Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[CH:6]1[C:14]2[C:13]3[CH:15]=CC=[CH:18][C:12]=3[O:11][C:10]=2[CH:9]=[CH:8][C:7]=1C=O.O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCCCCC.C1COCC1>[CH:3]([C:2]1[CH:1]=[CH:18][C:12]2[O:11][C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:14]=3[C:13]=2[CH:15]=1)=[CH2:4]
Reactant: [Li]CCCC
Reactant: O=Cc1ccc2oc3ccccc3c2c1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=Cc1ccc2oc3ccccc3c2c1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 95 %

Procedure:
22.7 g (63.7 mmol) of Methyl triphenylphosphonium bromide and 200 ml of dry THF are placed in a dried 500 ml three necked round bottomed flask, equipped with a magnetic stirrer and the reaction mixture is cooled to 0° C. internal temperature with a NaCl/ice bath. 41.8 ml (66.9 mmol) of 1.6 M Butyl lithium solution in Hexane are added within 30 minutes while keeping the internal temperature below 3° C. The reaction mixture is stirred at the same temperature for 45 minutes, then 47.2 mmol of Dibenzofuran-2-carboxaldehyde dissolved in 100 ml of dry THF are added within 30 minutes. After two hours the reaction mixture is warmed to room temperature, added to 500 ml of water and extracted three times with 500 ml of Ethylacetate. The combined organic phases are washed once with 500 ml of a 1:1 mixture of buffer pH=1 and brine, once with 30 ml of brine, dried over Magnesiumsulfate, filtered and evaporated. The crude product is dissolved in Dichloromethane, 100 g of silica are added and the solvent is evaporated. The resulting powder is added on top of 300 g of silica in a sintered glass funnel and the product eluted with Hexane/Ethylacetate=8:1. The product is crystallized from 2-Propanol. 2-Vinyl-dibenzofuran is isolated in 95% yield.
Reaction SMILES: Br[C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[S:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[N:20]=3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.C1(N(C)C2CCCCC2)CCCCC1.[O:39]1[CH:44]=[CH:43][CH2:42][CH2:41][CH2:40]1>[Pd].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.O1CCOCC1>[O:39]1[CH:40]=[CH:41][CH2:42][CH2:43][CH:44]1[C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[S:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[N:20]=3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1=COCCC1
Reactant: Brc1cccnc1Oc1ccc(Nc2nc3ccccc3s2)cc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CN(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: C1=COC(c2cccnc2Oc2ccc(Nc3nc4ccccc4s3)cc2)CC1
Temperature: 105 °C

Procedure:
A 25 mL reseable vial was charged with bis(tri-tert-butylphosphine) palladium (0) (83 mg, 0.163 mmol) and N-(4-(3-bromopyridin-2-yloxy)phenyl)benzo[d]thiazol-2-amine (650 mg, 1.632 mmol). The vial was sealed and placed under an atmosphere of nitrogen. After addition of dioxane (5.38 ml), N-cyclohexyl-N-methylcyclohexanamine (1.072 ml, 4.90 mmol) and 3,4-dihydro-2H-pyran (549 mg, 6.53 mmol) were added and the mixture was heated to 105° C. Following complete consumption of the starting material, the reaction mixture was cooled to room temperature and transferred to a 100 mL round bottom flask, and the solvent was removed under reduced pressure. Following purification by silica gel chromatography the desired product was obtained as a racemic mixture. MS (ESI, pos. ion) m/z: 402.0 (M+1).
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[CH2:13]([O:15][C:16](=[O:25])[CH:17]([N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[CH3:18])[CH3:14].IC>C1(C)C=CC=CC=1.CCCCCC>[CH2:13]([O:15][C:16](=[O:25])[C:17]([N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)([CH3:1])[CH3:18])[CH3:14]
Reactant: CCOC(=O)C(C)N1CCOCC1
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: CI
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCOC(=O)C(C)(C)N1CCOCC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 523.8 %

