH:45][C:33](=[O:34])[C:32]1[CH:36]=[CH:37][CH:38]=[C:30]([S:27]([CH2:26][C:16]2[C:17]3[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=3[CH:23]=[CH:24][C:15]=2[O:14][C@@H:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)(=[O:29])=[O:28])[CH:31]=1
Reactant: NCc1ccco1
Reactant: O=C(O)c1cccc(S(=O)(=O)Cc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)c1
Product: O=C(NCc1ccco1)c1cccc(S(=O)(=O)Cc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)c1
Yield: 90.2 %

Procedure:
Using the method in Example 172, 3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoic acid (53 mg, 0.10 mmol, 0.20M in DMF) and furfurylamine (29 mg, 0.30 mmol, 0.6M in DMF) were combined to give 55 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 610 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.BrN1C(=[O:18])CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(OCC)(=O)C>[N:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([CH2:1][OH:18])[CH:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2cccnc2c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCOC(C)=O
Product: OCc1ccc2cccnc2c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 3 %

Procedure:
To a solution of 7-methylquinoline (2.86 g) in ethyl acetate (100 mL) were added N-bromosuccinimide (3.56 g) and 2,2′-azobis(isobutyronitrile) (197 mg) at room temperature, and the mixture was refluxed for 1.5 hr. The reaction mixture was allowed to cool to room temperature, and washed with water. The obtained organic layer was concentrated under reduced pressure, to the residue were added DME (200 mL), water (100 mL), and silver carbonate (27.6 g), and the mixture was stirred at room temperature for 20 hr. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol), and then purified by NH silica gel column chromatography (ethyl acetate/hexane) to give the title compound (94 mg).
Reaction SMILES: [O:1]([CH2:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].O.O.O.O.O.O.[OH-].[Ba+2].[OH-].[C:28]([O:32][C:33]([NH:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1Br)=[O:34])([CH3:31])([CH3:30])[CH3:29]>COCCOC.[Cl-].[NH4+].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:28]([O:32][C:33]([NH:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[C:13]1[CH:14]=[CH:15][C:10]([CH2:9][O:1][Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3])=[CH:11][CH:12]=1)=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)NCc1ccccc1Br
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: [Ba+2]
Agent: [Cl-]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)NCc1ccccc1-c1ccc(CO[Si](C)(C)C(C)(C)C)cc1
Temperature: 80 °C
Yield: 75.1 %

Procedure:
To a solution of 1.0 g (3.8 mmol) of 4-(t-butyldimethaylsilyoxymethyl)phenylboronic acid (Step E) in 24 mL of 1,2-dimethyoxyethane was added 4 mL of water,m 1.02 g (5.37 mmol) of barium hydroxide hexahydrate, 1.02 g (3.58 mmol) of N-(t-butoxycarbonyl)-2-bromobenzylamine (Step F) and 206 mg (0.18 mmol) of tetrakis(triphenylphosphine) palladium. The resulting mixture was heated under nitrogen at 80° C. for 2.5 hours then cooled to room temperature. The reaction mixture was diluted with 40 mL of saturated aqueous ammonium chloride. The solution was transferred to a separatory funnel and extracted with ether (3×75 mL). The combined ether extracts were washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over magnesium sulfate and then filtered. The solvent was removed under vacuum to give a crude product which was purified by column chromatography on silica gel eluting with hexanes/ethyl acetate (85:15) to afford 1.15 g (75%) of the product as a clear oil. FAB-MS: calculated for C25H37NO3Si 427; found 314. 1H NMR (200 MHz, CDCl3): 0.10 (s, 6H), 0.92 (s, 9H), 1.40 (s, 9H), 4.27 (d, 5 Hz, 2H), 4.60 (s, 1H), 4.78 (s, 2H), 7.18-7.45 (m, 8H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15].[CH3:16][C:17]1[CH:22]=[C:21]([CH3:23])[N:20]=[C:19]([C:24](O)=[O:25])[CH:18]=1>>[CH3:1][N:2]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])[C:24]([C:19]1[CH:18]=[C:17]([CH3:16])[CH:22]=[C:21]([CH3:23])[N:20]=1)=[O:25]
Reactant: CNc1cnccc1-c1ccccc1C
Reactant: Cc1cc(C)nc(C(=O)O)c1
Product: Cc1cc(C)nc(C(=O)N(C)c2cnccc2-c2ccccc2C)c1

