Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([O:11][C:12]3[C:24]([CH:25]4[CH2:27][CH2:26]4)=[CH:23][C:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[C:14]([F:28])[CH:13]=3)[CH2:7][CH2:6]2)[O:4]CC1.FC(F)(F)C(O)=O.ClCCl>O1CCCC1.O>[CH:25]1([C:24]2[C:12]([O:11][CH:8]3[CH2:7][CH2:6][C:5](=[O:4])[CH2:10][CH2:9]3)=[CH:13][C:14]([F:28])=[C:15]([CH:23]=2)[C:16]([O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[O:17])[CH2:27][CH2:26]1
Reactant: CC(C)(C)OC(=O)c1cc(C2CC2)c(OC2CCC3(CC2)OCCO3)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1cc(C2CC2)c(OC2CCC(=O)CC2)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.8 %

Procedure:
To a mixture of tert-butyl 4-(1,4-dioxaspiro[4.5]decan-8-yloxy)-5-cyclopropyl-2-fluorobenzoate (0.557 g, 1.44 mmol) in tetrahydrofuran (1.5 mL) and water (1.5 mL) was added trifluoroacetic acid (0.5 mL) and the reaction mixture was stirred for 16 hours at ambient temperature. After addition of dichloromethane (100 mL), the mixture was washed with saturated sodium bicarbonate solution (10 mL), brine (10 mL), and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate in vacuo gave a residue which was purified by silica gel column chromatography using 0-30% ethyl acetate in hexanes as eluent to afford the title compound as a colorless oil (0.300 g, 60%): 1H NMR (300 MHz, CDCl3) δ 7.42 (d, J=8.4 Hz, 1H), 6.59 (d, J=12.6 Hz, 1H), 4.80-4.71 (m, 1H), 2.77-2.62 (m, 2H), 2.42-2.27 (m, 4H), 2.14-1.93 (m, 3H), 1.56 (s, 9H), 0.94-0.84 (m, 2H), 0.65-0.60 (m, 2H).
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C:9]2[CH:10]=[CH:11][C:12]([CH3:35])=[C:13]([C:15]3[CH:16]=[CH:17][C:18]4[O:22][C:21]([C:23]5[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=5)=[C:20]([C:30]([NH:32][CH3:33])=[O:31])[C:19]=4[CH:34]=3)[CH:14]=2)=[O:8])[CH2:5][CH2:4]1)#[N:2].Cl.[NH2:37][OH:38].CCN(CC)CC>C(O)C>[F:29][C:26]1[CH:25]=[CH:24][C:23]([C:21]2[O:22][C:18]3[CH:17]=[CH:16][C:15]([C:13]4[CH:14]=[C:9]([C:7](=[O:8])[NH:6][C:3]5([C:1](=[NH:2])[NH:37][OH:38])[CH2:4][CH2:5]5)[CH:10]=[CH:11][C:12]=4[CH3:35])=[CH:34][C:19]=3[C:20]=2[C:30]([NH:32][CH3:33])=[O:31])=[CH:28][CH:27]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(C#N)CC4)ccc3C)cc12
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(C(=N)NO)CC4)ccc3C)cc12
Temperature: 115 °C

Procedure:
To a mixture of 5-(5-(1-cyanocyclopropylcarbamoyl)-2-methylphenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (43.5 mg, 0.093 mmol) in ethanol (1.5 mL) at r.t. under N2 was added hydroxylamine hydrochloride (12.93 mg, 0.186 mmol), followed by Et3N (0.039 mL, 0.279 mmol). The mixture was stirred at reflux (115° C.) for about 4 hours. The mixture was cooled to r.t. and evaporated. The residue was used for the next step without further purification. LC/MS were performed by using Shimadzu-VP instrument with UV detection at 220 nm and Waters Micromass. HPLC method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=5 ml/min, Column: Phenomenex-Luna, 3.0×50 mm, S10; (ES+) m/z (M+H)+=501.13, HPLC Rt=1.385 min.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[N:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[N:3]=1.[NH2:20][CH2:21][C:22]([NH:24][CH:25]1[CH2:28][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26]1)=[O:23]>C1COCC1>[F:17][C:16]([F:19])([F:18])[C:4]1[N:3]=[C:2]([NH:20][CH2:21][C:22]([NH:24][CH:25]2[CH2:28][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26]2)=[O:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[N:5]=1
Reactant: FC(F)(F)c1ccc2nc(C(F)(F)F)nc(Cl)c2c1
Reactant: CC(C)(C)OC(=O)N1CC(NC(=O)CN)C1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(NC(=O)CNc2nc(C(F)(F)F)nc3ccc(C(F)(F)F)cc23)C1

