Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4].[C:25]1([C:36](O)=[O:37])[CH:26]=[CH:27][CH:28]=[C:29]2[CH2:35][CH2:34][CH2:33][CH:32]=[CH:31][C:30]=12.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(OCC)(=O)C>[CH2:20]([O:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[CH2:12][CH:2]([NH:1][C:36]([C:25]1[CH:26]=[CH:27][CH:28]=[C:29]2[CH2:35][CH2:34][CH2:33][CH:32]=[CH:31][C:30]=12)=[O:37])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4])[C:21]([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)COc1cccc(CC(N)C(O)c2cccc(Cl)c2)c1
Reactant: O=C(O)c1cccc2c1C=CCCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)COc1cccc(CC(NC(=O)c2cccc3c2C=CCCC3)C(O)c2cccc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.1 %

Procedure:
To a solution of (1RS,2SR)-2-amino-3-[3-(neopentyloxy)phenyl]-1-(3-chlorophenyl)-1-propanol (0.40 g, 0.86 mmol) in N,N-dimethylformamide (5 ml) were added 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (0.17 g, 0.90 mmol) and 1-hydroxybenzotriazole monohydrate (0.138 g, 0.90 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.173 g, 0.90 mmol) was finally added. The mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1, 0:1), and recrystallization (hexane-ethyl acetate) to give N-[(1RS,2SR)-1-[3-(neopentyloxy)benzyl]-2-(3-chlorophenyl)-2-hydroxyethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide (0.174 g, 39%) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]=[N:7][OH:8])=[CH:4][CH:3]=1.N([Cl:13])=O>CCOCC>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:13])=[N:7][OH:8])=[CH:4][CH:3]=1
Reactant: O=NCl
Reactant: Cc1ccc(C=NO)cc1
Solvent: CCOCC
Product: Cc1ccc(C(Cl)=NO)cc1
Yield: 35.4 %

Procedure:
By the method of Example I-B, 67.6 g of 4-methylbenzaldoxime in 600 ml of ether was treated with 39.3 g of nitrosyl chloride. After removal of the ether, the product was recrystallized twice from hexane to give 30 g of 4-methylbenzohydroximoyl chloride, m.p. 70°-73°.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Br[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1.O>CCCCCC.CS(C)=O>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([O:16][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: Brc1ccccn1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccccn2)CC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 66.7 %

Procedure:
60% sodium hydride (0.26 g, 6.5 mmol) was washed with hexane, and suspended in dry DMSO (10 mL). To the suspension was added a solution of 1-tert-butoxycarbonyl-4-hydroxypiperidine (1.01 g, 5.0 mmol) in dry DMSO (10 mL). The mixture was stirred at room temperature for 1 hour and at 60° C. for 1 hour, and cooled to room temperature. To the reaction mixture was added 2-bromopyridine (0.62 mL, 6.5 mmol), and the mixture was stirred at room temperature for 24 hours. To the reaction mixture was added water (50 mL), and the mixture was extracted with diethyl ether. The extract was washed with water and saturated aqueous solution of sodium hydrogen carbonate, successively, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (50 g, ethyl acetate-hexane 1:5) to give the titled compound as colorless crystals (928 mg, 67%).
Reaction SMILES: C([N:8]1[CH2:12][C@@H:11]2[C@@H:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:14][CH2:15][C@@H:10]2[CH2:9]1)C1C=CC=CC=1.[H][H]>[OH-].[OH-].[Pd+2].C(O)C>[CH2:9]1[C@H:10]2[CH2:15][CH2:14][C@H:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[C@H:11]2[CH2:12][NH:8]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H]2CNC[C@@H]21