Procedure:
Diisopropyl amine (0.12 moles) was added to a flask and diluted with 40 mL of toluene. The resultant was cooled to −78° C. under nitrogen, and then a hexane solution of n-butyl lithium (0.11 moles) was added thereto, followed by stirring at −78° C. for 1 hour. To this, 2-morpholinopropionic acid ethyl ester (0.105 moles) was added and the resultant was further stirred for 1 hour, and iodomethane (0.21 moles) was added thereto and after the temperature was restored to room temperature, the mixture was stirred for 1 hour. The reaction mixture was quenched with ice water, extracted with ethyl acetate and washed with a saturated sodium chloride aqueous solution, and then the organic layer was dried over magnesium sulphate. The solvent was evaporated, and the residue was purified by column chromatography (hexane/ethyl acetate=4/1) to obtain α-morpholino isobutyric acid ethyl ester (0.55 moles).
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.C(N(CC)CC)C.[C:18]([NH2:22])(=[O:21])[CH:19]=[CH2:20]>O>[S:1]=[C:2]1[N:6]([CH2:20][CH2:19][C:18]([NH2:22])=[O:21])[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[S:3]1
Reactant: C=CC(N)=O
Reactant: Sc1nc2ccccc2s1
Solvent: O
Solvent: CCN(CC)CC
Product: NC(=O)CCn1c(=S)sc2ccccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 77 %

Procedure:
To a stirred solution at 50° C. containing 86 g (0.5 mol) of 2-mercaptobenzothiazole, 60.8 g (0.6 mol) of triethylamine and 500 ml of water, 43 g (0.6 mol) of acrylamide was added in one portion. After stirring at 60°-70° C. for 24 hours, the stirred reaction mixture was cooled to 25° C., the solid collected by filtration, washed with water until neutral and air-dried at 50° C. The product, 2-thioxo-3(2H)-benzothiazolepropanamide, mp 226°-227° C. was obtained in 77% yield.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].Cl.[NH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:27][C:26]3[CH:25]=[N:24][N:23]([CH3:28])[C:22]=3[NH:21][C:20]3[CH:29]=[C:30]([Cl:33])[CH:31]=[CH:32][C:19]2=3)=[O:17])=[CH:12][C:11]=1[Cl:34].CC1C=C2N=C3C(=NC(NC3=O)=O)N(C[C@H](O)[C@H](O)[C@H](O)COP([O-])(O)=O)C2=CC=1C.[Na+]>ClCCl.C(N(CC)CC)C.CCOC(C)=O>[Cl:34][C:11]1[CH:12]=[C:13]([C:16]([N:18]2[CH2:27][C:26]3[CH:25]=[N:24][N:23]([CH3:28])[C:22]=3[NH:21][C:20]3[CH:29]=[C:30]([Cl:33])[CH:31]=[CH:32][C:19]2=3)=[O:17])[CH:14]=[CH:15][C:10]=1[CH2:9][NH:8][C:1](=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)Cl
Reactant: Cn1ncc2c1Nc1cc(Cl)ccc1N(C(=O)c1ccc(CN)c(Cl)c1)C2
Agent: Cc1cc2nc3c(=O)[nH]c(=O)nc-3n(C[C@H](O)[C@H](O)[C@H](O)COP(=O)([O-])O)c2cc1C
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(=O)NCc1ccc(C(=O)N2Cc3cnn(C)c3Nc3cc(Cl)ccc32)cc1Cl
Reaction time: 20 h
Yield: 58 %

Procedure:
Butyryl chloride (46 mg, 0.4 mmol) was added to a solution of (4-aminomethyl-3-chloro-phenyl)-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone hydrochloride from Example E106.2 (161 mg, 0.4 mmol) in dichloromethane (10 ml) and triethylamine (to pH9) at room temperature. The mixture was stirred for 20 h, diluted with EtOAc, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloro-methane) to give a white solid identified as the title compound (110 mg, 58%).
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([O:8]C)[N:5]=[CH:4][C:3]=1[C:10]#[N:11].[BrH:12].[NH+]1C=CC=CC=1>>[Br:12][C:2]1[C:3]([C:10]#[N:11])=[CH:4][NH:5][C:6](=[O:8])[CH:7]=1
Reactant: COc1cc(I)c(C#N)cn1
Reactant: Br
Agent: c1cc[nH+]cc1
Product: N#Cc1c[nH]c(=O)cc1Br

