Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)(=[O:13])=[O:12])[N:3]=1.[NH4+].[Cl-].C(OCC)(=O)C>CO.O1CCOCC1.O.[Fe]>[NH2:20][C:17]1[CH:18]=[CH:19][C:14]([S:11]([C:4]2[CH:5]=[C:6]([NH2:8])[CH:7]=[C:2]([Br:1])[N:3]=2)(=[O:13])=[O:12])=[CH:15][CH:16]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)c2cc([N+](=O)[O-])cc(Br)n2)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: Nc1ccc(S(=O)(=O)c2cc(N)cc(Br)n2)cc1
Yield: 43.4 %

Procedure:
0.10 g (0.00026 mol) of 2-bromo-4-nitro-6-(4-nitrobenzenesulphonyl)-pyridine was dissolved in a mixture of 1.5 ml of methanol and 1.5 ml of dioxane, treated with 0.20 g of iron powder and a solution of 0.20 g of NH4Cl in 2.5 ml of water and heated at reflux for 2 hrs. Thereafter, the reaction mixture was poured into a mixture of ethyl acetate and water, suction filtered and the organic phase was extracted with water and sat. sodium chloride solution and dried over MgSO4. After removal of the solvent the residue was chromatographed on silica gel with ethyl acetate/hexane 1:4. There was obtained 0.037 g (44%) of 2-(4-aminobenzenesulphonyl)-6-bromopyridin-4-ylamine as yellowish crystals; m.p.: 202-204° C.
Reaction SMILES: C(OC([N:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:10](Br)=[CH:9][C:8]=1[F:17])=O)C.[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:17][C:8]1[CH:9]=[C:10]([NH:29][CH2:28][C:27]2[CH:30]=[CH:31][C:24]([F:23])=[CH:25][CH:26]=2)[CH:11]=[C:12]([N+:13]([O-:15])=[O:14])[C:7]=1[NH:6][C:18](=[O:19])[O:20][CH2:21][CH3:22]
Reactant: NCc1ccc(F)cc1
Reactant: CCOC(=O)N(C(=O)OCC)c1c(F)cc(Br)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCOC(=O)Nc1c(F)cc(NCc2ccc(F)cc2)cc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 8 h
Yield: 50.4 %

Procedure:
To a stirred solution of compound 2 (0.300 g, 0.790 mmol, 1.00 equiv) in 1,4-dioxane (10 mL) were added 4-fluorobenzylamine (0.200 g, 1.58 mmol, 2.00 equiv), Cs2CO3 (0.500 g, 1.50 mmol, 2.00 equiv) followed by Pd2 (dba)3 (0.072 g, 0.079 mmol, 10 mol %) and Xantphos (0.045 g, 0.079 mmol, 10 mol %) at RT. The reaction mixture was heated at 90° C. and stirred at the same temperature for 8 h. After consumption of the starting material (by TLC), the reaction mixture was concentrated under vacuum. The obtained residue was diluted with water (50 mL) and extracted with EtOAc (2×50 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The crude material was purified by silica gel column chromatography (EtOAc/Hexane 2:23) to afford compound 3 (0.140 g, 50.3%) as yellow solid. TLC: 40% EtOAc/Hexane (Rf: 0.25); 1H NMR (500 MHz, CDCl3): δ 7.31-7.28 (m, 2H), 7.06 (t, J=8.5 Hz, 1H), 7.00 (s, 2H), 6.91 (br s, 1H), 6.60 (d, J=9.5 Hz, 1H), 4.46 (br s, 1H), 4.31 (d, J=4.4 Hz, 2H), 4.20 (q, J=7.0 Hz, 2H), 1.28 (t, J=7.0 Hz, 3H); LC-MS: m/z=350 (M+-1) at RT 3.69 (97.8% purity).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([OH:11])[CH2:7][CH2:6]1.[H-].[Na+].I[CH3:16]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][CH3:16])[CH2:7][CH2:6]1
Reactant: COC(=O)C[C@H]1CC[C@H](O)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C[C@H]1CC[C@H](OC)CC1
Temperature: 2.5 °C
Reaction time: 4 h

