Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[CH:19][C:18]([OH:21])=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)C(C)C)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[N:20]=[CH:19][C:18]([O:21][S:32]([CH3:31])(=[O:34])=[O:33])=[CH:17][N:16]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ncc(O)cn2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(Nc2ncc(OS(C)(=O)=O)cn2)CC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 93.4 %

Procedure:
To a stirred solution of 4-(5-hydroxy-pyrimidin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (0.74 g, 2.5 mmol, 1.0 equiv) in dichloromethane (20 mL) were added N-ethyl diisopropylamine (1.09 mL, 0.82 g, 6.3 mmol, 2.5 equiv), followed by methanesulfonyl chloride (0.24 mL, 0.35 g, 3.0 mmol, 1.2 equiv). After stirring for 4 h, the reaction mixture was poured into ice water and extracted twice with dichloromethane. The combined organic layers were washed with water, then dried over MgSO4, filtered and concentrated by evaporation under reduced pressure. The crude product was purified by column chromatography on silica eluting with a gradient of dichloromethane/methanol to give 0.87 g (93%) of the title compound as colorless foam. MS (ISP): 373.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]([CH3:25])[CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:26]([O:28][CH3:29])=[O:27])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:36][CH2:37]I>CN(C)C=O.O>[CH2:36]([N:22]1[CH2:23][CH2:24][CH:19]([N:18]([CH3:25])[C:17]2[NH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:26]([O:28][CH3:29])=[O:27])[CH:14]=3)[NH:9][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:20][CH2:21]1)[CH3:37]
Reactant: CCI
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N(C)C3CCNCC3)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN1CCC(N(C)C2=C(c3ccc(F)cc3)Nc3ccc(C(=O)OC)cc3N2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.9 %

Procedure:
To a solution of methyl 2-(4-fluorophenyl)-3-[methyl(piperidin-4-yl)amino]quinoxaline-6-carboxylate (100 mg, 0.25 mmol) in N,N-dimethylformamide (30 mL) was added potassium carbonate (157.6 mg, 1.14 mmol) and CH3CH2I (71.32 mg, 0.46 mmol), and the reaction mixture was stirred overnight at room temperature. The reaction mixture was then diluted with water (200 mL) and extracted with dichloromethane (4×50 mL). The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (1% methanol in dichloromethane) to afford methyl 3-[(1-ethylpiperidin-4-yl)(methyl)amino]-2-(4-fluorophenyl)-1,4-dihydroquinoxaline-6-carboxylate as light yellow oil (53 mg, 46%).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][N:5]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([N+]([O-])=O)=[CH:11]2)=[N:6]1.[Cl-].[NH4+:19].[CH2:20](O)[CH3:21].O>[Fe]>[N:2]1([CH2:3][CH2:4][N:5]2[CH:13]=[C:12]3[C:7]([CH:8]=[C:9]([NH2:19])[CH:10]=[CH:11]3)=[N:6]2)[CH2:17][CH2:21][CH2:20][CH2:1]1
Reactant: [NH4+]
Reactant: CCO
Reactant: CN(C)CCn1cc2cc([N+](=O)[O-])ccc2n1
Agent: [Fe]
Agent: [Cl-]
Solvent: O
Product: Nc1ccc2cn(CCN3CCCC3)nc2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Dimethyl-[2-(5-nitro-indazol-2-yl)-ethyl]-amine (0.275 g, 1.17 mmol), iron powder (0.656 g, 11.7 mmol) and ammonium chloride (0.0314 g, 0.587 mmol) was suspended in a 4:1 ethanol/H2O solution. The reaction mixture was heated to reflux for 3 hours and then cooled to room temperature. The solvent was removed in vacuo and the residue stirred in triethylamine/ethyl acetate (1/4, 30 mL) for 15 minutes and then filtered through a plug of silica gel. After rinsing with triethylamine/ethyl acetate (1/4), the filtrate was concentrated to provide the title product. 1H NMR (300 MHz, DMSO-d6) ppm 2.16 (s, 6H), 2.71 (t, 2H, J=6.44), 4.31 (t, 2H, J=6.44), 4.98 (s, 2H), 6.46 (m, 1H), 6.50 (m, 1H), 7.33 (s, 1H), 8.03 (s, 1H); MS (DCI/NH3) m/z 205 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([C:9]([Br:16])=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([N:24](C2C=CC(B(O)O)=CC=2)[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)=[CH:20][CH:19]=1.[C:41]1(C)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C.C(O)C>[CH3:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]([C:25]2[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=2)[C:2]2[C:3]3[C:8]([C:9]([Br:16])=[C:10]4[C:15]=2[C:14]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH:13][CH:12]=[CH:11]4)=[CH:7][CH:6]=[CH:5][CH:4]=3)=[CH:22][CH:23]=1
Reactant: Cc1ccccc1
Reactant: Brc1c2ccccc2c(Br)c2ccccc12
Reactant: Cc1ccc(N(c2ccc(C)cc2)c2ccc(B(O)O)cc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: Cc1ccc(N(c2ccc(C)cc2)c2c3ccccc3c(Br)c3cccc(-c4ccccc4)c23)cc1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
In a nitrogen flow, 1 g (2.98 mmol) of 9,10-dibromoanthracene and 1.44 g (4.46 mmol) of bis(4-methylphenyl)aminobenzene-4-boronic acid were dissolved and stirred in a deaerated mixture solvent of 100 ml of toluene and 50 ml of ethanol, followed by dropping a sodium carbonate aqueous solution prepared by dissolving 9 g of anhydrous sodium carbonate in 45 ml of water. After stirring the mixture for 30 minutes, 257 mg (0.223 mmol) of tetrakis(triphenylphosphine)palladium was added thereto. Then, the mixture was heated and stirred for about 3 hours in an oil bath heated at 80° C. After returning the reaction solution to room temperature, 40 ml of water and 50 ml of ethyl acetate were added thereto and the resultant solution was then separated into an aqueous layer and an organic layer. Furthermore, the aqueous layer was extracted with toluene and ethyl acetate, and was then combined with the previous organic layer and dried with magnesium sulfate. The solvent was evaporated and then the residue was purified by silicagel-column chromatography (toluene:hexane=1:2) to obtain 1.13 g of 9-[bis(4-methylphenyl)amino]phenyl-10-bromoanthracene.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][NH:11][C:12]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:32]/[CH:33]=[CH:34]/[C:35]([O:37][CH3:38])=[O:36].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH2:1]([N:8]([CH2:9][CH2:10][NH:11][C:12]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH2:32]/[CH:33]=[CH:34]/[C:35]([O:37][CH3:38])=[O:36])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CNCCNC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: COC(=O)/C=C/CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COC(=O)/C=C/CN(CCNC(c1ccccc1)(c1ccccc1)c1ccccc1)Cc1ccccc1
Temperature: 50 °C

