Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:17])[CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH:16]=[CH:15][N:14]=[N:13]1.[H-].[Na+].Cl[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)[N:23]=1.O>CN(C)C=O>[Cl:34][C:30]1[CH:29]=[C:28]([C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([CH2:21][O:17][C:4]3[CH:5]=[CH:6][C:7]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]4[CH:16]=[CH:15][N:14]=[N:13]4)=[C:2]([CH3:1])[CH:3]=3)[N:23]=2)[CH:33]=[CH:32][CH:31]=1
Reactant: ClCc1cccc(-c2cccc(Cl)c2)n1
Reactant: Cc1cc(O)ccc1CCCCn1ccnn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(OCc2cccc(-c3cccc(Cl)c3)n2)ccc1CCCCn1ccnn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
A solution of 97 mg (0.42 mmol) 3-methyl-4-(4-[1,2,3]triazol-1-yl-butyl)phenol in 4.0 ml N,N-dimethylformamide was treated at 0° C. with 17 mg (0.42 mmol) of 60% sodium hydride and stirred at 0° C. for 30 min. Then 100 mg (0.42 mmol) 2-Chloromethyl-6-(3-chloro-phenyl)-pyridine were added and stirred continued at r. t. over night. After addition of 8 ml water, the mixture was extracted with ethyl acetate tree times. The combined organic phases were dried (sodium sulphate) and evaporated. Chromatography on silica (eluent: ethyl acetate/n-heptane 2:1) gave 0.151 g (83%) the title compound as white powder.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[C:11]([CH3:15])=[CH:12][CH:13]=[CH:14][C:7]2=[N:6][C:5]=1[CH3:16].[NH:17]1[CH2:22][CH2:21][CH:20]([C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[NH:25][CH:24]=2)[CH2:19][CH2:18]1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C>O>[NH:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23]([CH:20]2[CH2:21][CH2:22][N:17]([CH2:2][CH2:3][C:4]3[C:9](=[O:10])[N:8]4[C:11]([CH3:15])=[CH:12][CH:13]=[CH:14][C:7]4=[N:6][C:5]=3[CH3:16])[CH2:18][CH2:19]2)=[CH:24]1
Reactant: Cc1nc2cccc(C)n2c(=O)c1CCCl
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: Cc1nc2cccc(C)n2c(=O)c1CCN1CCC(c2c[nH]c3ccccc23)CC1
Yield: 31 %

Procedure:
A mixture of 4.8 parts of 3-(2-chloroethyl)-2,6-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one, 4 parts of 3-(4-piperidinyl)-1H-indole, 8.5 parts of sodium carbonate and 120 parts of 4-methyl-2-pentanone is stirred and refluxed overnight using a water-separator. The reaction mixture is cooled, water is added and the precipitated product is filtered off. It is dissolved in a mixture of trichloromethane and methanol (90:10 by volume). The solution is filtered over silica gel and the filtrate is evaporated. The residue is crystallized from 2-propanol, yielding 2.5 parts (31%) of 3-[2-[4-(1H-indol-3-yl)-1-piperidinyl]ethyl]-2,6-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one; mp. 224.9° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:9]2)=[CH:4][CH:3]=1.[C:17]1([O:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH2:33]Br)=[C:26]([CH2:35][CH2:36][CH3:37])[CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(CC1C=C(CN(C)C)C(O)=C(CN(C)C)C=1)C>>[CH2:35]([C:26]1[CH:25]=[C:24]([O:23][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:29]=[CH:28][C:27]=1[O:30][CH2:31][CH2:32][CH2:33][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:9]2)=[CH:4][CH:3]=1)[CH2:36][CH3:37]
Reactant: CCOC(=O)C1CCc2ccc(O)cc2O1
Reactant: CCCc1cc(Oc2ccccc2)ccc1OCCCBr
Agent: CN(C)Cc1cc(CN(C)C)c(O)c(CN(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCCc1cc(Oc2ccccc2)ccc1OCCCOc1ccc2c(c1)OC(C(=O)OCC)CC2
Temperature: 70 °C
Reaction time: 5 h
Yield: 76 %