Procedure:
tert-Butyl(3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-ylcarbamate (1.06 g, 3.35 mmol) from Step A and ethanol (20 mL) were added to 20% Pd(OH)2 on carbon, wet (212.0 mg, 1.51 mmol) in a 250 mL stainless steel pressure bottle. The reaction mixture was stirred for 16 hours under 30 psi hydrogen at room temperature. The mixture was filtered through a nylon membrane and the solvent was removed in vacuo to give tert-butyl(3aR,4S,6aS)-octahydrocyclopenta[c]pyrrol-4-ylcarbamate: 1H NMR (500 MHz, pyridine-d5) δ ppm 4.02-3.99 (m, 1H), 3.03 (d, J=10.4, 1H), 2.98-2.89 (m, 1H), 2.84 (dd, J=10.1, 6.4, 1H), 2.61-2.50 (m, 3H), 2.06-1.98 (m, 1H), 1.91 (td, J=12.9, 6.7, 1H), 1.63 (dt, J=19.5, 7.6, 1H), 1.53 (s, 9H), 1.29-1.23 (m, 1H); MS (ESI+) m/z 227 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=1)([O-:3])=[O:2].[Cl-].[Al+3].[Cl-].[Cl-].[C:21](Cl)(=[O:23])[CH3:22].Cl>C(=S)=S.C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][C:11]1[CH:12]=[CH:13][C:14]([C:21](=[O:23])[CH3:22])=[CH:15][CH:16]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(Oc2ccccc2)c1
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(Oc2cccc([N+](=O)[O-])c2)cc1
Temperature: 0 °C

Procedure:
The compound 1-nitro-3-phenoxybenzene (10.17 g, 0.0473 mol) is put into solution in carbon disulphide (70 ml). Aluminium chloride (10.06 g, 0.076 mol) is added by portions at ambient temperature. The reaction medium is cooled down to 0° C. then acetyl chloride (2.4 ml, 0.038 mol) is added dropwise. The reaction medium is left to return to 23° C. then stirring is maintained for 5 hours, followed by cooling down again to 0° C., then the careful addition of ethyl acetate, crushed ice and 3 N hydrochloric acid. After decantation, the medium is extracted with ethyl acetate. The organic phase is washed with water, with a saturated solution of sodium carbonate then with a saturated solution of sodium chloride. It is then dried over sodium sulphate then evaporated. The residue obtained is adsorbed on silica then purified by chromatography on a Biotage-type silica column (eluent: ethyl acetate-heptane: 1-4). After washing with diethyl ether, a yellow-coloured powder is obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:13]2[N:18]=[C:17]([CH3:19])[N:16]=[C:15]([NH2:20])[CH:14]=2)[C:9](F)=[N:10][CH:11]=1)=[CH2:5])C.[F:21][C:22]1[CH:23]=[C:24]([NH2:30])[CH:25]=[N:26][C:27]=1[O:28][CH3:29].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[NH2:20][C:15]1[N:16]=[C:17]([CH3:19])[N:18]=[C:13]([C:8]2[CH:7]=[C:6]([C:4](=[O:3])[CH3:5])[CH:11]=[N:10][C:9]=2[NH:30][C:24]2[CH:25]=[N:26][C:27]([O:28][CH3:29])=[C:22]([F:21])[CH:23]=2)[CH:14]=1
Reactant: C=C(OCC)c1cnc(F)c(-c2cc(N)nc(C)n2)c1
Reactant: COc1ncc(N)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ncc(Nc2ncc(C(C)=O)cc2-c2cc(N)nc(C)n2)cc1F
Reaction time: 0.5 h
Yield: 32.1 %