Procedure:
trans-(4-Hydroxy-cyclohexyl)-acetic acid methyl ester (500 mg, 2.90 mmol) were dissolved in 1.5 ml DMF and cooled to 0-5° C. Sodium hydride (190 mg, 4.35 mmol, 55%) and iodomethane (3.62 ml, 23.2 mmol) were added and the reaction mixture stirred for 4 hours at 0-5° C. The reaction mixture was quenched with saturated NaHCO3-solution and extracted with dichloromethane. The organic extract was washed with brine, dried with sodium sulfate, filtered and evaporated. The crude product (561 mg, quant.) was obtained as a colourless oil and used without any further purification for the next step.
Reaction SMILES: C(Cl)CCl.[C:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[N:18]1[CH2:23][CH2:22][CH:21]([CH2:24][C:25](O)=[O:26])[CH2:20][CH2:19]1)(=[O:7])[NH2:6].[F:28][C:29]([F:45])([F:44])[C:30]1[CH:31]=[C:32]([S:40]([NH2:43])(=[O:42])=[O:41])[CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1.CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.CN(C=O)C>[F:39][C:36]([F:37])([F:38])[C:34]1[CH:33]=[C:32]([S:40]([NH:43][C:25](=[O:26])[CH2:24][CH:21]2[CH2:20][CH2:19][N:18]([C:9]3[CH:10]=[C:11]([C:14]([F:15])([F:17])[F:16])[CH:12]=[CH:13][C:8]=3[C:5]([NH2:6])=[O:7])[CH2:23][CH2:22]2)(=[O:42])=[O:41])[CH:31]=[C:30]([C:29]([F:45])([F:28])[F:44])[CH:35]=1
Reactant: NC(=O)c1ccc(C(F)(F)F)cc1N1CCC(CC(=O)O)CC1
Reactant: NS(=O)(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: NC(=O)c1ccc(C(F)(F)F)cc1N1CCC(CC(=O)NS(=O)(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
0.46 g of 2-fluoro-4-(trifluoromethyl)benzamide are added to a suspension of 1.8 g K2CO3 and 0.8 g of piperidin-4-yl acetic acid hydrochloride In 12 ml of DMSO, the mixture obtained is stirred for 4 h at 150°, solvent is evaporated, the evaporation residue obtained is suspended in MeOH and filtrated. The filtrate obtained is concentrated and subjected to chromatography on silica gel. [1-(2-Carbamoyl-5-trifluoromethyl-phenyl)-piperidin-4-yl]-acetic acid is obtained. 300 mg of EDC are added to a solution of 260 mg of [1-(2-carbamoyl-5-trifluoromethyl-phenyl)-piperidin-4-yl]-acetic acid, 230 mg of 3,5-bis-trifluoromethyl-benzenesulfonamide, 200 mg of DIEA and 90 mg of DMAP in 4 ml of DMF. The mixture obtained is stirred for 3 days at RT, solvent is evaporated in vacuo and the evaporation residue obtained is treated with EtAc. The mixture obtained is washed with 1 N HCl, saturated aqueous NaHCO3 solution and brine, dried, concentrated in vacuo and subjected to chromatography on silica gel. 2-{4-[2-(3,5-Bis-trifluoromethyl-benzenesulfonylamino)-2-oxo-ethyl]-piperidin-1-yl}-4-trifluoromethyl-benzamide is obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:16][C:17]#[N:18]>CN(C=O)C>[C:17]([CH2:16][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1)#[N:18]
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: N#CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc(OCC#N)cc1
Reaction time: 0.5 h
Yield: 99.1 %