Procedure:
A mixture of 4-chloro-2,6-bis(trifluoromethyl)quinazoline (120 mg, 0.399 mmol, prepared in the previous step), tert-butyl 3-(2-aminoacetamido)azetidine-1-carboxylate (133 mg, 0.58 mmol, prepared in Example 1, Step E) and TEA (0.12 mL, 0.863 mmol) was dissolved in dry THF (10 mL) and heated to reflux under argon for 18 hours. The reaction mixture as concentrated in vacuo and the residue purified by flash chromatography (silica gel, 50% EtOAc/Heptane).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[OH-].[Na+].[CH2:14]([OH:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([O:21][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:3]=1
Reactant: OCc1ccccc1
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Agent: [Na+]
Agent: [OH-]
Product: Nc1nc(OCc2ccccc2)c2[nH]cnc2n1
Temperature: 100 °C
Reaction time: 0.33 h

Procedure:
To a 500 mL 3 neck round bottom flask equipped with a magnetic stirrer, temperature probe and nitrogen inlet was added 2-amino-6-chloropurine (20 g), sodium hyroxide (28 g) and benzyl alcohol (200 mL). The mixture was stirred for 20 minutes and then heated at 100° C. for 2-3 hours. The reaction mixture was then cooled to room temperature and partitioned between methyl t-butyl ether (300 mL) and water (300 mL). The aqueous layer was separated and the pH was adjusted to 7-8 with 6 M HCl. The resulting solid was filtered, washed with water (50 mL) and dried under vacuum at 50° C. for 20 hours to provide the desired product as a pale yellow solid (24.3 g).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]1[CH:7]=[C:8]([CH:15]=[CH:16][C:17]=1[F:18])[NH:9][C:10](=[O:14])[CH2:11][CH2:12]Cl>Cl>[F:18][C:17]1[CH:16]=[C:15]2[C:8](=[CH:7][C:6]=1[F:5])[NH:9][C:10](=[O:14])[CH2:11][CH2:12]2
Reactant: O=C(CCCl)Nc1ccc(F)c(F)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C1CCc2cc(F)c(F)cc2N1
Temperature: 110 °C
Reaction time: 0.03 h
Yield: 235.5 %

Procedure:
Aluminium chloride (134 g) is added with vigorous stirring to 3',4'-difluoro-3-chloropropionanilide (67 g) and then, after approximately 2 minutes, 3',4'-difluoro-3-chloropropionanilide (135.9 g) and aluminium chloride (272 g) are added again in small portions in the course of 15 minutes. The temperature rises spontaneously to approximately 60° C. and the reaction mixture becomes liquid. The mixture is then heated to 110° C. in the course of 20 minutes and maintained at between 110° C. and 120° C. for 2 hours. The reaction mixture (at approximately 110° C.) is poured in the course of 10 minutes with vigorous stirring into a mixture of 35% strength hydrochloric acid (840 cc) and crushed ice (1 kg). The temperature is allowed to rise to approximately 20° C. and the product is drained, washed with water (2×600 cc), ethanol (300 cc) at 5° C. and ethyl ether (2×400 cc) at approximately 20° C. 6,7-Difluoro-1,4-dihydrocarbostyril (131.58 g) is obtained in the form of a beige solid, m.p. 216° C., which is used without further treatment for the subsequent steps.
Reaction SMILES: Cl[S:2]([N:5]=C=O)(=[O:4])=[O:3].[F:8][CH:9]([F:24])[C:10]1([O:13][Si](C(C)C)(C(C)C)C(C)C)[CH2:12][CH2:11]1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Na+].[Cl-]>CN1C(=O)CCC1.C(O)=O>[F:8][CH:9]([F:24])[C:10]1([O:13][S:2](=[O:3])(=[O:4])[NH2:5])[CH2:12][CH2:11]1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC(C)[Si](OC1(C(F)F)CC1)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: CN1CCCC1=O
Solvent: O=CO
Product: NS(=O)(=O)OC1(C(F)F)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 0 %