Procedure:
To a 50 ml round-bottom flask were added ethyl 7-hydroxychromane-2-carboxylate (100 mg, 0.45 mmol), 4-(3-bromopropoxy)-3-propylphenyl phenyl ether (U.S. Pat. No. 6,008,237) (188 mg, 0.54 mmol), cesium carbonate (176 mg, 0.54 mmol), and DMF 3 ml. The resulting suspension was stirred at 70° C. for 5 hr. The solvent was removed under reduced pressure. The residue was diluted with AcOEt and water. The organic layer was separated. The aqueous layer was extracted twice with AcOEt. The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated, and chromatographed on silica gel. Eluting with 10% AcOEt/hexanes gave the title compound as a pale yellow oil 167 mg (76%).
Reaction SMILES: [CH3:1][CH:2]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[NH:5]1)[CH3:3].C([Li])CCC.[CH:15]1([CH:18]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[C:19](Cl)=[O:20])[CH2:17][CH2:16]1.O>O1CCCC1>[Cl:28][C:25]1[CH:24]=[CH:23][C:22]([CH:18]([CH:15]2[CH2:17][CH2:16]2)[C:19]([N:5]2[C@@H:4]([CH:2]([CH3:3])[CH3:1])[CH2:8][O:7][C:6]2=[O:9])=[O:20])=[CH:27][CH:26]=1
Reactant: CC(C)[C@H]1COC(=O)N1
Reactant: O=C(Cl)C(c1ccc(Cl)cc1)C1CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[C@H]1COC(=O)N1C(=O)C(c1ccc(Cl)cc1)C1CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
In a separate reaction vessel a stirred solution of 2.0 grams (0.016 mole) of (S)-4-(1-methylethyl)-2-oxazolidinone in 50 mL of tetrahydrofuran was cooled to -78° C., and 6.25 mL (0.016 mole) of n-butyllithium (2.5 molar in hexane) was added dropwise. Upon completion of addition, the reaction mixture was stirred for 30 minutes, and then the 2-cyclopropyl-2-(4-chlorophenyl)acetyl chloride, prepared above, was added dropwise during several minutes. Upon completion of addition, the reaction mixture was stirred for an additional 30 minutes and then was poured into water. The organic layer was separated and washed with one portion of aqueous sodium bicarbonate. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil. The oil was subjected to chromatography on silica gel using hexane:diethyl ether (3:1) as eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 0.85 gram of diastereomer (A) and 0.8 gram of diastereomer (B) of (S)-N-[2-(4-chlorophenyl)-2-cyclopropylacetyl]-4-(1-methylethyl)-2-oxazolidinone. Upon standing, diastereomer (A) crystallized to a solid, m.p. 61°-64° C.
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[C:5]([O:12][CH3:13])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].[N+](=[CH2:19])=[N-]>CCOCC>[N+:14]([C:3]1[CH:4]=[C:5]([O:12][CH3:13])[C:6]([O:10][CH3:11])=[C:7]([O:8][CH3:9])[C:2]=1[O:1][CH3:19])([O-:16])=[O:15]
Reactant: COc1cc([N+](=O)[O-])c(O)c(OC)c1OC
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: COc1cc([N+](=O)[O-])c(OC)c(OC)c1OC

Procedure:
1-Hydroxy-2-nitro-4,5,6-trimethoxybenzene (4.58 g, 0.02 mol) was treated with diazomethane (prepared from 1-methyl-3-nitro-1-nitrosoguanidine, 5.88 g, 0.04 mol) in ether (300 ml) for 4 hours at room temperature. The reaction mixture was evaporated in vacuo to dryness, and the residue was chromatographed on a silica gel column (3×40 cm) using hexane/ethyl acetate (9:1) as the eluent. 1-Nitro-2,3,4,5-tetramethoxybenzene was obtained as syrup, 3.45 g (71%). 1NMR (CDCl3): δ3.80, 3.94, 3.96, and 3.98 (each 3H, s, 4×OMe), 7.18 (1H, s, H-6). Analyses: Calculated for C10H13NO6 : C, 49.38; H, 5.39; N, 5.76. Found: C, 49.14; H, 5.53; N, 5.75.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22][N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:17][CH2:16]1.[Cl:28][C:29]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[C:31]([Cl:44])[C:30]=1[OH:45].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[ClH:1].[ClH:28].[Cl:28][C:29]1[CH:34]=[C:33]([C:2]2[N:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[N:15]2[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:17][CH2:16]2)[CH:32]=[C:31]([Cl:44])[C:30]=1[OH:45]
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1N1CCC(CCN2CCCC2)CC1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)nc2c1N1CCC(CCN2CCCC2)CC1
Yield: 80.1 %