Procedure:
4.5 g (purity 90%, 15.6 mmol) of 4-iodo-6-methoxypyridin-3-carbonitrile and 20 eq. of pyridinium hydrobromide were reacted according to General Method 3A. After aqueous work-up, the crude product was reacted further without further purification. Yield: 1.99 g (purity 77%, 49% of theory) of the title compound as a mixture with 11% of the analogous iodine compound.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][CH2:6][OH:7])[CH3:2].[C:8](Cl)(=[O:12])[C:9]([Cl:11])=[O:10]>C(Cl)Cl>[CH2:1]([O:3][CH2:4][CH2:5][CH2:6][O:7][C:8](=[O:12])[C:9]([Cl:11])=[O:10])[CH3:2]
Reactant: CCOCCCO
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CCOCCCOC(=O)C(=O)Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-ethoxypropan-1-ol (404 mg, 3.9 mmol) in DCM (total volume: 0.5 mL) was added to a solution of oxalyl chloride (0.5 mL, 5.8 mmol) in DCM (total volume 1.0 mL) at 0° C. and the resulting mixture was stirred at room temperature for 30 minutes. The mixture was concentrated in vacuo and the resulting residue was dissolved in DCM (3.9 mL) to yield a 1.0M solution in DCM.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][O:9][CH3:10])[C:3]=1[Cl:11].[Cl:12][C:13]1[CH:29]=[CH:28][C:16]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C:25](Cl)=[O:26])=[CH:20][CH:19]=2)=[CH:15][CH:14]=1>C1(C)C(C)=CC=CC=1>[Cl:11][C:3]1[C:4]([CH2:8][O:9][CH3:10])=[N:5][CH:6]=[CH:7][C:2]=1[NH:1][C:25](=[O:26])[CH2:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][C:16]2[CH:28]=[CH:29][C:13]([Cl:12])=[CH:14][CH:15]=2)=[CH:19][CH:20]=1
Reactant: COCc1nccc(N)c1Cl
Reactant: O=C(Cl)Cc1ccc(Oc2ccc(Cl)cc2)cc1
Solvent: Cc1ccccc1C
Product: COCc1nccc(NC(=O)Cc2ccc(Oc3ccc(Cl)cc3)cc2)c1Cl
Yield: 28.5 %

Procedure:
0.58 g (3.36 mmol) of 4-amino-3-chloro-2-methoxymethylpyridine was added to 0.94 g (3.36 mmol) of 4-(4-chloro-phenoxy)phenylacetyl chloride in 40 ml of xylene, and the mixture was refluxed for 8 hours. After the xylene had been removed in vacuo, the residue was taken up in methylene chloride. The mixture was washed with water and 0.1N aqueous sodium hydroxide solution, the combined aqueous phases were rendered neutral and extracted three times using ethyl acetate, and the ethyl acetate phase was dried over sodium sulfate. After the solvent had been removed in vacuo and the residue purified by column chromatography (silica gel, ethyl acetate:petroleum ether=80:20), 0.40 g of a yellow oil were obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](Cl)[C:8]([CH3:13])=[C:7]2[Cl:14].C([Sn](CCCC)(CCCC)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)CCC>C1(C)C=CC=CC=1>[Cl:14][C:7]1[C:6]2[C:11](=[C:2]([C:9]3[CH:8]=[CH:7][CH:6]=[CH:11][N:10]=3)[CH:3]=[CH:4][CH:5]=2)[N:10]=[C:9]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:20][N:21]=2)[C:8]=1[CH3:13]
Reactant: Cc1c(Cl)nc2c(Br)cccc2c1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccn2)nc2c(-c3ccccn3)cccc2c1Cl
Temperature: 100 °C
Reaction time: 19 h

Procedure:
To a stirred solution of 8-bromo-2,4-dichloro-3-methylquinoline (0.35 g, 1.21 mmol) in toluene (2.4 mL) was added 2-(tributylstannyl)pyridine (0.94 mL, 2.55 mmol), and palladium tetrakistriphenylphosphine (0.140 g, 0.12 mmol). The reaction was stirred at 100° C. and stirring continued for 19 h. After which the reaction mixture was cooled to rt and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (0 to 50% EtOAc in hexane) to give the desired product 4-chloro-3-methyl-2,8-di(pyridin-2-yl)quinoline as a white solid. Mass Spectrum (ESI) m/e=332.0 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][CH:2]=1.[ClH:8].[CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=[CH2:10]>C(O)(C)C>[ClH:8].[Cl-:8].[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:9][CH2:10][N+:1]1[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][CH:2]=1
Reactant: C=Cc1ccccn1
Reactant: Cc1ccncc1
Agent: Cl
Solvent: CC(C)O
Product: Cc1cc[n+](CCc2ccccn2)cc1
Product: [Cl-]
Temperature: 30 °C

