Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([C@@H:11]([NH2:13])[CH3:12])[N:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[N:23]=[CH:24][NH:25]2.CCN(C(C)C)C(C)C>C(O)CCC>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]([C@@H:11]([NH:13][C:21]3[N:29]=[CH:28][N:27]=[C:26]4[C:22]=3[N:23]=[CH:24][NH:25]4)[CH3:12])[N:7]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](N)c1nc2c(Cl)cccc2n1-c1ccccc1
Reactant: Clc1ncnc2[nH]cnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2c(Cl)cccc2n1-c1ccccc1
Temperature: 120 °C
Reaction time: 16 h
Yield: 18.4 %

Procedure:
A mixture of (S)-1-(4-chloro-1-phenyl-1H-benzoimidazol-2-yl)ethylamine from Example 9 (250 mg, 0.92 mmol), 6-chloro-9H-purine (200 mg, 1.29 mmol) and DIPEA (0.29 mL, 1.66 mmol) in n-butanol (2 mL) was stirred in a sealed tube for 16 h at 120° C. Additional amounts of 6-chloro-9H-purine (100 mg, 0.64 mmol) and DIPEA (0.14 mL, 0.802 mmol) were added and the stirring was continued at 120° C. for 24 h. After cooling to RT, the crude reaction mixture was partitioned between DCM and water. The aqueous phase was further extracted with DCM (×3) and then the combined organic layers were washed with brine, dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-8% 2M NH3/MeOH in DCM) and then by preparative HPLC (Phenomenex Gemini 5 μm C18 on a 60 min gradient 20-98% 0.1% HCO2H in acetonitrile/water) affording 120 (66 mg, 42%). LCMS: RT 3.69 min [M+H]+ 390.0. 1H NMR (CDCl3, 400 MHz): δ 12.90 (1H, bs), 8.28-7.90 (3H, m), 7.71-7.41 (5H, m), 7.32 (1H, d, J=7.75 Hz), 7.19 (1H, t, J=7.90 Hz), 7.03 (1H, d, J=8.10 Hz), 5.46 (1H, br), 1.67-1.53 (3H, m)
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([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)[C:7]=2[O:6][CH2:5]1.[O:28]1[CH2:33][CH2:32][CH:31]([C:34](O)=[O:35])[CH2:30][CH2:29]1>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([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:34]([CH:31]5[CH2:32][CH2:33][O:28][CH2:29][CH2:30]5)=[O:35])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Reactant: O=C(O)C1CCOCC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1)C1CCOCC1

Procedure:
The title compound, white solid (29.5 mg, 81.6%), MS (ISP) m/z=444.3 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (30 mg, 81.5 mmol) and tetrahydro-2H-pyran-4-carboxylic acid.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Br:11])[C:5]=1[OH:12])[CH:2]=C.[O:13]=[O+][O-].[BH4-].[Na+]>ClCCl>[Br:11][C:6]1[CH:7]=[C:8]([Cl:10])[CH:9]=[C:4]([CH2:1][CH2:2][OH:13])[C:5]=1[OH:12]
Reactant: O=[O+][O-]
Reactant: C=CCc1cc(Cl)cc(Br)c1O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: OCCc1cc(Cl)cc(Br)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
A solution of 2-allyl-6-bromo-4-chlorophenol (1.378 g, 5.567 mmol) in 20 mL dichloromethane was cooled at −78° C. While stirring at this temperature, ozone was bubbled through the reaction solution for 6.5 hours. After flushing the reaction vessel with oxygen, while still at −78° C., the reaction was quenched with sodium tetrahydroborate (1.064 g, 28.12 mmol). The reaction was then warmed to room temperature and stirred overnight. The reaction mixture was partitioned between ethyl acetate and water, and the organic layer washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (10 to 60% ethyl acetate in heptanes) to yield 0.5911 g (42%) of 2-bromo-4-chloro-6-(2-hydroxyethyl)phenol. 1H NMR (400 MHz, CDCl3) δ: 7.38 (d, J=2.5, 1H), 7.27 (s, 1H), 7.06 (d, J=2.4, 1H), 3.96 (br s, 2H), 2.91 (t, J=5.7, 2H), 1.98 (s, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][CH2:7][Si:8](OC)(OC)[O:9]C.[OH-].[K+:16]>O>[NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][CH2:7][SiH2:8][O-:9].[K+:16]
Reactant: CO[Si](CCCNCCN)(OC)OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: NCCNCCC[SiH2][O-]
Yield: 40 %