Procedure:
Following general procedure II, 1-(6-chloro-4-{4-[2-(pyrrolidin-1-yl)ethyl]piperidin-1-yl}-1,5-naphthyridin-3-yl)ethanone (60 mg, 0.16 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (65 mg, 0.23 mmol) followed by formation of the dihydrochloride salt to afford the desired product (54 mg, 60%) as a yellow solid: 1H NMR (500 MHz, CD3OD) δ 8.91 (s, 1H), 8.46 (d, J=9.1 Hz, 1H), 8.35 (d, J=8.9 Hz, 1H), 8.16 (s, 2H), 4.63 (br s, 2H), 3.70-3.54 (m, 4H), 3.32-3.24 (m, 2H), 3.13-3.03 (m, 2H), 2.67 (s, 3H), 2.22-1.96 (m, 7H), 1.82-1.69 (m, 4H);
Reaction SMILES: C(S[C:4]1[S:5][C:6](=[CH:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([OH:30])([CH3:29])[CH3:28])=[CH:23][C:22]=2[C:31]([F:34])([F:33])[F:32])[N:15]=[CH:14]3)[C:7](=[O:9])[N:8]=1)C.[CH3:35][NH:36][CH2:37][C:38]([OH:40])=[O:39]>>[OH:30][C:27]([C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:16]2[C:17]3[C:13](=[CH:12][C:11]([CH:10]=[C:6]4[S:5][C:4]([N:36]([CH2:37][C:38]([OH:40])=[O:39])[CH3:35])=[N:8][C:7]4=[O:9])=[CH:19][CH:18]=3)[CH:14]=[N:15]2)=[C:22]([C:31]([F:33])([F:32])[F:34])[CH:23]=1)([CH3:29])[CH3:28]
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(C)(C)O)cc3C(F)(F)F)c2)S1
Reactant: CNCC(=O)O
Product: CN(CC(=O)O)C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(C)(C)O)cc3C(F)(F)F)c2)S1

Procedure:
[(5-{1-[4-(1-Hydroxy-1-methyl-ethyl)-2-trifluoromethyl-benzyl]-1H-indazol-5-ylmethylene}-4-oxo-4,5-dihydro-thiazol-2-yl)-methyl-amino]-acetic acid was prepared from 2-Ethylsulfanyl-5-{1-[4-(1-hydroxy-1-methyl-ethyl)-2-trifluoromethyl-benzyl]-1H-indazol-5-ylmethylene}-thiazol-4-one and N-Methyl Glycine following General Procedure C.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([NH2:21])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[F:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1>>[F:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:21][C:16]2[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]3[O:12][C:11]([CH3:24])([CH3:23])[CH:10]([C:7]4[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=4)[C:14]=3[C:15]=2[CH3:22])=[O:31])=[CH:28][CH:27]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Cc1c(C)c2c(c(C)c1N)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Product: Cc1c(C)c2c(c(C)c1NC(=O)c1ccc(F)cc1)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Yield: 65 %