Procedure:
To a solution of Example 12A (128 g, 326 mmol) in acetonitrile (652 mL) was added (E)-methyl 4-bromobut-2-enoate (38.4 mL, 326 mmol) and potassium carbonate (90 g, 652 mmol), and the mixture was heated at 50° C. for 17 hours. A small amount of water was added, and the mixture was decanted into a separatory funnel. The solid left behind was washed three times with ethyl acetate, and the ethyl acetate washings were added to the separatory funnel followed by more water. The layers were separated and the organic layer was concentrated, then dissolved in dichloromethane and loaded onto a silica gel column packed in hexanes. The product was eluted with 15% ethyl acetate/hexanes to afford the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 7.38 (d, J=7.3 Hz, 5H), 7.31-7.12 (m, 15H), 6.83 (dt, J=5.6 Hz, 15.7 Hz, 1H), 6.07 (d, J=15.7 Hz, 1H), 3.67 (s, 3H), 3.42 (s, 2H), 3.05 (d, J=4.4 Hz, 2H), 2.58-2.49 (m, 2H), 2.11 (dd, J=6.2 Hz, 12.9 Hz, 2H).
Reaction SMILES: [H-].[Na+].[CH:3]1([C:6]2[C:7]([CH:16]([C:19]3[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21](C)[CH:20]=3)C#N)=[N:8][C:9]([O:14][CH3:15])=[N:10][C:11]=2[O:12][CH3:13])[CH2:5][CH2:4]1.[O:27]=O.C(OCC)(=O)C.[CH3:35][N:36](C=O)C>>[CH:3]1([C:6]2[C:7]([C:16]([C:19]3[CH:20]=[C:21]([CH:22]=[C:23]([CH3:25])[CH:24]=3)[C:35]#[N:36])=[O:27])=[N:8][C:9]([O:14][CH3:15])=[N:10][C:11]=2[O:12][CH3:13])[CH2:5][CH2:4]1
Reactant: CN(C)C=O
Reactant: COc1nc(OC)c(C2CC2)c(C(C#N)c2cc(C)cc(C)c2)n1
Reactant: O=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1nc(OC)c(C2CC2)c(C(=O)c2cc(C)cc(C#N)c2)n1
Temperature: 0 °C
Yield: 48 %