Procedure:
A three-neck round bottom flask equipped with a reflux condenser was charged with chlorosulfonyl isocyanate (2.6 ml, 29.9 mol) and cooled to 0° C. Formic acid (1.13 mL, 29.9 mol) was added dropwise with rapid stirring and with rapid gas evolution observed. Upon complete addition of formic acid, the reaction was allowed to warm to room temperature. After 2 h, the reaction vessel was cooled to 0° C. and (1-difluoromethyl-cyclopropoxy)-triisopropyl-silane (500 mg, 1.89 mol) dissolved in NMP (5 mL) was added dropwise via an addition funnel. The mixture was warmed to RT and TBAF (7 ml, 7 mmol) was added. Stir mixture four days. The reaction mixture was poured into cold saturated aqueous NaCl and extracted with EtOAc two times. After removal of the separated organic solvent, the crude product was, purified by column chromatography on silica to provide sulfamic acid 1-difluoromethyl-cyclopropyl ester (10 mg, 2.8% yield): 1H NMR (CDCl3, 300 MHz) δ 6.24 (t, 1H), 5.18 (s, 2H), 1.49 (m, 2H), 1.19 (m, 2H).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.[NH2:13][C:14]1[CH:15]=[C:16]2[NH:22][C:21]([C:23]3[CH:28]=[CH:27][C:26]([N:29]([CH3:31])[CH3:30])=[CH:25][CH:24]=3)=[N:20][C:17]2=[N:18][CH:19]=1>>[CH3:12][N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:13][C:14]2[CH:15]=[C:16]3[NH:22][C:21]([C:23]4[CH:24]=[CH:25][C:26]([N:29]([CH3:31])[CH3:30])=[CH:27][CH:28]=4)=[N:20][C:17]3=[N:18][CH:19]=2)=[O:9])=[CH:10][CH:11]=1
Reactant: CN(C)c1ccc(C(=O)O)cc1
Reactant: CN(C)c1ccc(-c2nc3ncc(N)cc3[nH]2)cc1
Product: CN(C)c1ccc(C(=O)Nc2cnc3nc(-c4ccc(N(C)C)cc4)[nH]c3c2)cc1

Procedure:
Compound 631 was prepared according to the procedure similar to that described in Scheme III from 4-dimethylaminobenzoic acid and 6-amino-2-(4-dimethylaminophenyl)-1H-imidazo[4,5-b]pyridine. [M+H]+ calcd for C23H24N6O: 401.20; found 401.07.
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[CH:9][C:10]3[C:18]4[N:17]5[CH2:19][CH2:20][N:21]=[C:22]([CH3:23])[C:16]5=[CH:15][C:14]=4[CH2:13][CH2:12][C:11]=3[CH:24]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+].[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31]>CO.O.C(O)C>[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31].[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]3[C:18]4[N:17]5[CH2:19][CH2:20][NH:21][CH:22]([CH3:23])[C:16]5=[CH:15][C:14]=4[CH2:13][CH2:12][C:11]=3[CH:24]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC1=NCCn2c1cc1c2-c2ccc(C3CCCCC3)cc2CC1
Agent: O=C(O)/C=C/C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Solvent: O
Product: CC1NCCn2c1cc1c2-c2ccc(C3CCCCC3)cc2CC1
Yield: 27 %