Procedure:
A mixture of 6-(5-(1-ethoxyvinyl)-2-fluoropyridin-3-yl)-2-methylpyrimidin-4-amine (208 mg, 0.76 mmol) and 5-fluoro-6-methoxypyridin-3-amine (162 mg, 1.14 mmol) in 1.5 mL of THF at 0° C. was added sodium bis(trimethylsilyl)amide (1 M in THF) (2.28 mL, 2.28 mmol) dropwise at 0° C. and the dark red solution was stirred at this temperature for 30 min. It was quenched with 4 mL of 0.5 N HCl and stirred for 10 min. The mixture was basified with 1 N NaOH to pH of 8 and stirred with 10 mL of EtOAc for 5 min. The precipitated brown solid was filtered, washed with 2×2 mL of water followed by 2×2 mL of EtOAc. The brown solid was dried in a vacuum oven at 45° C. for 18 h to give 1-(5-(6-amino-2-methylpyrimidin-4-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)ethanone (90 mg, 32% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.93 (s, 1H), 8.90 (s, 1H), 8.50 (s, 1H), 8.37 (s, 1H), 8.24 (s, 1H), 7.10 (br., 2H), 6.93 (s, 1H), 3.95 (s, 3H), 2.60 (s, 3H), 1.58 (s, 3H). m/z (ESI, positive ion) 369.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([S:13](Cl)(=O)=O)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.P(OC)(OC)O[CH3:21].CO.[OH-].[K+]>C1(C)C=CC=CC=1>[CH3:21][S:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][C:5]2[CH:17]=[CH:18][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:8][CH:9]=1
Reactant: O=S(=O)(Cl)c1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: COP(OC)OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1
Product: CSc1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 60 °C
Yield: 76.6 %

Procedure:
4-(4′-Chlorophenoxy)phenyl sulfonyl chloride (3.0 kg), 3, was dissolved in three liters of toluene and the solution was added dropwise, with stirring, to 3.6 kg of trimethyl phosphite which had been preheated to 60° C. The reaction was exothermic and the reaction was allowed to heat to 80°-90° C. during the addition. Thin layer chromatography indicated a mixture of the desired thioether and two baseline products. The mixture was refluxed until the pot temperature rose to ˜130° C. The mixture was cooled to ˜60° C. and 1 liter of methanol was added. Potassium hydroxide solution (4.5 kg of 45% aqueous solution) was added dropwise, slowly, with rapid stirring to the reaction mixture. The addition was very exothermic and the pot temperature was controlled to 65°-80° C. The mixture was then refluxed for 2 hrs. More toluene (6 liters) was added and the mixture cooled to 60° C. The lower aqueous layer was separated and the organic layer washed with 3 liters of water. The organic layer was stripped to a low volume and 9 liters of isopropanol charged to the hot mixture. The solution as distilled until ˜3.5 liters of distillate had been collected. The mixture was held at 45° C. for several hours and was then cooled to ˜−10° C. and stirred several hours. The white, crystalline product was collected, washed with cold isopropanol and dried to yield 1.9 kg of 4-(4′-chlorophenoxy)phenyl methyl sulfide, 4.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH:8]([CH2:13][N+:14]([O-])=O)[CH2:9][N+:10]([O-])=O)[CH:5]=[CH:4][C:3]=1[N+:17]([O-])=O>[Pt].[Pd].[Ni].CO>[NH2:17][C:3]1[CH:4]=[CH:5][C:6]([CH:8]([CH2:13][NH2:14])[CH2:9][NH2:10])=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1cc(C(C[N+](=O)[O-])C[N+](=O)[O-])ccc1[N+](=O)[O-]
Agent: [Ni]
Agent: [Pd]
Agent: [Pt]
Solvent: CO
Product: Cc1cc(C(CN)CN)ccc1N
Temperature: 57.5 °C
Yield: 95.6 %