Procedure:
About 111 g of N-(2-aminoethyl)-3-aminopropyltrimethoxysilane (commercially available under the name "Silan GF 91" from Wacker-Chemie GmbH, Munich) are metered into a solution containing 95.g of potassium hydroxide in 400 g of water, with vigorous stirring. First methanol and then about 200 g of water are distilled off from the mixture by heating. The mixture is then made up to a total weight of 367 g by addition of water. A 40 percent potassium N-(2-aminoethyl)- 3-aminopropylsilanolate solution is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH2:14])=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH2:22][CH2:23][C:24](=O)[CH3:25])[CH:19]=[CH:20][CH:21]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:24]([CH3:25])[CH2:23][CH2:22][C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([Cl:15])[CH:17]=2)=[CH:6][CH:7]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1N
Reactant: CC(=O)CCc1cccc(Cl)c1
Product: Cc1noc(-c2ccc(Br)cc2)c1NC(C)CCc1cccc(Cl)c1

Procedure:
Prepared according to the procedure described in Example 8, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylamine and 4-(3-chloro-phenyl)-butan-2-one.
Reaction SMILES: [C:1](=[O:12])([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])OC(C)(C)C.C(N(CC)CC)C.[N+:20]([C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][N:27]=[C:26]2[NH2:32])([O-:22])=[O:21].[Cl-].[NH4+]>CN(C1C=CN=CC=1)C.C1COCC1>[N+:20]([C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][N:27]=[C:26]2[NH:32][C:1](=[O:12])[O:7][C:8]([CH3:9])([CH3:10])[CH3:11])([O-:22])=[O:21]
Reactant: Nc1n[nH]c2ccc([N+](=O)[O-])cc12
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1n[nH]c2ccc([N+](=O)[O-])cc12
Reaction time: 0.33 h
Yield: 79.5 %

Procedure:
Di-tert-butyl carbonate (1.76 g), triethylamine (1.13 ml), and DMAP (10 mg) were added to a THF (8.2 ml) solution containing 5-nitro-1H-indazol-3-amine (1.45 g) under ice cooling, followed by stirring for 20 minutes. A saturated ammonium chloride aqueous solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic layers were extracted with water and saturated saline and dried over sodium sulfate and the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane:ethyl acetate=1:0 to 3:2) and a yellow solid of tert-butyl (5-nitro-1H-indazol-3-yl)carbamate (1.8 g) was thus obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:49][C:50]1[CH:61]=[CH:60][C:53]2[NH:54][C:55]([CH:57]([NH2:59])[CH3:58])=[N:56][C:52]=2[CH:51]=1.ClCl>O1CCCC1.ClCCl.C(O)C>[Cl:49][C:50]1[CH:61]=[CH:60][C:53]2[NH:54][C:55]([CH:57]([NH:59][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([C:11]([N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)=[O:12])=[C:2]([CH3:1])[CH:3]=3)[CH3:58])=[N:56][C:52]=2[CH:51]=1
Reactant: CC(N)c1nc2cc(Cl)ccc2[nH]1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)NC(C)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1