Procedure:
The title compound was prepared in analogy to example 90, from N-methyl-4-o-tolylpyridin-3-amine (example 1, intermediate a) and 4,6-dimethylpyridine-2-carboxylic acid (CAS RN 18088-10-3) after a reaction time of 64 hours. The compound was purified by silica gel chromatography on a 10 g column using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Light brown oil (37%). MS (ESI): m/z=332.18 [M+H]+.
Reaction SMILES: [CH2:1]([C:9]1[CH:21]=[CH:20][C:19]2[C:18]3[C:13](=[CH:14][C:15]([C:22]4[S:23][C:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[N:25][N:26]=4)=[CH:16][CH:17]=3)[CH2:12][C:11]=2[CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH-:33].C[N+](C)(C)CC1C=CC=CC=1>N1C=CC=CC=1>[CH2:1]([C:9]1[C:10](=[O:33])[C:11]2[C:19](=[CH:20][CH:21]=1)[C:18]1[C:13](=[CH:14][C:15]([C:22]3[S:23][C:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[N:25][N:26]=3)=[CH:16][CH:17]=1)[CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: [OH-]
Reactant: CCCCCCCCc1ccc2c(c1)Cc1cc(-c3nnc(CCCCCC)s3)ccc1-2
Agent: C[N+](C)(C)Cc1ccccc1
Solvent: c1ccncc1
Product: CCCCCCCCC1=CC=C2C(=Cc3cc(-c4nnc(CCCCCC)s4)ccc32)C1=O
Temperature: 0 °C
Yield: 53.3 %

Procedure:
To a solution of 0.20 g (0.45 mM) of 2-octyl-7-(5-hexyl-1,3,4-thiadiazole-2-yl)fluorene in 20 ml of pyridine, 0.27 ml of 40%-trimethylbenzylammonium hydroxide aqueous solutions as added at 3.5°-4.5° C. under stirring on ice water bath, followed by stirring for 0.5 hour at 3.5°-4.5° C. After the reaction, the reaction mixture was poured into ice water to precipitate a crystal. The crystal was recovered by filtration, washed with water and dissolved in toluene, followed by drying with anhydrous sodium sulfate and distilling-off of the solvent under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (eluent: toluene/ethyl acetate=20/1) and recrystallized from a mixture solvent of toluene-acetone to obtain 0.11 g of 2-octyl-7-(5-hexyl-1,3,4-thiadiazole-2-yl)fluorenone (Yield: 53.3%). ##STR89##
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][C:9]([F:12])([F:11])[F:10].B(O)(O)[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl.CO>COCCOC.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>[F:10][C:9]([F:12])([F:11])[O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1
Reactant: FC(F)(F)Oc1ccccc1Br
Reactant: OB(O)c1ccncc1
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: COCCOC
Solvent: ClCCl
Solvent: CO
Product: FC(F)(F)Oc1ccccc1-c1ccncc1
Yield: 51 %