Procedure:
By using 3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine and 4-fluorobenzoyl chloride, the title compound was synthesized according to Example 1b. Yield: 65%. Amorphous.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][Mg]Cl.[Cu](C#N)C#N.Br[C:14]1[N:32]=[CH:31][CH:30]=[CH:29][C:15]=1[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:20]=1)=[O:17].[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[C:25]([C:21]1[CH:20]=[C:19]([NH:18][C:16](=[O:17])[C:15]2[CH:29]=[CH:30][CH:31]=[N:32][C:14]=2[CH2:1][C:2]([CH3:7])([CH3:6])[CH3:3])[CH:24]=[CH:23][CH:22]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)C[Mg]Cl
Reactant: CC(C)(C)c1cccc(NC(=O)c2cccnc2Br)c1
Agent: N#C[Cu]C#N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)Cc1ncccc1C(=O)Nc1cccc(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
2,2-Dimethylpropylmagnesium chloride (1 M-diethylether, 4.8 mL, 4.8 mmol) was added to a suspension of copper cyanide (215 mg, 2.40 mmol) in THF (6 mL) at −78° C. After stirring at the same temperature for 1 hour, 2-bromo-N-(3-tert-butylphenyl)nicotinamide (200 mg, 0.601 mmol) was added all at once as a solid. The reaction mixture was gradually warmed to room temperature and the reaction was allowed to stir overnight. Saturated ammonium chloride solution and ethyl acetate was added, and the reaction mixture was filtered through celite and rinsed with ethyl acetate. The layers were separated and the product was extracted once more with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After removing the solvent under reduced pressure, the crude material was purified using silica gel column chromatography using a gradient of 20%-50% ethyl acetate in hexanes to yield N-(3-tert-butylphenyl)-2-(2,2-dimethylpropyl)nicotinamide (168 mg, 0.517 mmol, 86%). Rf=0.45 (toluene:ethyl acetate=2:1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:15]2[CH2:19][C@H:18]([C:20](OCCCC)=[O:21])[O:17][C:16]2=[O:27])[CH:5]=[C:6]([F:14])[C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[CH3:28][NH2:29]>CO>[CH3:28][NH:29][C:20]([C@@H:18]1[O:17][C:16](=[O:27])[N:15]([C:4]2[CH:3]=[C:2]([F:1])[C:7]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)=[C:6]([F:14])[CH:5]=2)[CH2:19]1)=[O:21]
Reactant: CCCCOC(=O)[C@H]1CN(c2cc(F)c(N3CCOCC3)c(F)c2)C(=O)O1
Reactant: CN
Solvent: CO
Product: CNC(=O)[C@H]1CN(c2cc(F)c(N3CCOCC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The butyl (5R)-3-[3,5-difluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinecarboxylate (EXAMPLE 17, Step 1) is treated with 2M methylamine in MeOH (0.1 M in starting material), and the reaction mixture is stirred at ambient temperature for 30 mins and then concentrated under reduced pressure. The residue is purified by radial chromatography [4000 micron silica gel rotor; MeOH/CH2Cl2 (3/97) eluent] to give the title compound, mp 179-181° C.; MS (ESI+) for C15H17N3O4F2 m/z 342 (M+H)+; [α]25D−40 (c 0.95, DMSO).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][C:13](=[O:19])[NH:14]3)=[CH:6][CH:5]=1.[CH3:22][C:23]1[C:27]([C:28]([N:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)=[O:29])=[C:26]([CH3:37])[NH:25][C:24]=1[CH:38]=O>C(O)C.N1CCCCC1>[CH3:22][C:23]1[C:27]([C:28]([N:30]2[CH2:31][CH2:32][N:33]([CH3:36])[CH2:34][CH2:35]2)=[O:29])=[C:26]([CH3:37])[NH:25][C:24]=1[CH:38]=[C:12]1[C:11]2[C:15](=[CH:16][CH:17]=[CH:18][C:10]=2[C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:20])[F:21])=[CH:9][CH:8]=2)[NH:14][C:13]1=[O:19]
Reactant: O=C1Cc2c(cccc2-c2ccc(OC(F)(F)F)cc2)N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1CCN(C)CC1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4ccc(OC(F)(F)F)cc4)c32)c(C)c1C(=O)N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 60.9 %

Procedure:
To a solution of 4-(4-trifluoromethoxy-phenyl)-1,3-dihydro-indol-2-one (73.3 mg, 0.25 mmol) and 3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. The solvent was evaporated and the solid was washed by ether for three times to provide pure product 3-[3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-4-(4-trifluoromethoxy-phenyl)-1,3-dihydro-indol-2-one (79.9 mg, 61%).
Reaction SMILES: F[C:2](F)(F)C(O)=O.[N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[N:18]1[CH2:23][CH2:22][CH:21]([O:24][C:25]2[C:26]([CH:31]3[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32]3)=N[CH:28]=[CH:29][N:30]=2)[CH2:20][CH2:19]1>C(Cl)Cl>[NH:34]1[CH2:33][CH2:32][CH:31]([C:26]2[C:25]([O:24][CH:21]3[CH2:20][CH2:19][N:18]([C:9]4[CH:10]=[CH:11][C:16]5[C:17](=[CH:12][CH:13]=[CH:14][CH:15]=5)[N:8]=4)[CH2:23][CH2:22]3)=[N:30][CH:29]=[CH:28][CH:2]=2)[CH2:36][CH2:35]1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(c2nccnc2OC2CCN(c3ccc4ccccc4n3)CC2)CC1
Solvent: ClCCl
Product: c1cnc(OC2CCN(c3ccc4ccccc4n3)CC2)c(C2CCNCC2)c1
Temperature: 25 °C
Yield: 27 %

