Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH2:8][O:9][CH2:10][CH2:11][CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:7]=1.C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[C:39]3[C:44](=[N:45][CH:46]=2)[N:43]([C:47]([NH2:49])=[O:48])[CH2:42][CH2:41][CH2:40]3)O1.CCOC(C)=O>O>[CH3:16][S:13]([CH2:12][CH2:11][CH2:10][O:9][CH2:8][C:6]1[CH:7]=[C:2]([C:37]2[CH:38]=[C:39]3[C:44](=[N:45][CH:46]=2)[N:43]([C:47]([NH2:49])=[O:48])[CH2:42][CH2:41][CH2:40]3)[CH:3]=[N:4][CH:5]=1)(=[O:15])=[O:14]
Reactant: CS(=O)(=O)CCCOCc1cncc(Br)c1
Reactant: CC1(C)OB(c2cnc3c(c2)CCCN3C(N)=O)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CS(=O)(=O)CCCOCc1cncc(-c2cnc3c(c2)CCCN3C(N)=O)c1
Yield: 51.9 %

Procedure:
3-Bromo-5-(3-methanesulfonyl-propoxymethyl)-pyridine (61 mg, 0.20 mmol) and 2.0 M Na2CO3 aqueous solution (0.20 mL, 0.40 mmol) are added into the crude 6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide 1,4-dioxane solution (2.0 mL, 0.24 mmol) which is synthesized according to the procedure for Step 3 of Example 16. Argon gas is bubbled through the solution for 5 min. Then PdCl2dppf (7.3 mg, 0.010 mmol) is added. The mixture is heated at 100° C. for 3.5 hrs before EtOAc (15 mL) and water (15 mL) are added. The aqueous layer is separated and extracted with EtOAc (2×10 mL). The organic layers are combined and concentrated to give the crude product. Purification by flash column chromatography affords 42 mg of the titled product.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].CC(C)([O-])C.[K+].Br[CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O>[C:20]1([CH2:19][CH2:18][CH2:17][O:9][C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCCCc1ccccc1
Reactant: N#Cc1ccc(O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(OCCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.7 %

Procedure:
There was dissolved 3.574 g of p-cyanophenol in 30 ml of N,N-dimethylformamide, followed by addition of 4.364 g of a 90% potassium t-butoxide and stirring at room temperature for 30 minutes. Then 6.570 g of 1-bromo-3-phenylpropane was dropwise added to the solution and the mixture was stirred for 20 hours. The reaction solution was added to ice water, the resulting precipitates were filtered off, washed with water and recrystallized from a mixture of ethanol and n-hexane to give 5.176 g (yield 72.7%) of 4-(3-phenylpropoxy)benzonitrile.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:23])[CH3:22])=[CH:16][CH:15]=3)=[O:13])[CH:10]=2)[NH:5][C:4]1=[O:24].[NH2:25][C:26]1[CH:27]=[CH:28][C:29](OC)=[C:30]([OH:32])[CH:31]=1.[CH2:35]1COCC1>>[OH:32][C:30]1[CH:31]=[C:26]([NH:25][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]4[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:23])[CH3:22])=[CH:16][CH:15]=4)=[O:13])[CH:10]=3)[NH:5][C:4]2=[O:24])[CH:27]=[CH:28][C:29]=1[CH3:35]
Reactant: CC(=O)Nc1ccc(C(=O)c2ccc3c(c2)C(=CO)C(=O)N3)cc1
Reactant: C1CCOC1
Reactant: COc1ccc(N)cc1O
Product: CC(=O)Nc1ccc(C(=O)c2ccc3c(c2)C(=CNc2ccc(C)c(O)c2)C(=O)N3)cc1
Temperature: 65 °C
Reaction time: 24 h
Yield: 63 %