Procedure:
A solution of methyl 4-hydroxyphenylacetate (10 g, 0.06 mol) in DMF (100 ml) was added to 97% NaH (1.78 g, 0.072 mol) in DMF (60 ml) in an ice bath. The reaction mixture was stirred for 0.5 hours and then chloroacetonitrile (5.44 g, 0.072 mol) in DMF (50 ml) was added. The reaction mixture was stirred at room temperature for about 2 days, the solvent was removed in vacuo, and the residue was partitioned between water and ether. The organic layer was separated, washed with saturated Na2CO3 and then brine, and then was dried over MgSO4, filtered and concentrated in vacuo to afford 12.2 g of methyl 4-(cyanomethoxy)phenylacetate.
Reaction SMILES: Cl.[N+:2]([O-:11])([O:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)=[O:3].CCN(CC)CC.Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:21]>C1COCC1.CC#N>[N+:29]([C:26]1[CH:25]=[CH:24][C:23]([O:22][C:20]([N:8]2[CH2:9][CH2:10][CH:5]([O:4][N+:2]([O-:11])=[O:3])[CH2:6][CH2:7]2)=[O:21])=[CH:28][CH:27]=1)([O-:31])=[O:30]
Reactant: O=[N+]([O-])OC1CCNCC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCC(O[N+](=O)[O-])CC1
Temperature: 25 °C

Procedure:
To a solution of Piperidin-4-yl nitrate hydrochloride (INTERMEDIATE 13, Step B) (0.40 g, 2.20 mmol) and Et3N (0.67 g, 6.60 mmol) in THF/CH3CN 2/1 (24 mL) was added 4-Nitrophenyl chloroformate (0.44 g, 2.20 mmol) as solid. After stirring at rt over night, the mixture was concentrated. The residue was diluted with EtOAc and washed with NaH2PO4 5%. The organic layer was dried over MgSO4 and concentrated. The residue was purified by flash chromatography (Biotage SP1; column SNAP 50; TLC method: n-hexane/ethyl acetate 7/3; Rf=0.37), affording the title product as a white solid. 1H-NMR (300 MHz, CDCl3); δ 8.36-8.25 (2H, m), 7.39-7.28 (2H, m), 5.30-5.18 (1H, m), 4.00-3.50 (4H, m), 2.20-2.06 (2H, m), 2.02-1.86 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[O:10][C:9]3[N:11]=[CH:12][CH:13]=[CH:14][C:8]=3[C:6]=2[N:7]=1.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>CO>[Cl:1][C:2]1[N:3]=[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:5]2[O:10][C:9]3[N:11]=[CH:12][CH:13]=[CH:14][C:8]=3[C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2oc3ncccc3c2n1
Reactant: C1COCCN1
Solvent: CO
Product: Clc1nc(N2CCOCC2)c2oc3ncccc3c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
To a solution of 4 (64 mg, 0.27 mmol) in dry methanol (10 mL) was added morpholine (55 μL, 0.62 mmol) dropwise, and the resulting reaction was stirred for 2 h at rt. The resulting precipitate was then filtered, washed with water and then a mixture of 5:1 methanol/water, and the remaining solid was dried in vacuo to furnish 5 (50 mg, 0.17 mmol, 64%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:3]=1[CH2:4][N:5]([CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[CH3:6].[Br:19]Br>C(Cl)Cl>[NH2:1][C:2]1[C:16]([Br:19])=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:3]=1[CH2:4][N:5]([CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[CH3:6]
Reactant: BrBr
Reactant: COc1ccc(N)c(CN(C)C2CCCCC2)c1
Solvent: ClCCl
Product: COc1cc(Br)c(N)c(CN(C)C2CCCCC2)c1