Procedure:
Trifluoroacetic acid (0.272 mL, 3.53 mmol) was added to a solution of tert-butyl 4-(3-(1-(quinolin-2-yl)piperidin-4-yloxy)pyrazin-2-yl)piperidine-1-carboxylate (1726 mg, 3.53 mmol) in DCM (2 mL) and stirred at RT until the starting material was completely consumed. The mixture was then diluted with ethyl acetate and neutralized with saturated aqueous sodium bicarbonate. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organics were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated. The brown solid was triturated with acetone and dried to give the title compound as a white solid (370 mg, 27% yield). [M+1] 390.2. IC50 (uM) 0.05444. 1H NMR (CDCl3, 400 MHz) δ (ppm): 1.53-1.69 (m, 1H) 1.86-2.00 (m, 2H) 2.12-2.34 (m, 6H) 3.03-3.14 (m, 2H) 3.23-3.32 (m, 1H) 3.53-3.71 (m, 4H) 4.13-4.22 (m, 2H) 5.35-5.43 (m, 1H) 7.06 (d, J=9.19 Hz, 1H) 7.20-7.26 (m, 1H) 7.52-7.59 (m, 1H) 7.62 (d, J=7.82 Hz, 1H) 7.67-7.82 (m, 1H) 7.89-7.95 (m, 1H) 7.97 (d, J=2.74 Hz, 1H) 8.06 (d, J=2.74 Hz, 1H)
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH3:22])[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]1[C:20]([NH2:21])=[CH:19][CH:18]=[CH:17][N:16]=1.[C:23]([O:27][C:28]([NH:30][C@@H:31]([CH3:35])[C:32](O)=[O:33])=[O:29])([CH3:26])([CH3:25])[CH3:24].C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:23]([O:27][C:28](=[O:29])[NH:30][C@H:31]([C:32](=[O:33])[NH:21][C:20]1[C:15]([NH:14][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH3:22])=[N:16][CH:17]=[CH:18][CH:19]=1)[CH3:35])([CH3:24])([CH3:25])[CH3:26]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Cc1ccccc1Nc1ncccc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1Nc1ncccc1NC(=O)[C@H](C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Triethylamine (1.05 mL, 7.53 mmol) was added to a mixture of N2-o-tolylpyridine-2,3-diamine (500 mg, 2.51 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (520 mg, 2.76 mmol), HOAt (380 mg, 2.76 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (530 mg, 2.76 mmol) in anhydrous DCM (20 mL) at 0° C. under a nitrogen atmosphere. The reaction mixture was stirred at 0° C. for 10 min and then slowly warmed to RT. Stirring at RT was continued for 16 h. The resulting mixture was partitioned between DCM and a saturated aqueous solution of NaHCO3. The aqueous phase was further extracted with DCM and the combined organic fractions were washed with water, dried (Na2SO4) and concentrated in vacuo to afford the title compound. The crude material was used without further purification in the following step. Yield assumed to be quantitative. LCMS (Method J): RT 2.19 min [M+H]+ 371.1.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH:9]=[N:8][N:7]=[N:6]1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:16][C:17]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:18]=1[NH2:19]>CN(C=O)C>[N:5]1([CH2:4][CH2:3][CH2:2][NH:19][C:18]2[CH:20]=[CH:21][C:22]([N+:24]([O-:26])=[O:25])=[CH:23][C:17]=2[F:16])[CH:9]=[N:8][N:7]=[N:6]1
Reactant: ClCCCn1cnnn1
Reactant: Nc1ccc([N+](=O)[O-])cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(NCCCn2cnnn2)c(F)c1
Temperature: 25 °C
Yield: 14.1 %

Procedure:
To a mixture of 1-(3-chloropropyl)-1H-tetrazole (2.10 g, 14.33 mmol), cesium carbonate (4.66 g, 14.33 mmol) and a catalytic amount of KI in DMF (30 mL) in an ice bath was added 2-fluoro-4-nitroaniline (1.50 g, 9.61 mmol) in one portion. After the mixture was refluxed for 35 h, the mixture was cooled to rt and filtered. The filtrate was concentrated in vacuo. To the residue was added water (50 mL) and the resulting mixture was extracted with DCM (20 mL 2). The combined organic layers were washed with brine (20 mL×2) and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=2:1) to give the title compound as oil (0.36 g, 10%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]([C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[CH:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:8]=2)[CH2:3]1.[Br:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Br:26][C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH:1][CH:2]2[CH2:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:11]([C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)=[CH:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:8]=3)[CH2:3]2)(=[O:35])=[O:34])=[CH:29][CH:28]=1
Reactant: COC(=O)CCCC=C(c1cccnc1)c1ccc2c(c1)CC(N)C2
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)CCCC=C(c1cccnc1)c1ccc2c(c1)CC(NS(=O)(=O)c1ccc(Br)cc1)C2