Procedure:
Prepared analogously to Example 1g from 3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and rac.-1-(5-chloro-1H-benzimidazol-2-yl)ethylamine in tetrahydrofuran. Yield: quantitative; Rf value: 0.50 (silica gel; dichloromethane/ethanol=9:1); C22H23ClN4O2 (410.91); mass spectrum: (M−H)−=409/411 (chlorine isotope).
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([C:9]2[S:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)[CH:6]=[CH:5][CH:4]=1.[CH:20]1([C:26](Cl)=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.CN(C)C(=O)C>O>[CH3:1][N:2]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([C:9]2[S:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)[N:8]=1)[C:26]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:27]
Reactant: CNc1cccc(-c2nc(=O)c3ccccc3s2)n1
Reactant: O=C(Cl)C1CCCCC1
Solvent: CC(=O)N(C)C
Solvent: O
Product: CN(C(=O)C1CCCCC1)c1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 80 °C
Reaction time: 2 h
Yield: 73.2 %

Procedure:
A mixture of 2-(6-methylamino-2-pyridyl)-4H-1,3-benzothiazine-4-one (0.20 g, 0.72 mmol), cyclohexanecarbonyl chloride (0.22 g, 1.5 mmol) and N,N-dimethylacetamide (10 ml) was stirred at 80° C. for 2 hrs. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was successively washed with saturated aqueous sodium hydrogen carbonate solution and brine and dried. The solvent was evaporated. The residue was subjected to a silica gel column chromatography and eluted with hexane-ethyl acetate (1:1, v/v). The obtained crystals were recrystallized from tetrahydrofuran-hexane to give the titled compound (0.20 g, 71%).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH:11]=[O:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH2:13]([Mg]Br)[CH3:14]>>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH:11]([OH:12])[CH2:13][CH3:14])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: O=CC1CCC2(CC1)OCCO2
Reactant: CC[Mg]Br
Product: CCC(O)C1CCC2(CC1)OCCO2

Procedure:
Reacting 1,4-dioxaspiro[4.5]decane-8-carbaldehyde (prepared as described in Pearson, et al. in J. Org. Chem. 1997, 62(16), 5284-5292) with ethylmagnesium bromide as described in Example 2, Step A yielded the title compound.
Reaction SMILES: C[N+]([O-:5])(C)C.ClCCl.CS(C)=O.Cl[CH2:14][C:15]1[N:16]=[C:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][Cl:30])=[CH:22][CH:21]=2)[O:18][CH:19]=1>O>[Cl:30][CH2:29][CH2:28][CH2:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([C:17]2[O:18][CH:19]=[C:15]([CH:14]=[O:5])[N:16]=2)=[CH:21][CH:22]=1
Reactant: ClCCCOc1ccc(-c2nc(CCl)co2)cc1
Reactant: C[N+](C)(C)[O-]
Solvent: O
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=Cc1coc(-c2ccc(OCCCCl)cc2)n1
Temperature: 20 °C
Reaction time: 24 h
Yield: 41 %

Procedure:
A cold (−20° C.) solution of anhydrous trimethylamine N-oxide (2.10 g, 27.96 mmol) in a dry mixture of dichloromethane and dimethylsulfoxide (20 ml, 1/3 v/v) is treated with a solution of 4-chloromethyl-2-[4-(3-chloro-propoxy)-phenyl]-oxazole ax57 (2.00 g, 6.99 mmol) in the same mixture of solvents (20 ml). The mixture is then allowed to warm up to 20° C. and is stirred at that temperature for 24 h. The dark mixture is then poured into water (50 ml) and extracted with dichloromethane. The organic phases are concentrated and the resulting DMSO solution is treated with ether and water. The heterogeneous mixture is further extracted with ether (2×20 ml). The organic phases are then dried over magnesium sulfate and concentrated to afford 760 mg of 2-[4-(3-chloro-propoxy)-phenyl]-oxazole-4-carbaldehyde i100.
Reaction SMILES: Br[CH2:2][C:3](=O)/[C:4](=[N:10]/[O:11][CH:12]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)/[C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH2:20][C:21]([NH2:23])=[S:22]>>[NH2:23][C:21]1[S:22][CH:2]=[C:3](/[C:4](=[N:10]/[O:11][CH:12]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)/[C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:20]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)/C(=N\OC1CCCCCC1)C(=O)CBr
Product: CCOC(=O)/C(=N\OC1CCCCCC1)c1csc(N)n1
Yield: 69 %