Procedure:
2-Amino-3-bromo-N-cyclohexyl-5-methoxy-N-methyl-benzylamine was prepared from 2-amino-N-cyclohexyl-5-methoxy-N-methyl-benzylamine and bromine analogous to Example 9. Proof of structure by IR- and UV-spectra. IR-spectrum (methylenechloride):
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@:14]2([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([CH2:32][C:33]4[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH3:41])=[CH:35][CH:34]=4)[CH:26]=3)[O:24][C@@:11]([CH2:42][O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45])([CH2:12][O:13]2)[C@H:10]1[OH:51])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[Na]>ClCCl>[CH2:1]([O:8][C@@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@:14]2([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([CH2:32][C:33]4[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH3:41])=[CH:35][CH:34]=4)[CH:26]=3)[O:24][C@@:11]([CH2:42][O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45])([CH2:12][O:13]2)[C:10]1=[O:51])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@](CO[Si](C)(C)C(C)(C)C)(O3)[C@@H](O)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na]
Solvent: ClCCl
Product: CCOc1ccc(Cc2cc([C@]34OC[C@](CO[Si](C)(C)C(C)(C)C)(O3)C(=O)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 100.5 %

Procedure:
To a solution of (1R,2S,3S,4R,5S)-3,4-dibenzyloxy-1-[(tert-butyl(dimethyl) silyl)oxymethyl]-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octan-2-ol 28e (15.9 g, 21.7 mmol) in dichloromethane (40 mL) was added Dess-Martin periodinane (18.4 g, 43.5 mmol) at 0° C. The mixture was stirred at 0° C. for 3 hours and adjusted with saturated aqueous sodium bicarnonate till pH becomes 7. The resulting mixture was extracted with dichloromethane (100 mL×2). The combined organic phases were washed with saturated aqueous sodium chloride (100 mL×2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound 28f as colorless oil (15.9 g, 100%). The crude product was used for next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=1.C(Cl)(=O)C(Cl)=O.[C:29]([C:31]1[CH:32]=[C:33]([CH:35]=[CH:36][CH:37]=1)[NH2:34])#[N:30].CN(C=O)C>CN(C=O)C.C(Cl)Cl>[C:29]([C:31]1[CH:32]=[C:33]([NH:34][C:20]([C:17]2[CH:16]=[CH:15][C:14]([C:3]3[CH:4]=[C:5]([C:8]4[O:9][C:10]([CH3:13])=[N:11][N:12]=4)[CH:6]=[CH:7][C:2]=3[CH3:1])=[CH:19][CH:18]=2)=[O:22])[CH:35]=[CH:36][CH:37]=1)#[N:30]
Reactant: N#Cc1cccc(N)c1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)Nc4cccc(C#N)c4)cc3)c2)o1
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 8.2 %

Procedure:
2′-Methyl-5′-(5methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid (100 mg, 0.34 mmol), oxalyl chloride (0.03 ml, 0.41 mmol), and DMF (1 drop) were mixed in DCM (5 ml) and stirred at room temperature for 35 min. 3-Cyanoaniline (44 mg, 0.374 mmol) was added to the solution and the mixture stirred for 2 h; DMF (1 ml) was added and stirring continued for 18 h. The solvents were evaporated from the reaction under vacuum and the residue chromatographed on an SPE (silica, 5 g), eluting with DCM and then DCM/ethanol/ammonia (300:8:1). The product fractions were concentrated in vacuo to give N-(3-cyanophenyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide as a white solid (11 mg, 8%). NMR; δH [2H6]—DMSO 10.65,(1H, b), 8.28,(1H, m), 8.07,(3H, m), 7.91,(1H, dd), 7.79,(1H, d), 7.62-7.56,(5H, m), 2.57,(3H, s), 2.33,(3H, s). LCMS; retention time 3.49 min, MH+ 395
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13](C=O)[CH2:12][CH:11]([C:17]([O:19][CH3:20])=[O:18])[CH2:10]2)=[CH:5][C:4]=1[F:21])[CH3:2].O.[ClH:23]>CO>[ClH:23].[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][NH:13][CH2:12][CH:11]([C:17]([O:19][CH3:20])=[O:18])[CH2:10]2)=[CH:5][C:4]=1[F:21])[CH3:2]
Reactant: CCc1ccc(C2CC(C(=O)OC)CN(C=O)C2)cc1F
Agent: Cl
Solvent: CO
Solvent: O
Product: CCc1ccc(C2CNCC(C(=O)OC)C2)cc1F