Procedure:
A heavy-walled flask under N2 was charged with 10 wt % platinum on carbon (3.8 g), 10 wt % palladium on carbon (50% wet, 11.3 g), Raney Ni (wet, 11.3 g), 2-methyl-1-nitro-4-(2-nitro-1-nitromethyl-ethyl)-benzene (37.7 g, 0.14 mol), and MeOH (754 mL). After attaching the flask to the hydrogenation apparatus, it was subjected to three vacuum degas-nitrogen purge cycles, followed by three nitrogen outgas-hydrogen purge cycles. The resulting suspension was stirred under 60 psi of H2 at 55-60° C. for at least 72 h. The reaction mixture was filtered through a celite pad (27 g), rinsing with methanol (760 mL). The filtrate and rinse were concentrated to dryness in vacuo to give the crude title compound as red-brown gum (24 g, 96% yield). This material was used without further purification.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[NH:15][C:14](=O)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1.CN(C)C=O.S(Cl)([Cl:24])=O>>[Cl:24][C:14]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=[C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[N:15]=1
Reactant: O=S(Cl)Cl
Reactant: O=c1[nH]c(-c2cccs2)nc2ccccc12
Solvent: CN(C)C=O
Product: Clc1nc(-c2cccs2)nc2ccccc12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of 22.8 g of 2-(2-thienyl)-quinazolin-4(3H)-one in 200 ml of thionyl chloride was added in small quantities 7.3 g of dimethylformamide. The mixture was stirred for 2 hours, then poured into 2 liters of ice. The yellow solid was recrystallized three times from cyclohexane to give 16.7 g of 4-chloro-2-(2-thienyl)-quinazoline, m.p. 121.5°-123°; ir and nmr spectra were consistent with the assigned structure.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([C:12]([N:14]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[CH2:18][N:17]4[CH:25]=[CH:26][CH:27]=[C:16]4[CH2:15]3)=[O:13])=[CH:8][CH:7]=2)=[N:2]1.[Cl:28][C:29]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:30]=1[C:31](Cl)=[O:32]>N1C=CC=CC=1>[Cl:28][C:29]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:30]=1[C:31]([N:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([C:12]([N:14]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[CH2:18][N:17]4[CH:25]=[CH:26][CH:27]=[C:16]4[CH2:15]3)=[O:13])=[CH:8][CH:7]=2)=[N:2]1)=[O:32]
Reactant: O=C(c1ccc(-c2cc[nH]n2)cc1)N1Cc2cccn2Cc2ccccc21
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Solvent: c1ccncc1
Product: O=C(c1ccc(-c2ccn(C(=O)c3ccc(Cl)cc3Cl)n2)cc1)N1Cc2cccn2Cc2ccccc21
Yield: 62.5 %

Procedure:
In the manner of Example 32, employing [4-(1H-pyrazol-3-yl)-phenyl]-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone (0.71 g) in dry pyridine (20 ml) and 2,4-dichlorobenzoyl chloride (0.52 g), the title compound (0.66 g) was obtained as a crystalline solid, m.p. 180-182° C.; MS, m/z: 528 (M)+.
Reaction SMILES: [C:1]12([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[NH:7][C:6](=[O:14])[O:5]1)[CH2:4][CH2:3][CH2:2]2.C([O-])(=O)C.[K+].[Br:20]Br>C(O)(=O)C>[Br:20][C:11]1[CH:12]=[CH:13][C:8]2[NH:7][C:6](=[O:14])[O:5][C:1]3([CH2:4][CH2:3][CH2:2]3)[C:9]=2[CH:10]=1
Reactant: BrBr
Reactant: O=C1Nc2ccccc2C2(CCC2)O1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: O=C1Nc2ccc(Br)cc2C2(CCC2)O1
Yield: 53 %