Procedure:
A small screw cap test tube was charged with N-[4-(3-Hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-5-carbonyl)-phenyl]-acetamide (as prepared in Example 11, 50 mg, 0.155 mmol) and THF (2 mL). To the resulting solution was added 5-Amino-2-methoxy-phenol (21.0 mg, 0.170 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature. Hexanes were added to the reaction mixture. The solid precipitate that formed was washed with ˜1 mL of i-prOH yielding 63% (42 mg, 0.098 mmol) of the title compound.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C@@H:3]([OH:21])[CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[CH2:6]1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1.Cl>C(#N)C>[ClH:24].[F:23][C:2]([F:1])([F:22])[C@@H:3]([O:21][C:32](=[O:33])[NH:31][C:28]1[CH:29]=[CH:30][C:25]([Cl:24])=[CH:26][CH:27]=1)[CH2:4][N:5]1[CH2:10][CH2:9][O:8][C@@H:7]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:15][CH:16]=2)[CH2:6]1
Reactant: O[C@@H](CN1CCOC(c2ccc(C(F)(F)F)cc2)C1)C(F)(F)F
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: Cl
Solvent: CC#N
Product: O=C(Nc1ccc(Cl)cc1)O[C@@H](CN1CCO[C@@H](c2ccc(C(F)(F)F)cc2)C1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.4 %

Procedure:
(S)-1,1,1-Trifluoro-3-[2-(4-trifluoromethyl-phenyl)-morpholin-4-yl]-propan-2-ol (52 mg, 151 μmol) and 1-chloro-4-isocyanatobenzene (25.6 mg, 167 μmol) were combined in acetonitrile (2 mL). The mixture was stirred at room temperature overnight and evaporated. The residue was purified by flash chromatography (20% EtOAc/hexanes) to provide the later-running isomer, which was converted to the HCl salt to afford (4-chloro-phenyl)-carbamic acid (S)-2,2,2-trifluoro-1-[(S)-2-(4-trifluoromethyl-phenyl)-morpholin-4-ylmethyl]-ethyl ester hydrochloride as a white solid (30 mg). (M+H)+=497 m/e.
Reaction SMILES: [Na].[NH2:2][C:3]1[N:8]=[C:7]([NH2:9])[C:6]([N:10]=O)=[C:5]([NH2:12])[N:4]=1.[C:13]([O:16][C:17]1[CH:25]=[CH:24][C:20]([CH2:21][C:22]#[N:23])=[CH:19][CH:18]=1)(=[O:15])[CH3:14]>C(OCCO)C>[NH2:2][C:3]1[N:8]=[C:7]([NH2:9])[C:6]2[C:5](=[N:12][C:22]([NH2:23])=[C:21]([C:20]3[CH:19]=[CH:18][C:17]([O:16][C:13](=[O:15])[CH3:14])=[CH:25][CH:24]=3)[N:10]=2)[N:4]=1
Reactant: Nc1nc(N)c(N=O)c(N)n1
Reactant: CC(=O)Oc1ccc(CC#N)cc1
Agent: [Na]
Solvent: CCOCCO
Product: CC(=O)Oc1ccc(-c2nc3c(N)nc(N)nc3nc2N)cc1
Reaction time: 2 h

Procedure:
410 mg metallic sodium were dissolved while stirring in 100 ml of 2-ethoxy ethanol. Thereafter, 1100 mg 2,4,6-Triaminonitrosopyrimidine are added while stirring together with 1140 mg p-acetoxybenzylcyanide and the mixture is heated while stirring up to the boiling point. The color of the mixture changed from violet to brown. After two hours boiling under reflux, the heat is turned off and the reaction mixture is allowed to cool. Thereafter, 70 to 80% of the 2-ethoxyethanol is distilled under the vacuum of the water system, and the residue is taken up in 500 mls of water. After four-fold extraction with ether the pH is adjusted to pH 5 with 2 N hydrochloric acid. The precipitate is filtered, it is washed with a small amount of ice-cold acetone and recrystallized from 10% acetic acid. Further purification can be carried out over a silica gel column. The title compound obtained melts at 319°-321° C. (carbonization).
Reaction SMILES: [NH:1]([C:8]1[N:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[CH:14][C:13]([F:19])=[C:12]([CH2:20][OH:21])[N:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33](O)=[CH:32][CH:31]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C(Cl)Cl>[NH:1]([C:8]1[N:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[CH:14][C:13]([F:19])=[C:12]([CH2:20][O:21][C:33]1[CH:34]=[CH:35][C:30]([O:29][CH3:28])=[CH:31][CH:32]=1)[N:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1cc(Nc2ccccc2)n(-c2ccccc2)c2nc(CO)c(F)cc12
Reactant: COc1ccc(O)cc1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(OCc2nc3c(cc2F)c(=O)cc(Nc2ccccc2)n3-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.7 %