Procedure:
3-Cyclohexyl-5,6,10,11-tetrahydro-8-methyl-benzo[g]pyrazino[1,2-a]indole (0.34 g) was dissolved in a mixture of 15 ml of methanol and 1,5 ml of water under argon. The solution was treated portionwise with 0.15 g of sodium borohydride while stirring and stirred at room temperature for 3 hours. Thereafter, the methanol was removed in a vacuum and the residue was stirred with 20 ml of ether and 20 ml of 10% ammonia solution. The phases were separated and the aqueous phase was extracted twice with 20 ml of ether each time. The organic phases were combined, dried with MgSO4 and freed from solvent. The crude product, 0.35 g of colourless oil, was dissolved in a 20-fold amount of ethanol and boiled briefly with 1.1 equivalents of a saturated solution of fumaric acid in ethanol. There was obtained 0.11 g (27%) of 3-cyclohexyl-5,6,8,9,10,11-hexahydro-8-methyl-benzo[g]pyrazino[1,2-a]indole fumarate (2:1); m.pt.: 199°-202° C. (dec.).
Reaction SMILES: [C:1]([CH:8]=[CH:9][CH2:10][NH:11][CH2:12][C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:16]1([C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N+]=[N-])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(#N)C>[CH:22]([O:14][C:13](=[O:15])[CH2:12][NH:11][CH2:10][CH:9]=[CH:8][C:1]([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)C=CCNCC(=O)O
Solvent: CC#N
Product: CC(C)(C)OC(=O)C=CCNCC(=O)OC(c1ccccc1)c1ccccc1

Procedure:
N-BOC allylglycine, 269 mg, is treated with 243 mg of diphenyldiazomethane in 25 ml of acetonitrile for one hour. The solvent is evaporated. Benzene is added, washed with aqueous NaHCO3 and brine, dried with MgSO4, filtered and evaporated, affording crystalline product which is washed with hexane and dried, 380 mg, m.p. 79° C.
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10]([O:13][CH3:14])[CH:11]=2)[NH:6][C:5](=O)[C:4]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:2].P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:5]1[C:4]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:3]([CH2:1][CH3:2])[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1c(CC)c2cc(OC)c(F)cc2[nH]c1=O
Product: CCOC(=O)c1c(Cl)nc2cc(F)c(OC)cc2c1CC

Procedure:
A suspension of ethyl 4-ethyl-7-fluoro-6-methoxy-2-oxo-1,2-dihydro-3-quinolinecarboxylate (19.4 g, 0.066 mol) in phosphoryl chloride (243 ml) is heated at reflux for 6 hours. The phosphoryl chloride is distilled off. The reaction mixture is decanted into ice-cooled water, then taken up in dichloromethane to solubilize. The organic phase is washed with water, then with a saturated solution of sodium chloride. The organic phase is dried over magnesium sulphate and the solvent is evaporated off. The residue is suspended in ether and the non-converted starting product (4 g) is filtered out. The filtrate is evaporated and the residue is purified by column chromatography (SiO2, AcOEt/Hpt: 5/95 to 20/80). 10.9 g of a white solid is obtained.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[CH3:19][O:20][C:21]1[N:26]=[C:25]([O:27][CH3:28])[C:24](B(O)O)=[CH:23][N:22]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:24]3[C:25]([O:27][CH3:28])=[N:26][C:21]([O:20][CH3:19])=[N:22][CH:23]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Reactant: COc1ncc(B(O)O)c(OC)n1
Product: CCCNC(=O)c1nnc2c(-c3cnc(OC)nc3OC)cccc2c1N
Yield: 27.6 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (100 mg, 0.324 mmol) and (2,4-dimethoxypyrimidin-5-yl)boronic acid (125 mg, 0.68 mmol) were reacted to afford the title compound (33 mg, 28% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.52 (bm, 1H), 8.33 (s, 1H), 7.91 (dd, J=7.7, 2.0 Hz, 1H), 7.70-7.77 (m, 2H), 4.06 (s, 3H), 3.93 (s, 3H), 3.46 (apparent q, J=6.5 Hz, 2H), 1.67 (apparent sextet, J=7.2 Hz, 2H), 1.00 (t, J=7.4 Hz, 3H). MS APCI, m/z=369 (M+H) HPLC 1.69 min.
Reaction SMILES: [CH2:1]([S:6]([C:9]1[N:13]=[CH:12][NH:11][N:10]=1)(=[O:8])=[O:7])[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:14]([N:17]([CH2:21][CH:22]=[CH2:23])[C:18](Cl)=[O:19])[CH:15]=[CH2:16].O1CCCC1.C(N(CC)CC)C>CCOCC>[CH2:14]([N:17]([CH2:21][CH:22]=[CH2:23])[C:18]([N:11]1[CH:12]=[N:13][C:9]([S:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])(=[O:8])=[O:7])=[N:10]1)=[O:19])[CH:15]=[CH2:16]
Reactant: C=CCN(CC=C)C(=O)Cl
Reactant: CCCCCS(=O)(=O)c1nc[nH]n1
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CCN(CC=C)C(=O)n1cnc(S(=O)(=O)CCCCC)n1