Procedure:
At 0° C., NaH (60%, 9 mg, 0.4 mmol, 2 eq.) was added to (5-cyclopropyl-2,6-dimethoxy-pyrimidin-4-yl)-(3,5-dimethyl-phenyl)-acetonitrile (67 mg, 0.2 mmol) in 2 mL DMF solution. Oxygen balloon was applied. The reaction was stirred at 0° C. and warmed up to room temperature overnight. LC-MS shows the reaction complete. Ethyl acetate was added to the reaction mixture, followed by washing with brine. The organic layer was concentrated down and purified (silica gel, 0-50% EtOAc/hexane) to give white solid (31 mg, 48%). LC-MS shows 324.2 (M+1). 1H NMR (300 MHz, CDCl3): δ 7.98 (s, 1H), 7.90 (s, 1H), 7.63 (s, 1H), 4.05 (s, 3H), 3.93 (s, 3H), 2.43 (s, 3H), 1.53 (m, 1H), 0.77 (m, 2H), 0.42 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:20])[C:5]([Cl:19])=[C:6]([O:8][C:9]2[C:10]([F:18])=[C:11]([CH2:16][NH2:17])[CH:12]=[CH:13][C:14]=2[Cl:15])[CH:7]=1.[C:21]([Zn]C#N)#[N:22].CN(C=O)C>C(O)CC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:17][CH2:16][C:11]1[C:10]([F:18])=[C:9]([O:8][C:6]2[CH:7]=[C:2]([CH:3]=[C:4]([F:20])[C:5]=2[Cl:19])[C:21]#[N:22])[C:14]([Cl:15])=[CH:13][CH:12]=1
Reactant: NCc1ccc(Cl)c(Oc2cc(Br)cc(F)c2Cl)c1F
Reactant: N#C[Zn]C#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCCO
Product: N#Cc1cc(F)c(Cl)c(Oc2c(Cl)ccc(CN)c2F)c1
Temperature: 120 °C
Yield: 89.8 %

Procedure:
({3-[(5-bromo-2-chloro-3-fluorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)amine (3.00 g, 7.83 mmol) was combined with dicyanozinc (0.460 g, 3.92 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.453 g, 0.392 mmol) in n-propanol (15 mL) and heated at 120° C. for 25 min in a microwave reactor under an inert atmosphere. DMF (8 mL) was added and the reaction mixture was again heated at 120° C. for 90 min in a microwave reactor at which time LC-MS indicated complete conversion. The reaction mixture was concentrated to remove the n-propanol, diluted with EtOAc, washed four times with saturated aqueous NaHCO3, dried over MgSO4, filtered and concentrated to dryness. The residue was purified on 80 g silica gel eluted successively with EtOAc followed by 0 to 10% CH3OH/DCM to give 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-4-chloro-5-fluorobenzonitrile (1.16 g, 3.52 mmol, 45.0% yield) as a pale yellow oil which crystallized on standing. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.92 (dd, J=8.65, 1.51 Hz, 1H), 7.47-7.58 (m, 2 H), 7.25 (s, 1H), 3.77 (s, 2H), 1.93 (br. s., 2H). LC-MS (ES−) m/z 326.96, 329.05 [M−1]. LC-MS (ES+) m/z 329.00, 330.96 [M+H].
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[CH3:28][C:29]1[CH:33]=[C:32]([CH2:34][C:35](O)=[O:36])[O:31][N:30]=1>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:35](=[O:36])[CH2:34][C:32]5[O:31][N:30]=[C:29]([CH3:28])[CH:33]=5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reactant: Cc1cc(CC(=O)O)on1
Agent: Cl
Product: Cc1cc(CC(=O)N[C@H]2CC[C@H](CCN3CCN(c4nccc5c4OCC5)CC3)CC2)on1