Procedure:
1.6 g (5.3 mmol) of methyl 5-(4-ethyl-3-fluorophenyl)-1-formylpiperidine-3-carboxylate were taken up in 10 ml of methanol, and heated to reflux with 1 ml of water and 0.5 ml of concentrated hydrochloric acid for three hours. The reaction mixture was concentrated and dried under reduced pressure. Yield: 1.5 g (63% of theory; purity 68%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[C:12]([O:14][CH3:15])=[O:13])[C:6](O)=[O:7].C(Cl)(=O)C(Cl)=O.[NH3:22]>C1COCC1>[C:6]([C:5]1[CH:9]=[CH:10][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:7])[NH2:22]
Reactant: COC(=O)c1ccc(C(=O)O)cc1OC
Reactant: N
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(N)=O)cc1OC

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-26 by using 3-methoxy-4-(methoxycarbonyl)benzoic acid (2.00 g, 9.52 mmol), oxalyl chloride (1.02 g, 11.42 mmol), ammonia gas and THF (25 mL) to afford 1.40 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 3.79 (s, 3H), 3.87 (s, 3H), 7.49 (d, J=8.4 Hz, 1H), 7.57 (s, 2H), 7.68 (d, J=7.8 Hz, 1H), 8.14 (s, 1H); MS (m/z): 209.99 (M)+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[Cl-].[CH3:12][C:13]1[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=1[CH:15]=[N+:16]([CH3:18])[CH3:17].CC1C=CC=CC=1C=O.CNC>>[CH3:17][N:16]([CH3:18])[CH:15]([C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:2]([CH3:1])[CH:3]=1)[C:14]1[CH:19]=[CH:20][CH:21]=[CH:22][C:13]=1[CH3:12]
Reactant: Cn1ccc2ccccc21
Reactant: Cc1ccccc1C=[N+](C)C
Agent: CNC
Agent: Cc1ccccc1C=O
Agent: [Cl-]
Product: Cc1ccccc1C(c1cn(C)c2ccccc12)N(C)C

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 1-methyl-1H-indole and (2-methyl-benzylidene)-dimethylammonium chloride, which had been prepared in accordance with example 44 from 2-methyl-benzaldehyde and dimethylamine.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12]([OH:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>CN(C=O)C>[CH2:12]([O:19][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N+:9]([O-:11])=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1c(F)cccc1F
Reactant: OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1c(F)cccc1OCc1ccccc1
Temperature: 60 °C

Procedure:
A mixture of 1,3-difluoro-2-nitrobenzene (1.0 g, 6.29 mmol), benzyl alcohol (0.81 mL, 7.86 mmol) and potassium carbonate (1.74 g, 12.6 mmol) in DMF (5 mL) is heated at 60° C. for 18 h. The reaction mixture is poured into EtOAc, and washed with water and brine. The organic phase is concentrated and purified to give the title compound: 1H NMR (CDCl3) 7.36 (m, 6H), 6.83 (m, 2H), 5.20 (s, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]3([C:27]4[C:18](=[CH:19][C:20]5[O:25][CH2:24][CH2:23][O:22][C:21]=5[CH:26]=4)[O:17][CH2:16]3)[C:8]2=[O:28])=[CH:4][CH:3]=1.OC1C=[C:34](C=CC=1)[CH2:35][N:36]1[C:44]2C(=CC=CC=2)C2(COC3C=C4C(=CC2=3)CCO4)[C:37]1=O.Cl.CN(C)CCCl.ICC(N)=O>>[CH3:37][N:36]([CH3:44])[CH2:35][CH2:34][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]3([C:27]4[C:18](=[CH:19][C:20]5[O:25][CH2:24][CH2:23][O:22][C:21]=5[CH:26]=4)[O:17][CH2:16]3)[C:8]2=[O:28])=[CH:29][CH:30]=1
Reactant: O=C1N(Cc2ccc(O)cc2)c2ccccc2C12COc1cc3c(cc12)OCCO3
Reactant: O=C1N(Cc2cccc(O)c2)c2ccccc2C12COc1cc3c(cc12)CCO3
Agent: CN(C)CCCl
Agent: Cl
Agent: NC(=O)CI
Product: CN(C)CCOc1ccc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)cc1