Procedure:
3.4 g of methyl 6-(2-aminoindan-5-yl)-6-(3-pyridyl)hex-5-enoate is placed in 40 ml of chloroform together with 3.3 g of 4-bromobenzenesulphonic acid chloride and 1.8 g of triethylamine are added in batches at ambient temperature. After 30 minutes the solution is washed with water, dried and rotary evaporated. The yellow oil is then chromatographed over a silica gel column using cyclohexane/ethyl acetate (1:2).
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([CH3:4])[CH3:3].[Br:6][CH:7]([CH2:11][CH2:12][Br:13])[C:8](Cl)=[O:9].[OH-].[Na+]>O.ClCCl>[Br:6][CH:7]([CH2:11][CH2:12][Br:13])[C:8]([NH:5][CH2:1][CH:2]([CH3:4])[CH3:3])=[O:9]
Reactant: O=C(Cl)C(Br)CCBr
Reactant: CC(C)CN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC(C)CNC(=O)C(Br)CCBr
Temperature: 0 °C
Reaction time: 3 h

Procedure:
1.52 g (20.8 mmol) Isobutylamine were dissolved in 3 ml of water, and 13 ml dichloromethane were added. The mixture was cooled to 0° C. and vigorously stirred. A solution of 5.0 g (18.9 mmol) of 2,4-dibromobutanoic acid chloride (J. Med. Chem., 1987, 30, 1995) in 3 ml dichloromethane was added within 5 min. Thereafter a solution of 0.83 g (20.8 mmol) NaOH in 1.5 ml water was added a a rate resulting in the temperature remaining between 7 and 10° C. After complete addition, stirring was continued for 3 h at this temperature. Finally the phases were separated and the aqueous phase was extracted thrice with 15 ml dichloromethane. The combined organic phases were washed once with 17 ml 0.5M HCl, once with 14 ml 5% sodium bicarbonate solution and once with 10 ml brine and dried over magnesium sulfate. After evaporation of the solvent a colourless solid was obtained.
Reaction SMILES: CS(O[CH2:6][CH:7]1[N:12]2[C:13]3[CH:14]=[CH:15][CH:16]=[C:17]([F:20])[C:18]=3[CH:19]=[C:11]2[C:10]2[N:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:9]=2[O:8]1)(=O)=O.[N-:26]=[N+:27]=[N-:28].[Na+].O>CN(C=O)C>[N:26]([CH2:6][CH:7]1[N:12]2[C:13]3[CH:14]=[CH:15][CH:16]=[C:17]([F:20])[C:18]=3[CH:19]=[C:11]2[C:10]2[N:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:9]=2[O:8]1)=[N+:27]=[N-:28]
Reactant: CS(=O)(=O)OCC1Oc2ccc(Cl)nc2-c2cc3c(F)cccc3n21
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC1Oc2ccc(Cl)nc2-c2cc3c(F)cccc3n21
Temperature: 60 °C
Reaction time: 6 h
Yield: 97.4 %

Procedure:
To a solution of (2-chloro-11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-6-yl)methyl methanesulfonate (5 g, 13.08 mmol) in DMF (50 mL), NaN3 (4.18 g, 39.25 mmol) was added at room temperature. The mixture was stirred at 60° C. for 6 hours under N2 protection. After H2O was added, the mixture was extracted with EtOAc (20 mL*3). The combined organic phases were washed with water and brine, dried over Na2SO4 and concentrated to provide 6-(azidomethyl)-2-chloro-11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole (4.2 g, yield: 97.4%). The crude product was used in the next step without purification. 1H-NMR (CDCl3, 400 MHz) δ 3.62˜3.71 (m, 1H), 3.72˜3.81 (m, 1H), 5.28˜5.34 (t, J=5.6 Hz, 1H), 6.76˜6.83 (t, J=4.4 Hz, 1H), 6.92˜7.00 (m, 1H), 7.05˜7.13 (s, 1H), 7.23˜7.31 (m, 1H), 7.39˜7.51 (m, 2H), 7.57˜7.67 (d, J=8.8 Hz, 1H). MS (M+H)+: 330.