Procedure:
The title compound, white solid (110 mg, 97%), MS (ISP) m/z=454.4 [(M+H)+], mp 222.5° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and 2-(3-methylisoxazol-5-yl)-acetic acid.
Reaction SMILES: Cl[CH2:2][C:3]1[C:7]([S:8]([NH:11][CH3:12])(=[O:10])=[O:9])=[CH:6][S:5][CH:4]=1.[C-:13]#[N:14].[K+].Cl>C(O)COCCOCCO>[C:13]([CH2:2][C:3]1[C:7]([S:8]([NH:11][CH3:12])(=[O:10])=[O:9])=[CH:6][S:5][CH:4]=1)#[N:14]
Reactant: CNS(=O)(=O)c1cscc1CCl
Reactant: [C-]#N
Agent: Cl
Agent: [K+]
Solvent: OCCOCCOCCO
Product: CNS(=O)(=O)c1cscc1CC#N
Temperature: 0 °C

Procedure:
26.5 g (0.109 mol) of 3-chloromethyl-N-methyl-4-thiophenesulfonamide and 21.3 g (0.328 mol) of potassium cyanide are warmed to 80° C. for 20 minutes in 130 ml of triethyleneglycol. Thereafter, the mixture is poured into 200 ml of 2-N hydrochloric acid and 200 g of ice and extracted with three 250 ml portions of methylene chloride. The combined organic phases are dried over sodium sulfate, stirred with 3 g of active carbon, filtered and evaporated. There is obtained 3-cyanomethyl-N-methyl-4-thiophenesulfonamide in the form of a non-crystallizing oil which is used in the next step without further purification.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=C1)([N:3]1[CH:7]=[CH:6]N=C1)=[O:2].C[Si](C)(C)C1C=[C:17](N)[CH:18]=[CH:19][CH:20]=1.NC1C=[CH:41][C:28]([O:29][C:30]2[CH:35]=[CH:34][N:33]=[C:32]([NH:36][CH2:37][CH2:38][CH2:39][OH:40])[N:31]=2)=[CH:27][CH:26]=1>ClCCl>[OH:40][CH2:39][CH2:38][CH2:37][NH:36][C:32]1[N:31]=[C:30]([O:29][C:28]2[CH:41]=[CH:11][C:12]([NH:8][C:1]([NH:3][C:7]3[CH:6]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[O:2])=[CH:26][CH:27]=2)[CH:35]=[CH:34][N:33]=1
Reactant: Nc1ccc(Oc2ccnc(NCCCO)n2)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C[Si](C)(C)c1cccc(N)c1
Solvent: ClCCl
Product: O=C(Nc1ccccc1)Nc1ccc(Oc2ccnc(NCCCO)n2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
283 mg (1.75 mmol) 1,1′-Carbonyl-diimidazol (CDI) were given to a solution of 262 mg (1.59 mmol) 3-trimethylsilanyl-phenylamine (Kimes, A. S., J. Med. Chem. 35 (1992) 4683-4689) in 4.0 ml dichloro-methane and stirred for 12 h. A solution of 413 mg (1.59 mmol) 3-[4-(4-Amino-phenoxy)-pyrimidin-2-ylamino]-propan-1-ol in 6 ml dichloromethane was added within 30 min. and the mixture stirred for 12 h at r.t. The reaction mixture was evaporated and the residue was purified by chromatography on silica gel (dichloromethane/ethanol 96:4). The obtained material was washed with ether, the precipitate was isolated by filtration and dried.
Reaction SMILES: [C:1]([O:5][C:6]([N-:8][S:9]([N:12]1[CH:17]=[CH:16][C:15](=[N+](C)C)[CH:14]=[CH:13]1)(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.O1CCN(C2C3N(C=C(/C=C/C4C=CC5C(=CC=CC=5)N=4)N=3)C(C3C=CC(N4CCC(C(O)=O)CC4)=CC=3)=CN=2)CC1.FC(F)(F)C(O)=O.N1CCC([C:83]2[N:88]3[CH:89]=[C:90]([CH2:92][O:93][C:94]4[CH:103]=[CH:102][C:101]5[C:96](=[CH:97][CH:98]=[CH:99][CH:100]=5)[N:95]=4)[N:91]=[C:87]3[C:86]([N:104]3[CH2:109][CH2:108][O:107][CH2:106][CH2:105]3)=[N:85][CH:84]=2)CC1.CCN(C(C)C)C(C)C>C(Cl)Cl>[O:107]1[CH2:108][CH2:109][N:104]([C:86]2[C:87]3[N:88]([CH:89]=[C:90]([CH2:92][O:93][C:94]4[CH:103]=[CH:102][C:101]5[C:96](=[CH:97][CH:98]=[CH:99][CH:100]=5)[N:95]=4)[N:91]=3)[C:83]([CH:15]3[CH2:14][CH2:13][N:12]([S:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])(=[O:10])=[O:11])[CH2:17][CH2:16]3)=[CH:84][N:85]=2)[CH2:105][CH2:106]1
Reactant: C[N+](C)=c1ccn(S(=O)(=O)[N-]C(=O)OC(C)(C)C)cc1
Reactant: c1ccc2nc(OCc3cn4c(C5CCNCC5)cnc(N5CCOCC5)c4n3)ccc2c1
Agent: O=C(O)C1CCN(c2ccc(-c3cnc(N4CCOCC4)c4nc(/C=C/c5ccc6ccccc6n5)cn34)cc2)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)NS(=O)(=O)N1CCC(c2cnc(N3CCOCC3)c3nc(COc4ccc5ccccc5n4)cn23)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
N-(tert-Butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin-1-ylsulfonyl]azanide (38 mg, 0.12 mmol, prepared according to the Org. Lett., 2001, 3 (14), pp 2241-2243) was added to a solution of compound 111 (100 mg, 0.12 mmol, Example 26) and DIEA (54 μL, 0.38 mmol) in DCM (1 mL). The resulting mixture was stirred at rt for 3 h and concentrated. The residue obtained was purified by flash column chromatography on silica gel (0:1-1:0 EtAOc/hexane) to obtain compound 28a. Mass Spectrum (LCMS, ESI pos.) Calcd. for C30H37N7O6S: 624.2 (M+H). Found 624.2.
Reaction SMILES: [Cl:1][C:2]1[C:13]2=[C:14]3[N:9]([CH2:10][CH2:11][CH2:12]2)[CH:8]=[C:7]([C:15]([OH:17])=[O:16])[C:6](=[O:18])[C:5]3=[C:4]([Cl:19])[CH:3]=1.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>CS(C)=O>[ClH:1].[N:20]1([C:2]2[C:13]3=[C:14]4[N:9]([CH2:10][CH2:11][CH2:12]3)[CH:8]=[C:7]([C:15]([OH:17])=[O:16])[C:6](=[O:18])[C:5]4=[C:4]([Cl:19])[CH:3]=2)[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1
Reactant: C1CNCCN1
Reactant: O=C(O)c1cn2c3c(c(Cl)cc(Cl)c3c1=O)CCC2
Solvent: CS(C)=O
Product: Cl
Product: O=C(O)c1cn2c3c(c(N4CCNCC4)cc(Cl)c3c1=O)CCC2
Yield: 15.9 %