Procedure:
To 140 parts 4-picoline, also commonly called 4-methylpyridine, was added 540 parts of a 21.5% solution of hydrogen chloride in isopropanol, then 236 parts 2-vinylpyridine was added, and the resultant solution heated to 90° C. for 16 hours. The mixture was cooled to 30° C. and filtered to give 300 parts 1-[2-(2-pyridyl)ethyl]-4-picolinium chloride hydrochloride.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:24])[C:7]([C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)=[C:8]([C:12]([F:15])([F:14])[F:13])[O:9]2)=[CH:4][CH:3]=1.Cl.N[OH:27].C(N(CC)CC)C.C1N=C[N:37]([C:40](N2C=NC=C2)=[S:41])C=1>C(O)C>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:24])[C:7]([C:16]3[CH:23]=[CH:22][C:19]([C:20]4[NH:37][C:40](=[O:27])[S:41][N:21]=4)=[CH:18][CH:17]=3)=[C:8]([C:12]([F:15])([F:13])[F:14])[O:9]2)=[CH:4][CH:3]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: N#Cc1ccc(-c2c(C(F)(F)F)oc3cc(O)ccc3c2=O)cc1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=c1[nH]c(-c2ccc(-c3c(C(F)(F)F)oc4cc(O)ccc4c3=O)cc2)ns1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Synthesis: To a solution of 4-(7-hydroxy-4-oxo-2-(trifluoromethyl)-4H-chromen-3-yl)benzonitrile (see Example 1, step 1 for synthesis) (250 mg, 0.76 mmol) and hydroxylamine hydrochloride (105 mg, 1.51 mmol) in absolute ethanol (2 ml) was added dropwise triethylamine (0.5 ml). The resulting mixture was heated to reflux for 2 hours. The volatiles were evaporated and the residue was dissolved in anhydrous THF (5 ml). TCDI (202 mg, 1.13 mmol) was added and the suspension was stirred at room temperature for 2 hours, partitioned between EtOAc (50 ml) and water (20 ml). The organic phase was separated, dried with anhydrous Na2SO4, filtered and concentrated. The residue was dissolved in THF (5 ml), BF3-Et2O was added and stirred at room temperature for 2 hours. Workup with 1N HCl, then the volatiles were evaporated and the residue was purified by prep-HPLC to afford the desired product in Example 11 (17.5 mg, 5%) as a white solid.
Reaction SMILES: CO.S(C1C=CC(C)=CC=1)(O[CH:7]([CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:8])(=O)=O.[CH3:25][NH:26][CH3:27].C(OCC)C>C(Cl)(Cl)Cl>[CH3:8][CH:7]([N:26]([CH3:27])[CH3:25])[CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CNC
Reactant: Cc1ccc(S(=O)(=O)OC(C)CCOc2ccccc2)cc1
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: CC(CCOc1ccccc1)N(C)C
Yield: 66 %