Procedure:
To a solution of spiro[3,1-benzoxazine-4,1′-cyclobutan]-2(1H)-one (0.36 g, 1.9 mmol) and potassium acetate (0.56 g, 5.7 mmol) in acetic acid was added a solution of bromine (0.09 mL, 1.95 mmol) in acetic acid (2 mL) at room temperature. Upon completion by TLC of the reaction, the acetic acid was removed. The residue was treated with saturated sodium bicarbonate (100 mL) and the product extracted with ethyl acetate (50 mL). The organics were dried over magnesium sulfate and concentrated. Trituration of residue with ether gave 6-bromospiro[3,1-benzoxazine-4,1′-cyclobutan]-2(1H)-one (0.27 g, 52%) as a white solid. 1H NMR (DMSO-d6): δ 10.37 (s, 1H), 7.65 (d, 1H, J=2.1 Hz), 7.47 (dd, 1H, J=8.5, 2.2 Hz) 6.86 (d, 1H, J=8.5 Hz), 2.52-2.47 (m, 2H), 2.04-1.98 (m, 2H), 1.87-1.80 (m, 2H). MS (ESI) m/z 268/270 ([M+H]+); MS (ESI) m/z 266/268 ([M−H]−).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C@H:10]3[C:18]4[C:13](=[CH:14][C:15]([O:19][CH2:20][CH2:21][CH3:22])=[CH:16][CH:17]=4)[C:12](=[O:23])[CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[H-].[Na+].C[O-].[Na+].[C:29](=O)([O:32]C)[O:30][CH3:31]>C1(C)C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C@H:10]3[C:18]4[C:13](=[CH:14][C:15]([O:19][CH2:20][CH2:21][CH3:22])=[CH:16][CH:17]=4)[C:12](=[O:23])[C@@H:11]3[C:29]([O:30][CH3:31])=[O:32])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CCCOc1ccc2c(c1)C(=O)C[C@H]2c1ccc2c(c1)OCO2
Reactant: COC(=O)OC
Agent: C[O-]
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCOc1ccc2c(c1)C(=O)[C@H](C(=O)OC)[C@H]2c1ccc2c(c1)OCO2
Temperature: 40 °C
Yield: 39.8 %

Procedure:
A 100 mL three-necked flask under nitrogen was charged with (S)-3-(1,3-Benzodioxol-5-yl)-2,3-dihydro-6-propoxy-1H-inden-1-one (1.5 g, 4.84 mmol), toluene (20 mL), 60% NaH suspension (213 mg, 5.3 mmol), NaOMe (288 mg, 5.3 =mmol), and dimethyl carbonate (2.5 mL, 29 mmol). The solution was warmed to 40 ° C. for 3 h, cooled to 0° C., quenched with 3 M AcOH (0.5 mL) and diluted with H2O (50 mL) and EtOAc (50 mL). The organic phase was washed with brine (50 mL), dried (MgSO4) and concentrated. The crude material was triturated with EtOAc/hexane (1:3, 50 mL) affording (1S-trans)-methyl 1-(1,3-benzodioxol-5-yl) -2,3-dihydro-3-oxo-5-propoxy-1H-indene-2-carboxylate as a pale yellow solid (710 mg, 73% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17].CO.[BH4-].[Na+].C(O)(=O)C>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[OH:9])=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17]
Reactant: O=C(c1ccccc1)c1ccc(F)c([N+](=O)[O-])c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: O=[N+]([O-])c1cc(C(O)c2ccccc2)ccc1F
Reaction time: 0.25 h
Yield: 100 %

Procedure:
To a cooled (ice bath) solution of 24.5 parts of (4-fluoro-3-nitrophenyl) phenylmethanone in 120 parts of methanol were added portionwise 1.5 parts of sodium tetrahydroborate. Upon complete addition, stirring was continued for 15 minutes at 0° C. A solution of 3 parts of acetic acid in 25 parts of water was added dropwise to the mixture. Upon completion, the mixture was concentrated. Water was added to the residue and the product was extracted with dichloromethane. The extract was dried, filtered and concentrated, yielding 25.1 parts (100%) of 4-fluoro-3-nitro-α-phenylbenzenemethanol as an oily residue (int. 63).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.CS(O[CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOCC>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1
Reactant: Oc1cccc(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(Oc2cccc(Br)c2)CC1
Temperature: 65 °C
Yield: 85 %