Procedure:
4.4 g of 8,10-dichloro-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid and 4.5 g of piperazine were added to 10 ml of anhydrous dimethyl sulfoxide and the mixture was heated on an oil bath at 160° to 170° C. for 7 hours while stirring. Treatment of the reaction mixture in an analogous manner as in Example 4 gave 0.9 g of 8-(1-piperazinyl)-10-chloro-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid hydrochloride as white amorphous crystals having a melting point of 300° C. or more.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[Br:11]Br.O>C(O)(=O)C>[Br:11][C:8]1[N:6]2[N:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1
Reactant: BrBr
Reactant: Fc1ccc2nccn2n1
Solvent: CC(=O)O
Solvent: O
Product: Fc1ccc2ncc(Br)n2n1
Yield: 27.2 %

Procedure:
To an ambient temperature, stirred solution of 6-fluoro-imidazo[1,2-b]pyridazine (2.1 g, 15.3 mmol) in glacial acetic acid (20 mL) was slowly added bromine (2.5 g, 15.3 mmol). Upon completion of this addition the reaction solution was poured into water and extracted with ethyl acetate. The extract was dried (MgSO4) and flash chromatographed (silica gel, eluted with 30% (v/v) ethyl acetate/hexanes) to provide 0.9 g of 3-bromo-6-fluoro-imidazo[1,2-b]pyridazine. LRMS (ESI) m/z 215.9/217.9 [(M+H)]+, calc'd for C6H3BrFN3: 216.01.
Reaction SMILES: C([O:5][C:6](=[O:37])[C:7]([S:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[CH2:16][CH:15]([N:20]([CH2:35][CH3:36])[C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=1)=[O:22])[CH2:14]2)([CH3:9])[CH3:8])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:35]([N:20]([CH:15]1[CH2:14][C:13]2[C:17](=[CH:18][CH:19]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:37])=[O:5])[CH:12]=2)[CH2:16]1)[C:21]([NH:23][C:24]1[CH:25]=[CH:26][C:27]([O:30][C:31]([F:34])([F:32])[F:33])=[CH:28][CH:29]=1)=[O:22])[CH3:36]
Reactant: CCN(C(=O)Nc1ccc(OC(F)(F)F)cc1)C1Cc2ccc(SC(C)(C)C(=O)OC(C)(C)C)cc2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN(C(=O)Nc1ccc(OC(F)(F)F)cc1)C1Cc2ccc(SC(C)(C)C(=O)O)cc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.8 %