Procedure:
To 60 ml of absolute methyl alcohol were added 10 g of 4-phenoxy-2-butyl tosylate and 5.93 g of dimethylamine. The mixture was reacted in a sealed tube for one hour at 125° C. After the reaction solution was condensed under reduced pressure, 100 ml of diethyl ether was added into the solution and the solution was separated into the diethyl ether solution and 20% aqueous sodium hydroxide solution. The ether layer was dried over anhydrous sodium sulfate, and then the ether was removed under reduced pressure therefrom. The residue thus obtained was subjected to an alumina-column chromatography using chloroform as the developing solvent to give 3.98 g of 1-methyl-3-phenoxypropyldimethylamine in a yield of 66%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11]C(O)=O)[CH:6]=[CH:7][C:8]=1[CH3:9].S(Cl)(Cl)=O.[N-:19]=[N+]=[N-].[Na+].O.[O:24]1[CH2:29]COCC1>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][N:19]=[C:29]=[O:24])[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1cc(C=CC(=O)O)ccc1C
Reactant: C1COCCO1
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: COc1cc(C=CN=C=O)ccc1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3-(3-Methoxy-4-methylphenyl)propenoic acid (5.33 g, 27.7 mmol) (prepared according to the procedure described in J. Med. Chem. 1991, 34, 1662-1668) is suspended in benzene (30 mL) and treated dropwise with thionyl chloride (2.22 mL, 30.5 mmol) at 0° C. The reaction is heated to reflux and it is maintained for 1 hour. The volatiles are removed in vacuo and the resulting solid is dissolved in dioxane and added dropwise to a mixture of sodium azide (3.6 g, 55.4 mmol) in water/dioxane (30 mL, 1:5) at 0° C. After stirring 1 hours, the solution is poured over ice-water, the precipitate is collected and washed with water. The solid is dried under vacuum over P2O5(24 hours), dissolved in benzene (30 mL) and heated to reflux slowly over about 4 hours. The benzene is removed to give 2-(3-methoxy-4-methyl-phenyl)vinylisocyanate as a brown oil. The oil is taken tip in o-dichlorobenzene, treated with iodine and heated to reflux for 3.5 hours. The volatiles are removed and the residue is mixed with 2.5% MeOH/CH2Cl2 (10 mL), then allowed to stand overnight at room temperature. The resulting solid is collected washed with hexane and ether, and dried to give the title compound (2.67 g, 14.1 mmol).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.C([O-])([O-])=O.[K+].[K+].[F:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([CH3:26])=[C:20]2[C:27]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[S:30](=[O:38])(=[O:37])[NH:29][N:28]=1.Br[CH2:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42]>CC#N.O.C(Cl)Cl>[C:44]([O:43][C:41](=[O:42])[CH2:40][N:22]1[C:23]2[C:19](=[CH:18][C:17]([F:16])=[CH:25][CH:24]=2)[C:20]([C:27]2[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[S:30](=[O:37])(=[O:38])[N:29]([CH2:4][C:3]3[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=3[F:1])[N:28]=2)=[C:21]1[CH3:26])([CH3:47])([CH3:46])[CH3:45]
Reactant: Cc1[nH]c2ccc(F)cc2c1C1=NNS(=O)(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Fc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Solvent: O
Product: Cc1c(C2=NN(Cc3ccccc3F)S(=O)(=O)c3ccccc32)c2cc(F)ccc2n1CC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
2-Fluorobenzyl bromide (8 μL, 67 μmol) and K2CO3 (10 mg, 72 μmol) were added to a solution of 4-(5-fluoro-2-methyl-1H-indol-3-yl)-2H-benzo[e][1,2,3]thiadiazine 1,1-dioxide (20 mg, 61 μmol) in CH3CN (1 mL), and stirred overnight at 80° C. An additional amount of K2CO3 (10 mg, 72 μmol) and tert-butyl bromoacetate (14 μL, 92 μmol) was added, and the reaction mixture stirred an additional 2 h at 80° C. The reaction mixture was diluted with H2O and CH2Cl2, and filtered through an Extrelut column. The Extrelut column was washed with CH2Cl2, and the filtrate was concentrated to afford the sub-title compound, which was carried onto the next step without further purification or characterization.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:28][C@@H:29]1[CH2:38][CH2:37][C:36]2[C:31](=[C:32]([N:40]3[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]3)[CH:33]=[CH:34][C:35]=2[CH3:39])[CH2:30]1>CN(C)C=O>[NH3:4].[CH3:39][C:35]1[CH:34]=[CH:33][C:32]([N:40]2[CH2:41][CH2:42][N:43]([CH3:46])[CH2:44][CH2:45]2)=[C:31]2[C:36]=1[CH2:37][CH2:38][C@@H:29]([NH:28][C:11](=[O:13])[C:10]1[CH:9]=[CH:8][C:7]([N:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)=[CH:15][CH:14]=1)[CH2:30]2
Reactant: O=C(O)c1ccc(N2CCOCC2)cc1
Reactant: Cc1ccc(N2CCN(C)CC2)c2c1CC[C@@H](N)C2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: Cc1ccc(N2CCN(C)CC2)c2c1CC[C@@H](NC(=O)c1ccc(N3CCOCC3)cc1)C2
Product: N
Temperature: 75 °C
Reaction time: 1.5 h
Yield: 146.9 %

Procedure:
4-Morpholinobenzoic acid (92 mg, 0.44 mmol) was dissolved in dry N,N-dimethylformamide (2 mL) and flushed with nitrogen. To the solution was added 1,1′-carbonyldiimidazole (76 mg, 0.47 mmol) and the reaction mixture was stirred at 75° C. for 1.5 h. The solution was cooled to room temperature and (R)-2-amino-5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (110 mg, 0.42 mmol), dissolved in dry N,N-dimethylformamide (2 mL) was added. The solution was stirred at room temperature for 30 h. The solvent was evaporated in vacuo giving 290 mg of a crude product. Purification by preparative TLC on silica gel using chlorofonr/methanol/conc. NH3 (95:5:0.5) as the eluent afforded 145 mg (73% yield) of the title compound as a white ii; solid: mp>231° C. (dec); EIMS (70 eV) m/z (relative intensity) 448 (3, M+); [α]21D−60° (c 0. 15, chloroform).
Reaction SMILES: [CH2:1](O)[C@H:2]([C@H:4]([C@@H:6]([C@@H:8]([CH2:10][OH:11])[OH:9])O)O)[OH:3].[CH:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.S(=O)(=O)(O)O.[C:26](=[O:29])([O-])[O-:27].[K+].[K+]>CN(C)C=O.CCCCCC>[CH2:10]1[O:11][CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:20][C@@H:6]([C@@H:4]2[O:29][CH:26]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:27][CH2:1][C@H:2]2[OH:3])[C@@H:8]1[OH:9]
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: O=C([O-])[O-]
Reactant: O=Cc1ccccc1
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: O[C@@H]1COC(c2ccccc2)O[C@H]1[C@@H]1OC(c2ccccc2)OC[C@H]1O
Temperature: 0 °C
Reaction time: 72 h
Yield: 102.6 %