Procedure:
The mixture of 3-bromophenol (2.0 g, 11.56 mmol), tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (3.87 g, 13.872 mmol) and caesium carbonate (11.27 g, 34.68 mmol) in DMF (25 ml) was heated at 65° C. for 14 hours. Cooled to RT and diluted with ether. Ether layer was washed with water and brine, dried over sodium sulphate and distilled off the solvent to afford 3.5 g (85.3% yield) of the titled product after purification with (60/120 silica gel) column chromatography using 5% ethyl acetate in hexane as eluent. MS: m/z=356.0 (M+1).
Reaction SMILES: Cl[CH2:2][C:3](=[O:5])[CH3:4].[S:6]1([C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:10](=[O:11])[NH:9]1)(=[O:8])=[O:7].[Na]>>[CH2:2]([N:9]1[C:10](=[O:11])[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:8])=[O:7])[C:3]([CH3:4])=[O:5]
Reactant: CC(=O)CCl
Reactant: O=C1NS(=O)(=O)c2ccccc21
Agent: [Na]
Product: CC(=O)CN1C(=O)c2ccccc2S1(=O)=O
Temperature: 110 °C
Yield: 73.6 %

Procedure:
26 ml (324 millimoles) of chloroacetone were slowly added dropwise to 40.0 g (200 millimoles) of sodium saccharin, while stirring (exothermic reaction). The temperature was gradually increased to 110° C., and the reaction mixture was stirred at this temperature for 5 hours, after which it was cooled. An excess of ice-water was added, and stirring was continued for a further hour. The precipitated solid was filtered off under suction, recrystallized from ethanol and dried in a drying oven under reduced pressure at 50° C. to give 35.2 g (74%) of N-acetonylsaccharin of melting point 142°-143° C.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:13]=1[CH2:14][NH:15][C:16]1[CH:21]=[C:20]([I:22])[C:19]([CH3:23])=[CH:18][N:17]=1.[CH:30]1([C:33](Cl)=[O:34])[CH2:32][CH2:31]1>C(Cl)Cl.[Cl-].[NH4+]>[CH3:10][O:11][C:12]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:13]=1[CH2:14][N:15]([C:16]1[CH:21]=[C:20]([I:22])[C:19]([CH3:23])=[CH:18][N:17]=1)[C:33]([CH:30]1[CH2:32][CH2:31]1)=[O:34]
Reactant: COc1ccc(CNc2cc(I)c(C)cn2)c(OC)c1
Reactant: O=C(Cl)C1CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN(C(=O)C2CC2)c2cc(I)c(C)cn2)c(OC)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 76.5 %

Procedure:
To a solution of DIEA (1.8 mL, 10.4 mmol) in DCM (50 mL) at 0° C. was added N-(2,4-dimethoxybenzyl)-4-iodo-5-methylpyridin-2-amine (2.0 g, 5.2 mmol) and cyclopropanecarbonyl chloride (0.66 mL, 7.3 mmol). The reaction mixture was allowed to stir at 0° C. for 2 h and then diluted with DCM and aqueous ammonium chloride. The aqueous solution was removed and the organic solution was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography to give N-(2,4-dimethoxybenzyl)-N-(4-iodo-5-methylpyridin-2-yl)cyclopropanecarboxamide (1.8 g, 78%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][O:11][C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2[CH:14]=[C:15]([C:21](O)=[O:22])[NH:16]3)=[CH:2]1.Cl.Cl.Cl.[NH2:27][CH:28]1[CH2:33][CH2:32][N:31]([CH2:34][C@@H:35]([N:37]2[CH2:42][CH2:41][C@H:40]([OH:43])[C@@H:39]([CH3:44])[CH2:38]2)[CH3:36])[CH2:30][CH2:29]1>>[OH:43][C@H:40]1[CH2:41][CH2:42][N:37]([C@@H:35]([CH3:36])[CH2:34][N:31]2[CH2:32][CH2:33][CH:28]([NH:27][C:21]([C:15]3[NH:16][C:17]4[C:13]([CH:14]=3)=[C:12]([O:11][CH2:10][C:3]3[C:4]5[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=5[O:1][CH:2]=3)[CH:20]=[CH:19][CH:18]=4)=[O:22])[CH2:29][CH2:30]2)[CH2:38][C@@H:39]1[CH3:44]
Reactant: O=C(O)c1cc2c(OCc3coc4ccccc34)cccc2[nH]1
Reactant: C[C@H]1CN([C@@H](C)CN2CCC(N)CC2)CC[C@@H]1O
Agent: Cl
Product: C[C@H]1CN([C@@H](C)CN2CCC(NC(=O)c3cc4c(OCc5coc6ccccc56)cccc4[nH]3)CC2)CC[C@@H]1O