Procedure:
A mixture of 10.2 g. 3-pentylsulphonyl-1,2,4-triazole, 8.2 g. diallylcarbamoyl chloride, 75 ml. dry tetrahydrofuran and 7.5 ml. dry triethylamine was refluxed under anhydrous conditions for 1.5 hours. The reaction mixture was worked up as described in Example 1, using ether in place of methylene dichloride. An oily residue was obtained which was distilled under reduced pressure to give a product, b.p. 193° - 194°C./0.25 mm., which solidified on cooling. This product was recrystallized from petroleum ether (b.p. 60° - 80°C.) to give 1-diallylcarbamoyl-3-n-pentylsulphonyl-1,2,4-triazole, m.p. 28° - 30°C. Elemental analysis satisfactory.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:26](=[O:27])[N:25]([CH3:28])[C:11]3[N:12]([CH3:24])[C:13]4[C:18]([C:10]=3[CH:9]=2)=[CH:17][C:16]([C:19]2[NH:20][N:21]=[CH:22][CH:23]=2)=[CH:15][CH:14]=4)=[CH:4][CH:3]=1.[CH3:29][O:30][CH2:31]Br>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:26](=[O:27])[N:25]([CH3:28])[C:11]3[N:12]([CH3:24])[C:13]4[C:18]([C:10]=3[CH:9]=2)=[CH:17][C:16]([C:19]2[CH:23]=[CH:22][N:21]([CH2:29][O:30][CH3:31])[N:20]=2)=[CH:15][CH:14]=4)=[CH:4][CH:3]=1
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2)cc2c3cc(-c4ccn[nH]4)ccc3n(C)c21
Reactant: COCBr
Agent: Cn1c(=O)c(-c2ccc(Cl)cc2)cc2c3cc(-c4cc[nH]n4)ccc3n(C)c21
Product: COCn1ccc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4)c(=O)n(C)c2n3C)n1

Procedure:
The process is carried out as in Example 110 above, using compound from Example 104, 3-(4-chlorophenyl)-1,9-dimethyl-6-(1H-pyrazol-3-yl)-1,9-dihydropyrido[2,3-b]indol-2-one and bromomethyl methyl ether.
Reaction SMILES: [CH3:1][C:2]1([CH3:46])[C:6](=[O:7])[N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:20])[CH2:16][N:17]([CH3:19])[CH3:18])=[C:10]([C:21]([F:24])([F:23])[F:22])[CH:9]=2)[C:4](=[O:25])[N:3]1[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][S:35][CH2:36][CH2:37][CH2:38][C:39]([F:45])([F:44])[C:40]([F:43])([F:42])[F:41].CC1(C)N(CCCCCCCCCSCCCC(F)(F)C(F)(F)F)C(=[O:73])N(C2C=CC([N+]([O-])=O)=C(C(F)(F)F)C=2)C1=O>>[CH3:1][C:2]1([CH3:46])[C:6](=[O:7])[N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:20])[CH2:16][N:17]([CH3:18])[CH3:19])=[C:10]([C:21]([F:24])([F:23])[F:22])[CH:9]=2)[C:4](=[O:25])[N:3]1[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][S:35]([CH2:36][CH2:37][CH2:38][C:39]([F:45])([F:44])[C:40]([F:41])([F:42])[F:43])=[O:73]
Reactant: CN(C)CC(=O)Nc1ccc(N2C(=O)N(CCCCCCCCCSCCCC(F)(F)C(F)(F)F)C(C)(C)C2=O)cc1C(F)(F)F
Reactant: CC1(C)C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)N1CCCCCCCCCSCCCC(F)(F)C(F)(F)F
Product: CN(C)CC(=O)Nc1ccc(N2C(=O)N(CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F)C(C)(C)C2=O)cc1C(F)(F)F
Yield: 65 %