Procedure:
DBM was obtained according to the method described in J. Chem. Soc., I, 1977, 1123 or by the following procedure. A mixture of 12.5 g of D-mannitol, 12.5 g of benzaldehyde in 40 mL of dimethylformamide was treated with 5 mL of sulfuric acid added in one portion. The resulting mixture was allowed to stand at room temperature for 72 h and then poured into a mixture of 5 g of potassium carbonate, 0.5 L of ice water covered with a layer of hexane. The hexane layer containing unreacted benzaldehyde was removed and the aqueous layer was allowed to stand at 5-10° C. whereupon a white, cheese-like solid deposited thereon. The aqueous layer was filtered, and the solid air-dried and recrystallized from CHCl3 to afford 13.3 g (53%) of the above-titled compound as white crystals. The resulting white crystals were washed with dry hexane (2×10 mL) and benzene (10 mL), and then dissolved in hot benzene. The benzene solution was evaporated and the resulting solid residue dried over P2O5 in an Abderhalden apparatus for 18 h at 40° C./0.3 torr to provide an analytical specimen melting at 152-53° C. (189-91° C. (MeOH)): 1H NMR (90 MHz, CDCl3) δ3.54-3.65 (m, 2H, H-2 and H-5), 4.0 (d, 4H, H-1 and H-6), 4.22 (d, 2H, H-3 and H-4), 4.38 (br. s., 2H, OH), 5.52 (c, 2H, H-7 and H-8), 7.24-7.48 (m, Ph, Ph); 13C δ58.8 (C-3 and C-4), 70.55 (C-2, C-5), 78.1 (C-1, C-6), 100.34 (C-7, C-8), 125.49, 127.05, 127.17, 137.77 (Ph groups).
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][CH:21]([N:24]5[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]5)[CH2:20][CH2:19]4)=[CH:14][C:13]=3[O:31][CH3:32])=[N:9]2)=[CH:4][CH:3]=1.[Cl:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][N:35]=1>>[Cl:33][C:34]1[N:35]=[CH:36][C:37]([C:2]2[N:10]3[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]4[CH:17]=[CH:16][C:15]([N:18]5[CH2:19][CH2:20][CH:21]([N:24]6[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]6)[CH2:22][CH2:23]5)=[CH:14][C:13]=4[O:31][CH3:32])=[N:9]3)=[CH:4][CH:3]=2)=[CH:38][CH:39]=1
Reactant: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1Nc1ncc2ccc(Br)n2n1
Reactant: OB(O)c1ccc(Cl)nc1
Product: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1Nc1ncc2ccc(-c3ccc(Cl)nc3)n2n1
Temperature: 80 °C
Yield: 22.9 %

Procedure:
Following the example of 532 (D), (7-Bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-{2-methoxy-4-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-phenyl}-amine (0.088 g, 0.00018 mol) and 2-Chloro-5-pyridineboronic acid (0.028 g, 0.00018 mol) were heated at 80° C. overnight. Purification by Gilson chromatography gave [7-(6-Chloro-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-{2-methoxy-4-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-phenyl}-amine (0.022 g, 23%) as a tan solid. MP: 186-188° C.; 1H-NMR (DMSO-d6, 400 MHz) δ 9.18-9.17 (d, 1H, J=2.40 Hz), 8.98 (s, 1H), 8.64-8.61 (d, 1H, J=5.88 Hz), 8.05 (s, 1H), 7.61 (s, 1H), 7.59 (s, 1H), 7.34-7.32 (d, 1H, J=4.80 Hz), 6.97-6.95 (d, 1H, J=4.84 Hz), 6.77 (br, 1H), 6.63 (br, 1H), 3.83 (s, 1H), 3.46 (br, 2H), 2.78 (br, 2H), 2.08-2.01 (br, 3H), 1.66 (m, 2H).