Procedure:
This compound is synthesized analogously to example 1 from 4-(benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid, 105 (see example 50) and amine 56.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:28][C:12]2=[CH:13][C:14]3[C:15](=[O:27])[N:16]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[C:17](=[O:21])[C:18]=3[C:19]([CH3:20])=[C:11]2[N:10]=1.[F:29][C:30]1[CH:31]=[CH:32][C:33]([CH3:40])=[C:34]([CH2:36][CH:37]([NH2:39])[CH3:38])[CH:35]=1.CCN(C(C)C)C(C)C>C(O)CCC>[CH3:25][N:24]([CH3:26])[CH2:23][CH2:22][N:16]1[C:15](=[O:27])[C:14]2[CH:13]=[C:12]3[NH:28][C:9]([C:3]4[C:4](=[O:8])[NH:5][CH:6]=[CH:7][C:2]=4[NH:39][CH:37]([CH3:38])[CH2:36][C:34]4[CH:35]=[C:30]([F:29])[CH:31]=[CH:32][C:33]=4[CH3:40])=[N:10][C:11]3=[C:19]([CH3:20])[C:18]=2[C:17]1=[O:21]
Reactant: Cc1ccc(F)cc1CC(C)N
Reactant: Cc1c2c(cc3[nH]c(-c4c(Cl)cc[nH]c4=O)nc13)C(=O)N(CCN(C)C)C2=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1ccc(F)cc1CC(C)Nc1cc[nH]c(=O)c1-c1nc2c(C)c3c(cc2[nH]1)C(=O)N(CCN(C)C)C3=O
Yield: 55 %

Procedure:
A mixture of 2-(4-chloro-2-oxo-1,2-dihydropyridin-3-yl)-6-(2-(dimethylamino)ethyl)-4-methylimidazo[4,5-f]isoindole-5,7(1H,6H)-dione (0.48 g, 1.20 mmol), 1-(5-fluoro-2-methylphenyl)propan-2-amine (0.24 g, 1.44 mmol), Hunig's base (0.78 g, 6.00 mmol), and 10 mL of anhydrous 1-butanol was heated at reflux for 12-13 h under an argon atmosphere. Product was purified by a silica gel column using methylene chloride and methanol (9:1 v/v) as eluent to afford 0.35 g of the designed compound as yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 13.36 (s, 1H, NH), 11.24 (d, J=6.0 Hz, 1H, NH), 11.02 (d, J=8.5 Hz, 1H, NH), 7.99 (s, 1H, ArH), 7.32 (t, J=6.5 Hz, 1H, ArH), 7.15-7.08 (m, 2H, ArH), 6.91-6.87 (m, 1H, ArH), 6.16 (d, J=7.5 Hz, 1H, ArH), 4.22-4.18 (m, 1H, CH), 3.73-3.71 (m, 2H, CH2), 2.97-2.96 (m, 2H, CH2), 2.86 (s, 3H, CH3), 2.72-2.68 (m, 2H, CH2), 2.36 (s, 6H, 2×CH3), 2.27 (s, 3H, CH3), 1.34 (d, J=6.5 Hz, 3H, CH3); Mass (ESI, negative) m/z 529.0 [M−H]−.