Procedure:
Ethyl 4-bromo-(Z)-2-(cycloheptyloxyimino)-3-oxobutyrate (6.3 g) was treated with thiourea as described in Example 4d. Crystallisation from dichloromethane/hexane gave the title compound as a white solid (4.1 g, 69%), m.p. 107°-8° C. (Found: C: 54.24, H: 6.72, N: 13.33. C14H21N3O3S requires C: 54.00, H: 6.80, N:13.49%). νmax (KBr) 3433, 2930, 1723, 1611, 1540 cm -1 ; δH (CDCl3) 1.33 (3H, t) 1.4-2.0 (12H, m), 4.35 (3H, q+m) 5.60 (2H, br s, exch. D2O), 6.64 (1H,ss).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=1)=[O:4].[N+:13]([C:16]1[C:17]([C:21]([NH2:23])=[O:22])=[N:18][NH:19][CH:20]=1)([O-:15])=[O:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:12][C:8]1[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:19]2[CH:20]=[C:16]([N+:13]([O-:15])=[O:14])[C:17]([C:21]([NH2:23])=[O:22])=[N:18]2)[CH:11]=[CH:10][CH:9]=1
Reactant: O=C(CCl)Nc1cccc(F)c1
Reactant: NC(=O)c1n[nH]cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1nn(CC(=O)Nc2cccc(F)c2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 68.7 %

Procedure:
A mixture of 2-chloro-N-(3-fluorophenyl)acetamide (0.65 g, 3.46 mmol), 4-nitro-1H-pyrazole-3-carboxamide (0.54 g, 3.46 mmol) and potassium carbonate (0.57 g, 4.13 mmol) in dimethylformamide (10 ml) was stirred at room temperature for 48 hours. The mixture was evaporated and the residue partitioned between ethyl acetate and water. The organic phase was separated, washed, dried and then concentrated to yield 1-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-4-nitro-1H-pyrazole-3-carboxamide (730 mg, 69% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([S:13]([NH2:16])(=[O:15])=[O:14])[S:10][N:9]=1.CCCCCC.[C:23](OC)(OC)([O:27][CH3:28])[CH:24]([CH3:26])[CH3:25]>>[CH3:28][O:27][C:23](=[N:16][S:13]([C:11]1[S:10][N:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[N:12]=1)(=[O:14])=[O:15])[CH:24]([CH3:26])[CH3:25]
Reactant: NS(=O)(=O)c1nc(-c2ccccc2Cl)ns1
Reactant: COC(OC)(OC)C(C)C
Solvent: CCCCCC
Product: COC(=NS(=O)(=O)c1nc(-c2ccccc2Cl)ns1)C(C)C
Temperature: 25 °C

Procedure:
A mixture of 2.9 g of 3-(2-chlorophenyl)-1,2,4-thiadiazole-5-sulfonamide in 11 ml of trimethyl orthoisobutyrate was warmed to about 85° with an oil bath. After 2.5 hours the solution was cooled to room temperature, whereupon a precipitate formed. Hexane (25 ml) was added to insure complete precipitation. The solid was filtered, washed with hexane and vacuum dried (P2O5) to give 3.08 g of solid, m.p. 75°-76°.
Reaction SMILES: [C:1]([O:9]CC)(=O)[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[CH2:14]([N:21]1[C:26]2[N:27]=[CH:28][CH:29]=[CH:30][C:25]=2[C:24](=O)[O:23]C1=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl>CC(N(C)C)=O>[CH2:6]([O:5][C:3]([C:2]1[C:1](=[O:9])[N:21]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:26]2[C:25]([C:24]=1[OH:23])=[CH:30][CH:29]=[CH:28][N:27]=2)=[O:4])[CH3:7]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=c1oc(=O)n(Cc2ccccc2)c2ncccc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1c(O)c2cccnc2n(Cc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.5 %