Procedure:
Following the procedure as described in EXAMPLE 13 and making non-critical variations using 1′-(4-hydroxybenzyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1H)-one to replace 1′-(3-hydroxybenzyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and 2-(dimethylamino)ethyl chloride hydrochloride to replace 2-iodoacetamide, 1′-{4-[2-(dimethylamino)ethoxy]benzyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1H)-one was obtained (26%) as a colorless solid: mp 77-79° C.; 1H NMR (300 MHz, CDCl3) δ 7.30-7.11 (m, 4H), 7.05-6.97 (m, 1H), 6.92-6.86 (m, 2H), 6.82-6.78 (m, 1H), 6.51 (s, 1H), 6.21 (s, 1H), 4.88 (ABq, J=77.2, 15.3 Hz, 2H), 4.79 (ABq, J=83.8, 8.9 Hz, 2H), 4.23-4.05 (m, 6H), 2.84-2.75 (m, 2H), 2.40 (s, 6H); 13C NMR (300 MHz, CDCl3) δ 177.5, 158.3, 155.2, 144.6, 142.1, 138.3, 132.3, 128.7, 127.9, 123.8, 123.3, 121.1, 114.9, 111.5, 109.3, 99.4, 80.2, 65.8, 64.5, 63.9, 58.2, 58.0, 45.8, 43.6; MS (ES+) m/z 472.8 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[CH:25][C:5]([CH:6]=[C:7]2[C:16]3[N:15]=[C:14]4[CH:17]=[CH:18][C:19]([C:21]([OH:23])=[O:22])=[CH:20][N:13]4[C:12](=[O:24])[C:11]=3[CH2:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[C:27](OC(=O)C)(=[O:29])[CH3:28].N1C=CC=CC=1>CN(C)C=O>[C:27]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[C:7]2[C:16]3[N:15]=[C:14]4[CH:17]=[CH:18][C:19]([C:21]([OH:23])=[O:22])=[CH:20][N:13]4[C:12](=[O:24])[C:11]=3[CH2:10][CH2:9][CH2:8]2)=[CH:25][CH:26]=1)(=[O:29])[CH3:28]
Reactant: Nc1ccc(C=C2CCCc3c2nc2ccc(C(=O)O)cn2c3=O)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(C=C2CCCc3c2nc2ccc(C(=O)O)cn2c3=O)cc1

Procedure:
4-(4-amino-benzylidene)-1,2,3,4-tetrahydro-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid (1 g) in dimethylformamide (40 ml) was reacted with acetic anhydride (4 ml) in the presence of pyridine (8 ml) at 60° C. for 7 hours. After cooling and dilution with ice water, the precipitate was filtered and washed with water: crystallization from dimethylformamide-ethanol gave 0.7 g of 4-(4-acetylamino-benzylidene)-1,2,3,4-tetrahydro-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid.
Reaction SMILES: [C:1]1(=[O:7])O[C:4](=[O:5])[CH:3]=[CH:2]1.[CH2:8]([NH2:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C[Si](C)(C)N[Si](C)(C)C.Cl>C1C=CC=CC=1.[Br-].[Zn+2].[Br-]>[CH2:8]([N:16]1[C:4](=[O:5])[CH:3]=[CH:2][C:1]1=[O:7])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: O=C1C=CC(=O)O1
Reactant: CCCCCCCCN
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Agent: [Br-]
Solvent: c1ccccc1
Product: CCCCCCCCN1C(=O)C=CC1=O
Temperature: 30 °C
Yield: 82.5 %