Procedure:
To a solution of (commercially available) (1-bromo-2-trifluoromethoxy-benzene) in DME (first degased with argon) under argon was added 3 mol % Pd(PPh3)4, pyridyl-4-boronic acid and 2N Na2CO3, the resulting reaction mixture was vigorously stirred under reflux. After 5 h at reflux, reaction as monitored by TLC showed completion. Two phases were separated, evaporation of most of the DME, redissolution of the residue in EtOAc and washing with aq. NaOH followed by evaporation gave a yellow oil. Flash Chromatography on SiO2 gel with a mixture of CH2Cl2/MeOH gave the title compound in 51% yield.
Reaction SMILES: [CH:1]([N:4]1[CH2:10][C:9]2[CH:11]=[C:12]([C:15]([NH:17][CH2:18][C:19]3[NH:20][C:21]4[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=4[N:23]=3)=[O:16])[CH:13]=[CH:14][C:8]=2[NH:7][CH:6]([CH2:28][C:29]([O:31]C)=[O:30])[C:5]1=[O:33])([CH3:3])[CH3:2].[Li+].[OH-].C1COCC1.CC#N.O>O>[CH:1]([N:4]1[CH2:10][C:9]2[CH:11]=[C:12]([C:15]([NH:17][CH2:18][C:19]3[NH:23][C:22]4[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=4[N:20]=3)=[O:16])[CH:13]=[CH:14][C:8]=2[NH:7][CH:6]([CH2:28][C:29]([OH:31])=[O:30])[C:5]1=[O:33])([CH3:3])[CH3:2]
Reactant: COC(=O)CC1Nc2ccc(C(=O)NCc3nc4ccccc4[nH]3)cc2CN(C(C)C)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC#N
Product: CC(C)N1Cc2cc(C(=O)NCc3nc4ccccc4[nH]3)ccc2NC(CC(=O)O)C1=O
Temperature: 35 °C
Reaction time: 0.75 h
Yield: 110.5 %

Procedure:
A mixture of methyl (±)-4-isopropyl-7-[[[(2-benzimidazolyl)methyl]amino]carbonyl]-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate (275.1 mg, 0.61 mmol), 1.0 N LiOH (0.73 mL, 0.73 mmol), THF (3 mL), and H2O (2.3 mL) was stirred at 35° C. for 45 min, and the resulting solution was stirred at RT. After 17.5 h, the solution was filtered, and the filtrate was neutralized with 1.0 N HCl (0.73 mL). Since the product did not precipitate, the solution was acidified with TFA (0.2 mL) and concentrated. The resulting solid was triturated with H2O to leave a nearly colorless solid, which was dissolved with warming in 1:1 CH3CN/H2O. The solution was cooled to RT and diluted with several volumes of H2O/0.1% TFA. ODS chromatography (20% CH3CN/H2O-0.1% TFA), concentration, and lyophilization gave the title compound (293.4 mg, 80%) as a colorless powder: HPLC (PRP-1®, 20% CH3CN/H2O-0.1% TFA) K'=2.5; 1H NMR (400 MHz, CD3OD) δ 7.70-7.76 (m, 2H), 7.65 (d, J=2.2 Hz, 1H), 7.61 (dd, J=8.5, 2.2 Hz, 1H), 7.53-7.60 (m, 2H), 6.62 (d, J=8.5 Hz, 1H), 5.33 (d, J=16.9 Hz, 1H), 5.21 (dd, J=8.9, 5.2 Hz, 1H), 4.97 (d, J=1.9 Hz, 2H), 4.72-4.85 (m, 1H), 4.10 (d, J=16.9 Hz, 1H), 2.96 (dd, J=16.8, 8.9 Hz, 1H), 2.65 (dd, J=16.8, 5.2 Hz, 1H), 1.21 (d, J=6.7 Hz, 3H), 1.03 (d, J=6.8 Hz, 3H); MS (ES) m/e 436.2 (M+H)+. Anal. Calcd for C23H25N5O4.1.25 CF3CO2H.1.25 H2O: C, 51.00; H, 4.83; N, 11.66. Found: C, 51.12; H, 4.91; N, 11.37.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[N:11]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH:12]=[CH:13][C:3]=12.Cl.[O:24]1[CH2:29][CH2:28][CH2:27][CH:26]([NH2:30])[CH2:25]1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[N+:8]([C:7]1[CH:6]=[N:5][C:4]2[N:11]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH:12]=[CH:13][C:3]=2[C:2]=1[NH:30][CH:26]1[CH2:27][CH2:28][CH2:29][O:24][CH2:25]1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Reactant: NC1CCCOC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCCOC1
Temperature: 82 °C
Reaction time: 4 h
Yield: 88.1 %