Procedure:
Diethyl malonate (0.6 mL, 4 mmol) was added slowly to a suspension of NaH (60% in mineral oil, 164 mg, 4.1 mmol) in dimethylacetamide (20 mL) and stirred at room temperature for 0.5 h under inert atmosphere. 1-Benzyl-1H-pyrido[2,3-d][1,3]oxazine-2,4-dione (2) (1 g, 4 mmol) was added to the solution and heated at 110° C. for 4 h (TLC control). The solution was cooled and poured into ice water. The pH of the solution was adjusted to 3 by cold 10% HCl. The solids formed were filtered, washed by excess water, and dried in a vacuum oven to yield 940 mg (72%) of 1-benzyl-4-hydroxy-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid ethyl ester (3) as white solids. MP: 143° C.; 1H-NMR (DMSO-d6): δ 1.29 (t, J=6.9 Hz, 3H), 4.31 (q, J=6.9 Hz, 2H), 5.55 (s, 2H), 7.23 (m, 5H), 7.36 (m, 1H), 8.45 (dd, J=1.5, 7.5 Hz, 1H), 8.70 (dd, J=1.5, 7.5 Hz, 1H); EIMS: 325 (M+1), 347 (M+23).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[CH:9]([NH:17][S:18]([C:20]([CH3:23])([CH3:22])[CH3:21])=[O:19])[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1.CI.[CH2:26](N(CC)CC)C>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[CH:9]([N:17]([CH3:26])[S:18]([C:20]([CH3:23])([CH3:22])[CH3:21])=[O:19])[C:10]1[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=1
Reactant: CC(C)(C)S(=O)NC(c1ccc(Cl)cc1)c1cc(Br)ccc1N
Reactant: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CI
Product: CN(C(c1ccc(Cl)cc1)c1cc(Br)ccc1N)S(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-Methyl-propane-2-sulfinic acid [(2-amino-5-bromo-phenyl)-(4-chloro-phenyl)-methyl]-amide (9.73 g, 0.024 mmol) solved in 150 mL DMF is added LiHNDS (1.06M, 24.5 mL) at −30° C. After 1 h, methyl iodide (3.4 g, 0.024 mol) and triethylamine (33.5 mL, 0.24 mol) is added. The mixture is stirred at RT for 2 h. The mixture is then quenched with H2O, extracted with CH3O(CH3)3, dried over Na2SO4, concentrated. This produces the desired compound.
Reaction SMILES: Br.[CH2:2]([NH:4][C:5](=[O:21])[C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1C(OCC1C=CC=CC=1)=O)[CH3:3].CCOCC>C(O)(=O)C>[CH2:2]([NH:4][C:5](=[O:21])[C@@H:6]1[CH2:10][CH2:9][CH2:8][NH:7]1)[CH3:3]
Reactant: CCNC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCNC(=O)[C@@H]1CCCN1
Reaction time: 1 h