Procedure:
2-Anilino-6-fluoro-7-(hydroxymethyl)-1-phenyl-1,8-naphthyridin-4(1H)-one (62 mg, 0.175 mmol) was dissolved in CH2Cl2 (1.2 mL). 4-methoxyphenol (22 mg, 0.175 mmol) was added followed by Ph3P (91.8 mg, 0.35 mmol), and ADDP (88.31 mg, 0.35 mmol). The reaction was left to stir overnight at room temperature under argon. Hexanes (5 mL) were added and the reaction was filtered. The filtrate was concentrated in vacuo. Purification of the residue using Biotage silica gel chromatography eluting with 7:3 to 9:1 EtOAc:Hex provided 2-anilino-6-fluoro-7-[(4-methoxyphenoxy)methyl]-1-phenyl-1,8-naphthyridin-4(1H)-one (30.0 mg, 37%) as a white solid: LCMS RT 2.87 min, MH+: 464.2.
Reaction SMILES: [OH-].[K+].[C:3]([N:5]=[C:6]([NH2:8])[NH2:7])#[N:4].CC(C)=O.[CH3:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[S:19])=[CH:16][CH:15]=1>O.C(O)(=O)C>[CH3:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH:7][C:6]([NH:5][C:3]#[N:4])=[NH:8])=[S:19])=[CH:16][CH:15]=1
Reactant: Cc1ccc(C(=S)Cl)cc1
Reactant: N#CN=C(N)N
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CC(C)=O
Product: Cc1ccc(C(=S)NC(=N)NC#N)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Potassium hydroxide, 13.02 g (0.2 mole) is dissolved in 40 ml of water and 10.51 g (0.125 mole) of dicyanodiamide is added, followed by the addition of 50 ml of acetone. The mixture is cooled to 0° C and the 4-methylthiobenzoyl chloride from Step 1A, above, is added dropwise. The mixture is stirred at 0° C for 1 hour and placed in the refrigerator overnight. The mixture is poured into 500 ml of water and the water is then acidified with an excess of acetic acid. The product forms a precipitate which is filtered, washed with water followed by ether and air dried to give 12.1 g of 1-(4'-methylthiobenzoyl)-3-cyanoguanidine, m.p. 314° C dec.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[O:3][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[CH2:7][NH:8][CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.[Br:20][C:21]1[N:22]([CH3:29])[CH:23]=[C:24]([C:26](O)=[O:27])[N:25]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(#N)C>[Br:20][C:21]1[N:22]([CH3:29])[CH:23]=[C:24]([C:26]([N:8]([CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH2:7][C:6]2[CH:15]=[CH:16][CH:17]=[C:4]([O:3][C:2]([F:18])([F:1])[F:19])[CH:5]=2)=[O:27])[N:25]=1
Reactant: FC(F)(F)Oc1cccc(CNC2CCOCC2)c1
Reactant: Cn1cc(C(=O)O)nc1Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cn1cc(C(=O)N(Cc2cccc(OC(F)(F)F)c2)C2CCOCC2)nc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.7 %

Procedure:
A mixture of N-[3-(trifluoromethoxy)benzyl]tetrahydro-2H-pyran-4-amine (190 mg), 2-bromo-1-methyl-1H-imidazole-4-carboxylic acid (100 mg), HATU, diisopropylethylamine (190 mg) and acetonitrile (3 mL) was stirred overnight at room temperature. Acetonitrile was distilled off under reduced pressure and the residue was purified by column chromatography (NH silica gel cartridge; hexane/ethyl acetate=3:1 to 1:2) to give the titled compound (130 mg).
Reaction SMILES: [N:1]1[CH:5]=[CH:4][C:3](=[O:6])[N:2]=1.C1O[C:17]2[CH:16]=[C:15]3[C:11]([C:12]([CH:20]=O)=[CH:13][N:14]3[CH3:19])=[CH:10][C:9]=2O1.[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>C(O)C>[CH3:19][N:14]1[C:15]2[C:11](=[C:10]([C:9]3[CH:10]=[CH:11][CH:15]=[CH:16][CH:17]=3)[CH:9]=[CH:17][CH:16]=2)[C:12]([CH:20]=[C:4]2[C:3](=[O:6])[NH:2][N:1]=[C:5]2[C:23]2[CH:24]=[CH:25][C:26]3[CH:19]=[N:14][CH:13]=[CH:12][C:27]=3[N:22]=2)=[CH:13]1
Reactant: C1CCNCC1
Reactant: O=C1C=CN=N1
Reactant: Cn1cc(C=O)c2cc3c(cc21)OCO3
Solvent: CCO
Product: Cn1cc(C=C2C(=O)NN=C2c2ccc3cnccc3n2)c2c(-c3ccccc3)cccc21
Temperature: 87.5 °C
Yield: 59 %