Procedure:
To a suspension of maleic anhydride (3.0 g, 30.6 mmol) in 80 mL of benzene, a solution of octylamine (3.59 g, 27.8 mmol) in 50 mL of benzene was added. The resulting mixture was stirred at 30° C. for an hour and zinc bromide (ZnBr2, 6.89 g, 30.6 mmol) and hexamethyl disilazane (6.72 g, 41.7 mmol) in 20 mL of benzene were added. The resulting suspension was heated under reflux for 2 hours. After cooling to room temperature, the reaction mixture was poured into 200 mL of 0.5 M hydrochloric acid (HCl). The organic layer was separated and the aqueous portion was extracted twice with 150 mL portions of ethyl acetate (EtOAc). The combined organic layers were washed with saturated aqueous sodium bicarbonate (NaHCO3, 2×150 mL), brine (1×150 mL), and dried over magnesium sulfate (MgSO4). The solution was concentrated under vacuum to yield a viscous solid, which is subsequently sublimed to produce N-octylmaleimide as a white solid (4.8 g, 92%). 1H NMR (400 MHz, CDCl3): δ 0.87 (t, 3H, J=6 Hz), 1.20-1.40 (m, 10H), 1.50-1.70 (m, 2H), 3.51 (t, 2H, J=6 Hz), 6.69 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH2:11][CH2:12][N:13]([CH3:22])[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][CH2:8][S:7][C:6]=2[CH:23]=1.I.[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C:30](SC)=[NH:31].N>CCO.C(Cl)Cl.CO>[CH3:22][N:13]([CH2:12][CH2:11][N:10]1[CH2:9][CH2:8][S:7][C:6]2[CH:23]=[C:2]([NH:1][C:30]([C:26]3[S:25][CH:29]=[CH:28][CH:27]=3)=[NH:31])[CH:3]=[CH:4][C:5]1=2)[CH2:14][C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16]
Reactant: CN(CCN1CCSc2cc(N)ccc21)CC(=O)OC(C)(C)C
Reactant: CSC(=N)c1cccs1
Agent: I
Agent: N
Solvent: CO
Solvent: CCO
Solvent: ClCCl
Product: CN(CCN1CCSc2cc(NC(=N)c3cccs3)ccc21)CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.3 %

Procedure:
To a solution of tert-butyl 2-((2-(7-amino-2H-benzo[b][1,4]thiazin-4(3H)-yl)ethyl)(methyl)amino)acetate (850 mg, 2.52 mmol) in EtOH (25 mL) was added methyl thiophene-2-carbimidothioate hydroiodide (1.43 g, 5.04 mmol). The resulting suspension was stirred at room temperature for 17 hours (overnight). At this time, the suspension was diluted with 20 mL CH2Cl2 to give a dark yellow solution. Argon was then bubbled through this solution for 30 minutes. The solution was transferred to a separatory funnel containing saturated sodium bicarbonate solution (50 mL) and CH2Cl2 (100 mL) then extracted. After extraction, the organic layer was separated, dried (Na2SO4), filtered, and concentrated to give a dark residue. This residue was subjected to flash chromatography on silica gel using 2:98 MeOH:CH2Cl2 followed by 2.5:97.5 (2M NH3 in MeOH):CH2Cl2 to give a yellow-green residue (420 mg, 37.3%). Some impure fractions were collected (˜340 mg). 1H-NMR (CDCl3) δ 7.43-7.35 (m, 2H), 7.06 (pseudo t, J=4.8 Hz, 1H), 7.71 (brd, J=8.1 Hz, 2H), 6.65 (dd, J=1.8, 8.4 Hz, 1H), 4.91 (brs, 2H), 3.66-3.58 (m, 2H), 3.43 (t, J=7.2 Hz, 2H), 3.21 (s, 2H), 3.07-2.99 (m, 2H), 2.74 (t, J=7.5 Hz, 2H), 2.45 (s, 3H), 1.47 (s, 9H); ESI-MS (m/z, %): 447 (MH+, 100), 391 (50); HPLC purity: 99.7% a/a.