Procedure:
40 ml. of 36% hydrogen bromide in acetic acid was added to 11 grams of a solution of benzyloxycarbonyl proline ethylamide in 10 ml. of acetic acid. After 1 hour 300 ml. of ether was added to the reaction solution, so resulting in the separation of a non-crystalline hydrobromide. The hydrobromide was dried for 2 hours in desiccator over phosphorus pentoxide and sodium hydroxide, and then suspended in 60 ml. of a saturated amoniacal solution of chloroform at 0 degrees C. The resultant suspension was permitted to stand at 3 degrees C. for 20 minutes and then filtered, the filtrate being evaporated. 5.7 g of a non-crystalline product was obtained. Rf 0.25/S1 ; 0.56/S2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:21][OH:22])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:25]I>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:21][O:22][CH3:25])[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccc(Cl)cc2)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCC1(c2ccc(Cl)cc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
440 mg tert-butyl 4-(4-chlorophenyl)-4-hydroxymethylpiperidine-1-carboxylate are placed in 2.5 ml dimethylformamide and 92 mg sodium hydride (60% in mineral oil) are added. The reaction mixture is stirred for 30 min at ambient temperature, then 95 μl methyl iodide are added. After 1 h the reaction mixture is poured onto ice and the product is extracted with diethyl ether. 370 mg product are obtained as an oil.
Reaction SMILES: [CH3:1][C:2]1[O:8][CH:7]=[CH:6][C:4](=[O:5])[C:3]=1[OH:9].[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:10]([O:9][C:3]1[C:4](=[O:5])[CH:6]=[CH:7][O:8][C:2]=1[CH3:1])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCc1ccccc1
Reactant: Cc1occc(=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1occc(=O)c1OCc1ccccc1
Temperature: 80 °C
Yield: 75 %

Procedure:
To a 500 mL flask with 10.0 g (0.08 mol) of maltol (3-hydroxy-2-methyl-4H-pyran-4-one) in 120 mL of anhydrous DMF was added 14.1 mL (0.12 mol) of benzyl bromide and potassium carbonate (16.4 g, 0.12 mol) and heated at 80° C. overnight. After cooling to room temperature, the reaction was filtered and the solvents evaporated. The residual oil was brought up in 100 mL CH2Cl2 and washed twice with a saturated NaHCO3 solution, water, and brine. The organic layer was dried over MgSO4, filtered and concentrated. Product was purified on a silica gel column eluting with 0.5% MeOH in CH2Cl2 to yield a pale yellow solid in 75% yield (12.8 g, 59 mmol). 1H NMR (400 MHz, CDCl3) δ=7.59 (d, J=5.6 Hz, 1H), 7.36 (m, 5H), 6.36 (d, J=5.6 Hz, 1H), 5.15 (s, 2H, OCH2), 2.08 (s, 3H, CH3). ESI-MS(+): m/z 217.03 [M+H]+, 239.07 [M+Na]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][N:15]=[CH:16][CH:17]=3)[C:12]3[CH:19]=[CH:20][C:21]([C:23]([NH:25][NH2:26])=[O:24])=[CH:22][C:11]=3[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH:27](OCC)(OCC)OCC>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][N:15]=[CH:16][CH:17]=3)[C:12]3[CH:19]=[CH:20][C:21]([C:23]4[O:24][CH:27]=[N:26][N:25]=4)=[CH:22][C:11]=3[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NNC(=O)c1ccc2c(c1)nc(Nc1cccc(Cl)c1)c1ccncc12
Reactant: CCOC(OCC)OCC
Product: Clc1cccc(Nc2nc3cc(-c4nnco4)ccc3c3cnccc23)c1
Yield: 56 %