Procedure:
A mixture of the above pyrazolone, (VIk) (10 mg, 0.047 mmol), 5,6-methylenedioxy-1-methyl-indole-3-carboxaldehyde (11 mg, 0.054 mmol) in 1 mL of absolute ethanol along with a drop of piperidine was kept under stirring at 85-90° C. A solid separated. After 2 h the mixture was cooled to room temperature and the solid was filtered, washed with ethanol and dried to isolate the product (11 mg, 59% yield). MS: 398 (M+H).
Reaction SMILES: [N:1]1([C:5]2[O:6][C:7]3[C:8](=[C:10]([C:22]#[N:23])[C:11]([CH3:21])=[C:12]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:13]=3F)[N:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH2:24]([N:26]([CH2:29]C)[CH2:27][CH3:28])C.[NH:31]1CC[CH2:33][CH2:32]1>CS(C)=O.ClCCl>[N:1]1([C:5]2[O:6][C:7]3[C:8](=[C:10]([C:22]#[N:23])[C:11]([CH3:21])=[C:12]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:13]=3[N:31]3[CH2:32][CH2:33][C@H:27]([N:26]([CH3:24])[CH3:29])[CH2:28]3)[N:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CCN(CC)CC
Reactant: C1CCNC1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(N3CCC3)nc2c1C#N
Solvent: CS(C)=O
Solvent: ClCCl
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(N3CCC3)nc2c1C#N
Temperature: 150 °C
Reaction time: 4 h
Yield: 15.9 %

Procedure:
2-(Azetidin-1-yl)-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-134) (0.11 g, 0.36 mmol) was dissolved in dimethyl sulfoxide (3.5 ml), then triethylamine (0.10 ml, 0.72 mmol) and (3S)-3-dimethylamino)pyrrolidine (92.0 μl, 0.73 mmol) were added, followed by stirring in a sealed tube at an external temperature of about 150° C. for 4 hours. This was diluted with dichloromethane, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified by preparative thin-layer chromatography (dichloromethane:methanol=20:1), then diisopropyl ether was added, and the insoluble matter was collected by filtration to obtain a pale beige solid (23 mg, 17%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][N:11]([CH2:15][CH2:16][OH:17])[CH2:12][CH2:13][OH:14])([O-:3])=[O:2].[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.[OH2:29]>N1C=CC=CC=1>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][N:11]([CH2:15][CH2:16][O:17][S:24]([C:21]1[CH:22]=[CH:23][C:18]([CH3:28])=[CH:19][CH:20]=1)(=[O:25])=[O:29])[CH2:12][CH2:13][O:14][S:24]([C:21]1[CH:22]=[CH:23][C:18]([CH3:28])=[CH:19][CH:20]=1)(=[O:26])=[O:25])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1SN(CCO)CCO
Reactant: O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCN(CCOS(=O)(=O)c2ccc(C)cc2)Sc2ccccc2[N+](=O)[O-])cc1
Reaction time: 4 h

Procedure:
389 g (1.5 mol) of crude N-(2-nitrophenylsulphenyl)-bis(2-hydroxyethyl)-amine are dissolved in 2 l of absolute pyridine, and 580 g (3 mol) of 4-toluenesulphonyl chloride are added at -10° in the course of 20 minutes. The mixture is stirred at -5° to 0° for 4 hours and left to stand at 0° overnight, and 4 l of water are added. Thereafter, the mixture is extracted with 3×1 l of methylene chloride and the extract is washed with 7×1 l of water, dried with sodium sulphate and concentrated. The oily residue is stirred with 1 l of a mixture of acetonitrile/methanol (1:1), a solid product precipitating, which is filtered off with suction with methanol. Yield: 423.6 g of melting point 91°-93°.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9](C)[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[NH:25]1[CH2:29][CH2:28][C@@H:27]([NH:30][C:31](=[O:33])[CH3:32])[CH2:26]1>CN1C(=O)CCC1>[C:31]([NH:30][C@@H:27]1[CH2:28][CH2:29][N:25]([C:2]2[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]3[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:21])[CH3:22])=[CH:16][CH:15]=3)[CH:3]=2)[CH2:26]1)(=[O:33])[CH3:32]
Reactant: CC(=O)N[C@@H]1CCNC1
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Solvent: CN1CCCC1=O
Product: CC(=O)N[C@@H]1CCN(c2cc(NC(=O)c3ccc(C(C)(C)O)cc3)nc3ccnn23)C1
Temperature: 25 °C
Yield: 108.5 %