Procedure:
A stirred suspension of 4-chloro-5-nitro-1-(phenyl sulfonyl)-1H-pyrrolo[2,3-b]pyridine (11.10 g, 33.0 mmol) in isopropanol (IPA) (100 ml) was treated with tetrahydro-2H-pyran-3-amine hydrochloride (5.0 g, 36.0 mmol) and N,N-diisopropylethylamine (15.0 mL, 84.0 mmol), and stirred at 82° C. for four hours. The mixture was then cooled and left to stand at 5° C. for 2 h. The resulting precipitate was collected by filtration and washed with IPA. Trituration (water) afforded 11.7 g (89%) of 5-nitro-1-(phenylsulfonyl)-N-(tetrahydro-2H-pyran-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine. LCMS (Method E, ESI): RT=1.65 min, m+H=403.2; 1H NMR (400 MHz, CDCl3) δ 9.22 (d, J=7.6 Hz, 1H), 9.11 (s, 1H), 8.20 (d, J=8.0 Hz, 2H), 7.69-7.56 (m, 2H), 7.60-7.42 (m, 2H), 6.76 (d, J=4.2 Hz, 1H), 4.14 (ddt, J=10.7, 7.1, 3.5 Hz, 1H), 3.98 (dd, J=11.5, 2.7 Hz, 1H), 3.85-3.62 (m, 2H), 3.58 (dd, J=11.5, 6.4 Hz, 1H), 2.27-2.06 (m, 1H), 1.86 (tdt, J=11.8, 7.5, 3.9 Hz, 2H), 1.79-1.63 (m, 1H).
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([CH2:13][NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:6]2[N:5]=1)=O.[CH2:21]1[N:26]([C:27]2[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=2)[CH2:25][CH2:24][O:23][CH2:22]1.C(N(CC)C(C)C)(C)C.COCC(O)C>>[N:26]1([C:27]2[CH:28]=[CH:29][C:30]([NH:33][C:4]3[N:9]=[CH:8][C:7]4=[CH:10][CH:11]=[C:12]([CH2:13][NH:14][C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=5)[N:6]4[N:5]=3)=[CH:31][CH:32]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: CS(=O)c1ncc2ccc(CNc3ccccc3)n2n1
Reactant: Nc1ccc(N2CCOCC2)cc1
Solvent: COCC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc(NCc2ccc3cnc(Nc4ccc(N5CCOCC5)cc4)nn23)cc1
Yield: 30.5 %

Procedure:
(2-Methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-ylmethyl)-phenyl-amine (40.0 mg, 0.140 mmol), 4-(4-morpholino)aniline (49.8 mg, 0.279 mmol) and N,N-Diisopropylethylamine (0.0730 mL, 0.419 mmol) were dissolved in 1-Methoxy-2-propanol (0.50 mL, 5.1 mmol) and the reaction was irradiated at 300 watts, 200° C. for 20 minutes or longer depending on HPLC monitoring. The reaction was then reduced under nitrogen. The crude reaction mixture was purified via Gilson reverse phase chromatography. Combined fractions were lyophilized to afford 17.12 mg of (4-Morpholin-4-yl-phenyl)-(7-phenylaminomethyl-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-amine as a TFA salt. (M+H)=401.16. 1H NMR (400 MHz, DMSO, d6) δ 9.32 (s, 1H), 8.87 (s, 1H), 7.72 (d, 2H, J=8.29 Hz), 7.09 (t, 2H, J=7.32 Hz), 6.97 (m, 2H), 6.76 (m, 1H), 6.67 (m, 3H), 6.60 (t, 1H, J=7.32 Hz), 4.59 (s, 2H), 3.77 (m, 4H), 3.12 (m, 4H).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1/[C:21](/[CH3:27])=[CH:22]/[C:23](OC)=[O:24].[NH4+].[Cl-]>C1(C)C=CC=CC=1.C(Cl)Cl>[CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1/[C:21](/[CH3:27])=[CH:22]/[CH2:23][OH:24]
Reactant: COC(=O)/C=C(\C)c1ccc2ccccc2c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C/C(=C\CO)c1ccc2ccccc2c1
Temperature: -78 °C
Reaction time: 4 h
Yield: 98 %