Procedure:
5-(3-chlorophenylamino)benzo[c][2,6]naphthyridine-8-carbohydrazide (1.0 eq, 21 mg, 0.057 mmol) was suspended in triethyl orthoformate (0.5 ml) and the mixture reacted in a microwave reactor at 120° C. for 80 minutes. The precipitate that formed upon cooling was filtered and dried to afford N-(3-chlorophenyl)-8-(1,3,4-oxadiazol-2-yl)benzo[c][2,6]naphthyridin-5-amine as a solid (12 mg, 56% yield). LCMS (ES): 95% pure, m/z 374 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[O:11][N:10]=[C:9]([CH2:12][N:13]3[CH:17]=[CH:16][CH:15]=[C:14]3[C:18]([OH:20])=O)[CH:8]=2)=[CH:4][CH:3]=1.C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C.Cl.Cl.[CH:54]([N:57]1[CH2:62][CH2:61][CH:60]([NH2:63])[CH2:59][CH2:58]1)([CH3:56])[CH3:55]>C(Cl)Cl.COCCOC>[CH:54]([N:57]1[CH2:62][CH2:61][CH:60]([NH:63][C:18]([C:14]2[N:13]([CH2:12][C:9]3[CH:8]=[C:7]([C:5]4[S:6][C:2]([Cl:1])=[CH:3][CH:4]=4)[O:11][N:10]=3)[CH:17]=[CH:16][CH:15]=2)=[O:20])[CH2:59][CH2:58]1)([CH3:56])[CH3:55]
Reactant: O=C(O)c1cccn1Cc1cc(-c2ccc(Cl)s2)on1
Reactant: CC(C)N1CCC(N)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCOC
Product: CC(C)N1CCC(NC(=O)c2cccn2Cc2cc(-c3ccc(Cl)s3)on2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.9 %

Procedure:
To 1-[5-(5-chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-1H-pyrrole-2-carboxylic acid (62 mg) in DCM (5 mL) was added HOAt (27 mg), EDCI hydrochloride (38 mg) and DIEA (106 μL). The mixture was stirred for 30 min at RT. 1-Isopropyl-piperidin-4-ylamine dihydrochloride (47 mg) and DME (1 mL) were added and stirring was continued for 16 h at RT. The mixture was concentrated in vacuo and the residue was purified by preparative HPLC. The fractions containing the product were evaporated to provide 66 mg of 1-[5-(5-chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-1H-pyrrole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide as its trifluoroacetate salt, MS (ESI+): m/e 433 [M+H]+, chloro pattern.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([CH:12]=[CH:13][CH:14]=2)[NH2:11])[CH2:4][CH2:3]1.CS([C:18]1[N:23]=[CH:22][C:21]2=[CH:24][CH:25]=[C:26]([C:27]3[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=3)[N:20]2[N:19]=1)=O>>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:9]=[C:10]([NH:11][C:18]3[N:23]=[CH:22][C:21]4=[CH:24][CH:25]=[C:26]([C:27]5[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=5)[N:20]4[N:19]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:7]1
Reactant: Cn1cc(-c2ccc3cnc(S(C)=O)nn23)cn1
Reactant: CN1CCN(c2cccc(N)c2)CC1
Product: CN1CCN(c2cccc(Nc3ncc4ccc(-c5cnn(C)c5)n4n3)c2)CC1
Yield: 29.6 %

Procedure:
3-(4-Methylpiperazin-1-yl)aniline (0.110 g, 0.574 mmol) and 2-Methanesulfinyl-7-(1-methyl-1H-pyrazol-4-yl)-pyrrolo[2,1-f][1,2,4]triazine (0.100 g, 0.383 mmol) were reacted in an analogous manner to Example 881D at 170° C. for 4 hours. Product was purified on Gilson HPLC, lyophilized and free-based with NaHCO3 to afford title compound as a yellow solid (44 mg, 27%) LC/MS: 389 (M+H)HPLC: retention time 1.781 minutes, purity=90%. 1H NMR (400 MHz, DMSO, δ, ppm): 9.65 (br s, 1H), 9.26 (s, 1H), 8.88 (s, 1H), 8.39 (s, 1H), 8.21 (s, 1H), 7.32 (d, J=6.69 Hz, 2H), 7.26 (dd, J=8.61, 8.13 Hz, 1H), 7.04 (d, J=4.8 Hz, 1H), 6.91 (d, J=4.8 Hz, 1H), 6.68 (d, J=7.4 Hz, 1H), 3.94 (s, 3H), 3.78 (d, J=13.0 Hz, 2H), 3.52 (d, J=12.0 Hz, 2H), 3.18-3.16 (m, 2H), 3.00-2.93 (m, 2H), 2.88 (d, J=4.0 Hz, 3H).