Procedure:
To 2-{2-[1-ethyl-3-(4-trifluoromethoxyphenyl)ureido]indan-5-ylsulfanyl}-2-methylpropionic acid tert butyl ester (4.8 g; 8.91 mmol) dissolved in CH2Cl2 (15 mL) is added TFA (15 mL) and the reaction was stirred at RT for 2 h. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (SiO2) eluting with a hexanes-EtOAc gradient to afford 3.13 g (73%) of 2-{2-[1-ethyl-3-(4-trifluoromethoxyphenyl)ureido]indan-5-ylsulfanyl}-2-methylpropionic acid as a white solid.
Reaction SMILES: F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.O.ON1C2C=CC=CC=2N=N1.[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][C:44]2([CH2:51][CH2:50][CH:49]([C:52]([OH:54])=O)[CH2:48][CH2:47]2)[CH2:43][CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35].[CH3:55][N:56]1[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]1.C(N(C(C)C)C(C)C)C>O1CCCC1>[CH3:55][N:56]1[CH2:61][CH2:60][N:59]([C:52]([CH:49]2[CH2:48][CH2:47][C:44]3([CH2:43][CH2:42][N:41]([C:39]([O:38][C:34]([CH3:37])([CH3:35])[CH3:36])=[O:40])[CH2:46][CH2:45]3)[CH2:51][CH2:50]2)=[O:54])[CH2:58][CH2:57]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(C(=O)O)CC2)CC1
Reactant: CN1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: CN1CCN(C(=O)C2CCC3(CC2)CCN(C(=O)OC(C)(C)C)CC3)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
O-(1H-Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.32 g, 1 eq.) and 1-hydroxybenzotriazole hydrate (0.14 g, 1 eq.) were added to a solution of 3-(tert-butoxycarbonyl)-3-azaspiro[5.5]undecane-9-carboxylic acid (commercially obtainable from Anthem, Order No. A1106) (0.3 g, 1 eq.) in tetrahydrofuran (20 ml) and the reaction mixture was stirred at room temperature for 0.5 h. 1-Methylpiperazine (0.11 ml, 1 eq.) and N-ethyl-diisopropylamine (0.17 ml, 1 eq.) were then added and the mixture was stirred at room temperature overnight. For working up, the reaction mixture was concentrated, methylene chloride and sat. NaHCO3 solution were added to the residue and the aqueous phase was extracted with methylene chloride a further 2×. The combined organic phases were washed 1× with sat. NaCl solution, dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (silica; ethyl acetate/ethanol/ammonia (25% aq.) 10:1:0.05) in order to obtain the desired product (AMN-10). Yield: 0.22 g (101%)
Reaction SMILES: Br[C:2]1[C:3]([Cl:8])=[N:4][CH:5]=[CH:6][CH:7]=1.C([Mg]Cl)(C)C.[O:14]1[CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]1>C1COCC1>[Cl:8][C:3]1[C:2]([C:17]2([OH:20])[CH2:18][CH2:19][O:14][CH2:15][CH2:16]2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: O=C1CCOCC1
Reactant: Clc1ncccc1Br
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: OC1(c2cccnc2Cl)CCOCC1
Reaction time: 8 h

Procedure:
To a solution of 3-bromo-2-chloropyridine (0.33 g, 1.715 mmol) in THF (2 mL) at room temperature was added isopropylmagnesium chloride (0.857 mL, 1.715 mmol, 2M solution). Reaction mixture was stirred for 1 hr at room temperature before addition of dihydro-2H-pyran-4(3H)-one (0.158 mL, 1.715 mmol). After overnight stirring, reaction mixture was quenched with saturated NH4Cl solution followed by aqueous workup. Purification by Prep-plate TLC (10% MeOH/DCM) produced product that was advanced to the next step.