Procedure:
In a 2 mL microwave vial were placed N-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D, 80 mg, 0.24 mmol) and (R)—N-(pyrrolidin-3-yl)acetamide (62 mg, 0.48 mmol). To the sealed vial were then added NMP (2 ml), and the mixture was then heated in the microwave at 100° C. for 15 minutes. After cooling to room temperature, the reaction mixture was filtered by syringe filter and was then directly purified by preparatory HPLC (20-40% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white powder (110 mg, 99% yield). 1H NMR (400 MHz, DMSO-d6) δ=10.84 (s, 1H), 8.24 (d, J=6.3 Hz, 1H), 8.01 (d, J=2.3 Hz, 1H), 8.00-7.95 (m, 2H), 7.65-7.59 (m, 2H), 6.90 (s, 1H), 6.28 (d, J=2.3 Hz, 1H), 4.41-4.31 (m, 1H), 4.19 (br. s., 1H), 3.96 (br. s., 2H), 2.19 (dd, J=5.8, 12.6 Hz, 1H), 2.01-1.91 (m, 1H), 1.83 (s, 3H), 1.46 (s, 6H); ESI-MS: m/z 423.4 (M+H)+.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21](S(C)=O)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:27][C:28]1[CH:37]=[CH:36][C:31]2[NH:32][C:33](=[O:35])[NH:34][C:30]=2[CH:29]=1>>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21]([NH:27][C:28]4[CH:37]=[CH:36][C:31]5[NH:32][C:33](=[O:35])[NH:34][C:30]=5[CH:29]=4)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)c1ncc2ccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)n2n1
Reactant: Nc1ccc2[nH]c(=O)[nH]c2c1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(Nc4ccc5[nH]c(=O)[nH]c5c4)nn23)c1

Procedure:
Following the synthetic and purification procedures described in Example 1293d, a N-tert-butyl-3-(2-methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzenesulfonamide (103 mg, 0.262 mmol) was coupled with 5-amino-1,3-dihydro-benzimidazol-2-one (67 mg, 0.45 mmol) at 105° C. for 72 h to afford the title compound. Yield of TFA salt: 82 mg (52%) of brown powder; LC/MS: 478 (M+H); HPLC: 97% pure, RT=2.83 min; 1H NMR: (DMSO, δ) 10.46 (s, 1H), 10.42 (s, 1H), 9.34 (s, 1H), 9.00 (s, 1H), 8.52 (s, 1H), 8.44 (d, J=8.0, 1H), 7.84 (d, J=8.3, 1H), 7.73 (appt, J=8.0, 1H), 7.63 (s, 1H), 7.47 (dd, J=8.1, 1.8, 1H), 7.23 (s, 1H), 7.19 (d, J=5.0, 1H), 6.98 (d, J=3.6, 1H), 6.93 (d, J=8.3, 1H), 1.11 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[C:6]([OH:15])[C:5]=2[NH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:22](Br)[CH:23]=[CH2:24]>C1COCC1.CN1C(=O)CCC1>[CH2:24]([N:4]1[C:5]2[C:6]([OH:15])=[N:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]=2[C:2]([CH3:1])=[CH:3]1)[CH:23]=[CH2:22]
Reactant: Cc1c[nH]c2c(O)nc3ccccc3c12
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: C=CCn1cc(C)c2c3ccccc3nc(O)c21
Temperature: 40 °C
Reaction time: 12 h
Yield: 54.1 %

Procedure:
A solution of 1-methyl-3H-pyrrolo[2,3-c]quinolin-4-ol (1.2 g, 6.05 mmol) in a mixture of THF (30 mL) and NMP (60 mL) was treated with Cs2CO3 (2.95 g, 9.08 mmol). Allyl bromide (0.524 mL, 6.06 mmol) was added dropwise, and the resulting mixture was stirred at 40° C. for 12 h. The mixture was cooled and quenched with aqueous HCl (1 N) and EtOAc. The organic layer was separated, washed with aqueous HCl (1 N), brine, and dried over Na2SO4. Filtration and removal of the volatiles gave a residue that was triturated with Et2O to give the title compound (0.78 g, 54%) as a solid. LCMS (ES+) m/z 239 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[O:7][CH:8]1[CH2:11][NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1.C(OCC)(=O)C>[C:1]([C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[O:7][CH:8]1[CH2:9][N:10]([C:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:30])[CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1OC1CNC1
Reactant: O=C(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccccc1OC1CN(C(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.5 %