Procedure:
Compound 43a described below was synthesized according to a method similar to that described in Example 2 using the compound of Example 42 as starting reagent replacing the compound of Example 1. The expected compound is obtained in the form of a pale yellow oil with a yield of 65%.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:7]2=[N:8][CH:9]=[N:10][C:11]([NH2:12])=[C:6]2[CH:5]=[N:4]1.[C:13]1([C:19]2[C:20]3[CH:33]=[CH:32][CH:31]=[CH:30][C:21]=3[S:22][C:23]=2[CH2:24]OS(C)(=O)=O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C>[C:13]1([C:19]2[C:20]3[CH:33]=[CH:32][CH:31]=[CH:30][C:21]=3[S:22][C:23]=2[CH2:24][N:3]2[C:7]3=[N:8][CH:9]=[N:10][C:11]([NH2:12])=[C:6]3[CH:5]=[N:4]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CS(=O)(=O)OCc1sc2ccccc2c1-c1ccccc1
Reactant: Nc1ncnc2[nH]ncc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1cnn2Cc1sc2ccccc2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
NaH (60% in mineral oil, 13 mg, 0.314 mmol) was added in one portion to a mixture of 1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (42 mg, 0.314 mmol) in DMF (5 mL) at RT. After 5 min stirring a solution of methanesulfonic acid 3-phenylbenzo[b]thiophen-2-ylmethyl ester from Example 26 (100 mg, 0.314 mmol) in DMF (1 mL) was added dropwise and stirring at RT was continued for 30 min. The reaction mixture was then quenched by addition of water and diluted with EtOAc. The aqueous phase was further extracted with EtOAc (2×100 mL) and the combined organic layers were washed with brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% MeOH in EtOAc) and triturated from MeOH with water affording 164 as an off-white solid (17 mg, 15%). LCMS: RT 4.13 min [M+H]+ 358.1. 1H NMR (DMSO, 400 MHz): δ 8.23 (1H, s), 8.16 (1H, s), 7.95-7.90 (1H, m), 7.70-7.59 (4H, m), 7.56-7.49 (2H, m), 7.42-7.35 (2H, m), 5.72 (2H, s)
Reaction SMILES: [C:1]([C:4]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH2:10][CH2:11][C:12]([OH:14])=O)[CH2:5][CH2:6][C:7]([OH:9])=O)(=[O:3])[NH2:2]>S(=O)(=O)(O)O>[NH:2]1[C:12](=[O:14])[CH2:11][CH2:10][C:4]2([C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:7](=[O:9])[CH2:6][CH2:5]2)[C:1]1=[O:3]
Reactant: NC(=O)C(CCC(=O)O)(CCC(=O)O)c1ccccc1
Agent: O=S(=O)(O)O
Product: O=C1CCC2(CCC(=O)c3ccccc32)C(=O)N1
Yield: 34.5 %