Procedure:
A solution of diisobutylaluminum hydride in toluene (1.5M, 45 ml) was added dropwise to a solution of methyl (E)-3-(2-naphthyl)crotonate (6.01 g) in CH2Cl2 at −78° C. and the mixture was stirred at −78° C. for 4 hours. 1N-Hhydrochloric acid and saturated aqueous solution of NH4Cl were added to the mixture and organic layer was washed with 1N HCl and brine, dried and concentrated. The residue was crystallized from hexane to give the titled compound (5.16 g) as a white solid.
Reaction SMILES: [C:1]([NH2:4])#[C:2][CH3:3].[C:5](Cl)(=[O:14])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>C(N(CC)CC)C>[C:1]([NH:4][C:5](=[O:14])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])#[C:2][CH3:3]
Reactant: CC#CN
Reactant: CCCCCCCCC(=O)Cl
Solvent: CCN(CC)CC
Product: CC#CNC(=O)CCCCCCCC
Yield: 62 %

Procedure:
Propynylamine (10.4 ml, 151.2 mmol) was mixed with 150 ml of triethylamine in a round bottom flask immersed in a cold water bath, and vigorously stirred while nonanoyl chloride (27.0 ml, 149.75 retool) was added in portions from a dropping funnel over a 30 minute period. Additional triethylamine (100 ml) was added to facilitate stirring. At the end of the addition, the water bath was removed and the reaction was stirred for 30 minutes, then filtered. The filtrate was stripped down to a yellow solid. The solid was partitioned between ether and aqueous NaOH, requiring a considerable quantity of ether to dissolve. The combined ether extracts were stripped and recrystallized from heptane to give product as a white crystalline solid, 18.12 g, 92.8 mmol, 62% yield; top. 78°-79.5° C.; 1H NMR (CDCl3) ∂0.88 (t, J=6.0 Hz, 3 H), 1.28 (m, 10 H), 1.63 (m, 2 H), 2.19 (t, J= 7.6 Hz, 2 H), 2.22 (t, J=2.7 Hz, 1 H), 4.06 (dd, J=5.2, 2.6 Hz), 5.62 (br s, 1 H); EI mass spectrum m/z 196 (M+H)+.
Reaction SMILES: [C:1]1([S:7]([N:10]=[C:11]=[O:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:13][CH2:14][CH2:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[CH2:18][C:19](=[O:25])[NH:20]2.[OH-].[Na+]>O1CCCC1.CN(C)C=O.N1C=CC=CC=1>[O:25]=[C:19]1[CH2:18][C:17]2[C:21](=[CH:22][CH:23]=[CH:24][C:16]=2[CH2:15][CH2:14][O:13][C:11](=[O:12])[NH:10][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:8])=[O:9])[NH:20]1
Reactant: O=C1Cc2c(CCO)cccc2N1
Reactant: O=C=NS(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C1Cc2c(CCOC(=O)NS(=O)(=O)c3ccccc3)cccc2N1
Temperature: 80 °C
Yield: 27.1 %

Procedure:
Benzene sulfonyl isocyanate (1.07 mL, 8 mmol) was added dropwise to a stirred mixture of 4-(2-hydroxy-ethyl)-1,3-dihydro-indol-2-one (709 mg, 4 mmol) in tetrahydrofuran (8 mL), dimethylforamide (2 mL) and pyridine (3 drops) under nitrogen atmosphere. The mixture was heated at 80° C. for 15 hours. The reaction was cooled, poured into 1 N sodium hydroxide solution (100 mL) and extracted with ethyl acetate (200 mL). The organic layer was discarded and the basic aqueous layer was acidified with 6 N hydrochloric acid (18 mL) followed by extraction into ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was recrystallized from methanol/ethyl acetate/hexane to give 390 mg (27%) of benzene sulfonyl-carbamic acid 2-(2-oxo-2,3-dihydro-1H-indol-4-yl)-ethyl ester as an off-white powder.