Procedure:
To a stirred solution of 3-(2-tert-butylphenoxy)azetidine (0.30 g, 1.46 mmol) and triethylamine (0.16 g, 1.61 mmol) in THF (10.0 mL) was added benzoyl chloride (0.23 g, 1.61 mmol). After stirring for 16 h at room temperature, the reaction mixture was diluted with ethyl acetate, washed with water, saturated sodium chloride, dried (Na2SO4), filtered and concentrated under reduced pressure. Purification by flash column chromatography (silica gel; 85:15 to 50:50 heptane/ethyl acetate) provided (3-(2-tert-butylphenoxy)azetidin-1-yl)(phenyl)methanone (0.21 g, 46%) as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11](Cl)[C:10]=1[C:16]([F:19])([F:18])[F:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:21][NH2:22]>O1CCOCC1.C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([NH:21][NH2:22])[C:10]=1[C:16]([F:19])([F:18])[F:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1c(OCc2ccccc2)ccnc1Cl
Reactant: NN
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: NNc1nccc(OCc2ccccc2)c1C(F)(F)F
Temperature: 160 °C
Yield: 82.9 %

Procedure:
To a suspension of compound D7 (1.09 g g, 3.789 mmol) in 1,4-dioxane (9 ml), was added hydrazine monohydrate (3.676 ml, 75.78 mmol). The reaction mixture was heated at 160° C. under microwave irradiation for 30 min. After cooling the resulting solution was concentrated in vacuo. The residue thus obtained was dissolved in DCM and washed with NaHCO3 (aqueous sat. solution). The organic layer was separated, dried (Na2SO4) and concentrated in vacuo to yield intermediate compound D8 (0.890 g, 83%) as a white solid.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][OH:11])[CH2:2][CH2:3][CH3:4].[H-].[Na+].Cl[C:15]1[C:19]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)=[N:18][S:17][N:16]=1.O>O1CCCC1>[CH2:1]([O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][C:15]1[C:19]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)=[N:18][S:17][N:16]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOCCO
Reactant: Clc1nsnc1-c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCOCCOCCOc1nsnc1-c1cccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(2-butoxyethoxy)ethanol (1.46 g, 9 mmol) and sodium hydride (310 mg, 9 mmol) in dry tetrahydrofuran was added a solution of 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (590 mg, 3 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 1 h. Water was added and the mixture was extracted with ether. The ether phase was dried and evaporated to give the title compound.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].C([O-])([O-])=O.[K+].[K+].[C:19]([O:23][C:24]([N:26]1[CH2:31][C@H:30]([CH2:32][N:33]2[CH2:38][CH2:37][O:36][CH2:35][C@H:34]2[CH3:39])[NH:29][CH2:28][C@H:27]1[CH3:40])=[O:25])([CH3:22])([CH3:21])[CH3:20]>C(#N)C>[C:19]([O:23][C:24]([N:26]1[CH2:31][C@H:30]([CH2:32][N:33]2[CH2:38][CH2:37][O:36][CH2:35][C@H:34]2[CH3:39])[N:29]([CH2:2][C:3]([O:5][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4])[CH2:28][C@H:27]1[CH3:40])=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: O=C(CBr)OCc1ccccc1
Reactant: C[C@@H]1COCCN1C[C@H]1CN(C(=O)OC(C)(C)C)[C@H](C)CN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@@H]1COCCN1C[C@H]1CN(C(=O)OC(C)(C)C)[C@H](C)CN1CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.7 %

Procedure:
Benzyl bromoacetate (25.2 mL, 126 mmol) and K2CO3 (50 g, 389 mmol) were added to a solution of (2R,5S)-2-methyl-5-((R)-3-methyl-morpholin-4-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester (30.5 g, 97.4 mmol) in acetonitrile (300 mL) and the reaction was stirred at room temperature for 18 h. The solid was removed by filtration and the solvent was removed in vacuo. The crude material was purified by chromatography using a pad of silica eluting with EtOAc/Petrol (1/9 to 4/6) to give the title compound (39 g). MS: [M+H]+=462.