Procedure:
Five (5) grams (0.0179 M) of γ-carbamoyl-γ-phenylpimelic acid prepared by the method of Koelsch, J. Org. Chem., 25, 164 (1960), in 100 ml of concentrated sulfuric acid were heated on a steam bath for two hours. The cooled reaction mixture was poured with stirring into crushed ice. The separated solid was washed with sodium bicarbonate solution. Recrystallization from 30 ml of acetone solution (treated with activated charcoal) gave 1.5 grams (34.5%) of 2,3-dihydrospiro-[naphthalene-1(4H),3'-piperidine]-2',4,6'-trione.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][O:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]1=2.S(O[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)(=O)(=O)C.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(#N)C>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][CH2:25][N:2]([CH2:3][CH2:4][N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[CH2:9][O:8][C:7]3[CH:16]=[CH:17][CH:18]=[CH:19][C:6]2=3)[CH3:1])=[CH:28][CH:29]=1
Reactant: CNCCN1c2ccccc2COc2ccccc21
Reactant: CS(=O)(=O)OCCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CN(CCc1ccc(Cl)cc1)CCN1c2ccccc2COc2ccccc21
Temperature: 70 °C
Reaction time: 22 h

Procedure:
5,11-Dihydro-5-[2-(N-methylamino)ethyl]dibenzo[b,e][1,4]oxazepine (254 mg, 1.00 mmol), 4-chlorophenethyl mesylate (352 mg, 1.50 mmol), sodium carbonate (160 mg, 1.50 mmol) and sodium iodide (20 mg, 0.13 mmol) were added to acetonitrile (25 ml), and they were heated at 70° C. under stirring for 22 hours and then at 90° C. under reflux for 6 hours. The solvent was evaporated under reduced pressure. The obtained residue was distributed in ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with water and then dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography. The product was eluted with dichloromethane and then with dichloromethane and methanol (100:1). The appropriate fractions were combined, and the solvent was evaporated under reduced pressure to obtain 5-[2-[N-(4-chlorophenethyl)-N-methyl-amino]ethyl]-5,11-dihydrodibenzo[b,e][1,4]oxazepine in the form of a light yellow oil (171 mg, 44%).
Reaction SMILES: C(O[C:4]([C:6]1[NH:10][C:9]2[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)[O:13][C:8]=2[CH:7]=1)=[O:5])C.C(OC(=O)C(CC)CCN1C(=S)N2C3C=C(C4C=CC([N+]([O-])=O)=CC=4)OC=3C=C2C1=O)C.[CH2:55]([O:57][C:58](=[O:67])[CH2:59][C:60]([CH3:66])([CH3:65])[CH2:61][N:62]=[C:63]=[S:64])[CH3:56].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[CH2:55]([O:57][C:58](=[O:67])[CH2:59][C:60]([CH3:66])([CH3:65])[CH2:61][N:62]1[C:63](=[S:64])[N:10]2[C:9]3[CH:11]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=4)[O:13][C:8]=3[CH:7]=[C:6]2[C:4]1=[O:5])[CH3:56]
Reactant: CCOC(=O)c1cc2oc(-c3ccc([N+](=O)[O-])cc3)cc2[nH]1
Reactant: CCOC(=O)CC(C)(C)CN=C=S
Agent: CCOC(=O)C(CC)CCN1C(=O)c2cc3oc(-c4ccc([N+](=O)[O-])cc4)cc3n2C1=S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CC(C)(C)CN1C(=O)c2cc3oc(-c4ccc([N+](=O)[O-])cc4)cc3n2C1=S
Temperature: 140 °C
Reaction time: 16 h
Yield: 99.6 %

Procedure:
2-(4-nitro-phenyl)-4H-furo[3,2-b]pyrrole-5-carboxylic acid ethyl ester (212 mg, 0.71 mmol, 1 molequivalent), prepared as described hereinabove (see, preparation of Compound 1), was placed in a round bottom flask and 4-isothiocyanato-3,3-dimethyl-butyric acid ethyl ester (1.4 grams, 7.1 mmol, 10 molequivalents) was added thereto, followed by addition of grinded anhydrous potassium carbonate (K2CO3; 147 mg, 1.1 mmol, 1.5 molequivalents). The mixture was heated while stirring at 140° C. for 16 hours. The reaction mixture was thereafter dissolved in chloroform and 5% citric acid solution, the organic phase was extracted, and the aqueous layer was washed with chloroform several times. The combined organic layers were dried over Na2SO4, the solvent was removed under reduced pressure, and the crude product was triturated in ethanol to give Compound 7 (322 mg, 40% yield) as an orange solid.