Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([N:16]2[CH:20]=[C:19]([C:21]([OH:23])=O)[N:18]=[CH:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:46][CH2:47][C:48]([N:50]1[CH2:55][CH2:54][CH:53]([O:56][C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([C:63]([F:66])([F:65])[F:64])[CH:58]=2)[CH2:52][CH2:51]1)=[O:49]>CN(C=O)C.O>[O:49]=[C:48]([N:50]1[CH2:51][CH2:52][CH:53]([O:56][C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([C:63]([F:66])([F:64])[F:65])[CH:58]=2)[CH2:54][CH2:55]1)[CH2:47][NH:46][C:21]([C:19]1[N:18]=[CH:17][N:16]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:20]=1)=[O:23]
Reactant: NCC(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)CC1
Reactant: O=C(O)c1cn(-c2ccccc2)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NCC(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)CC1)c1cn(-c2ccccc2)cn1
Reaction time: 0.03 h
Yield: 85.3 %

Procedure:
DIPEA (186 mg, 1.4 mmol) was added to a stirred solution of 1-phenyl-1H-imidazole-4-carboxylic acid (60 mg, 0.32 mmol) in DMF (5 mL) followed by HOBt (47 mg, 0.35 mmol) and EDCI (153 mg, 0.8 mmol). After 2 minutes of stirring, 2-amino-1-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethanone hydrochloride (119 mg, 0.35 mmol) (prepared according to Step 1 and 5 of the General Scheme) was added and the resulting mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with cold water, the solid was collected to afford the 129 mg (86% Yield) of 1-phenyl-1H-imidazole-4-carboxylic acid {2-oxo-2-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethyl}-amide. LC/MS [M+H]+: Purity: 473 (M+1), 96.61%. 1H NMR (300 MHz, DMSO-d6): δ 8.4 (s, 1H), 8.32 (s, 1H), 8.08 (t, 1H), 7.8 (d, 2H), 7.6-7.48 (t, 3H), 7.46 (t, 1H), 7.36-7.24 (t, 3H), 4.9 (s, 1H), 4.2 (d, 2H), 4.0 (bs, 1H), 3.8 (bs, 1H), 3.5 (d, 2H), 2.1 (t, 2H), 1.8 (d, 2H).
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[CH2:6]([OH:10])[CH:7]([CH3:9])[CH3:8].CN(C)C1C=CC=CC=1.CCOCC>O>[Br:1][CH2:2][C:3]([O:10][CH2:6][CH:7]([CH3:9])[CH3:8])=[O:4]
Reactant: O=C(Br)CBr
Reactant: CC(C)CO
Solvent: CN(C)c1ccccc1
Solvent: O
Solvent: CCOCC
Product: CC(C)COC(=O)CBr
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Over a period of 6-8 hours there was added dropwise 1 M of bromoacetyl bromide to a stirred solution of 1 M of isobutyl alcohol, 1 M of dimethylaniline and 200 ml of anhydrous ether. The solution was kept just below boiling by adjusting the rate of addition and by occasional cooling in an ice bath. After complete addition, the mixture was stirred overnight at room temperature. Water (100 ml) was added and the mixture stirred until all of the precipitate had dissolved. The layers were separated and the ether layer was washed with 100 ml portions of 10% sulfuric acid until neutralization of the washings resulted in a clear solution. The washed ether solution was dried over anhydrous sodium sulfate and after removal of the drying agent and solvent the residue was distilled in vacuo. The recovered product had a bp / 14 mm = 72° - 76° C, n25 = 1.4468.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH:12]=[CH:11][CH:10]=[C:9]2[CH:13]=[O:14])=[N:4][CH:5]=[CH:6][CH:7]=1.[I:15]N1C(=O)CCC1=O.O>CN(C)C=O>[Cl:1][C:2]1[C:3]([N:8]2[CH:12]=[C:11]([I:15])[CH:10]=[C:9]2[CH:13]=[O:14])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: O=Cc1cccn1-c1ncccc1Cl
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cc(I)cn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 40.1 %

Procedure:
To a solution of 5.0 g of 3-chloro-2-(2-formyl-1H-pyrrol-1-yl)pyridine in 50 ml of N,N-dimethylformamide was added 5.4 g of N-iodosuccinimide. The resulting mixture was stirred at room temperature for 1 day. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate two times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 3.2 g of 1-(3-chloro-2-pyridinyl)-4-iodo-1H-pyrrole-2-carbaldehyde of the formula:
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[C:17]([F:18])=[C:16](F)[C:15]([Cl:20])=[C:14]2[C:9]=1[C:10](=[O:33])[C:11]([C:30]([OH:32])=[O:31])=[CH:12][N:13]2[C:21]1[C:26]([F:27])=[CH:25][C:24]([F:28])=[C:23]([NH2:29])[N:22]=1.C(O)(=O)C.C(O)(=O)C.[CH3:42][NH:43][CH:44]1[CH2:47][NH:46][CH2:45]1.CN1CCCC1>C(OCC)C>[NH2:7][C:8]1[C:17]([F:18])=[C:16]([N:46]2[CH2:47][CH:44]([NH:43][CH3:42])[CH2:45]2)[C:15]([Cl:20])=[C:14]2[C:9]=1[C:10](=[O:33])[C:11]([C:30]([OH:32])=[O:31])=[CH:12][N:13]2[C:21]1[C:26]([F:27])=[CH:25][C:24]([F:28])=[C:23]([NH2:29])[N:22]=1
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3c(N)c(F)c(F)c(Cl)c32)c(F)cc1F
Reactant: CNC1CNC1
Agent: CN1CCCC1
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: CNC1CN(c2c(F)c(N)c3c(=O)c(C(=O)O)cn(-c4nc(N)c(F)cc4F)c3c2Cl)C1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 51.5 %

Procedure:
To 300 mg of pyridine were added 120 mg of 5-amino-1-(6-amino-3,5-difluoropyridine-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 80 mg of 3-methylaminoazetidine diacetate, and 250 mg of N-methylpyrrolidine, and the mixture was stirred at 100° C. for 10 minutes. After adding 5 ml of diethylether, the mixture was stirred and allowed to cool for 1 hour, and decanted. 2 ml of ethanol was added and the mixture was stirred. The precipitate was collected by filtration and washed with ethanol and diethylether successively to obtain 72 mg of the title compound as a yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]([CH2:18][C:19]#N)[CH2:15][CH2:16][CH2:17][C:12]=3[N:11]=[C:10]2[CH:21]([CH3:23])[CH3:22])=[CH:4][CH:3]=1.[OH-:24].[K+].C[OH:27]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]([CH2:18][C:19]([OH:27])=[O:24])[CH2:15][CH2:16][CH2:17][C:12]=3[N:11]=[C:10]2[CH:21]([CH3:23])[CH3:22])=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: CC(C)c1nc2c(n1Cc1ccc(Cl)cc1)C(CC#N)CCC2
Reactant: CO
Agent: [K+]
Product: CC(C)c1nc2c(n1Cc1ccc(Cl)cc1)C(CC(=O)O)CCC2
Temperature: 160 °C
Reaction time: 1 h

Procedure:
A solution of Intermediate 42 (45 mg) in methanol (0.4 ml) was treated with 4.5M potassium hydroxide (0.2 ml). The reaction vessel was sealed and heated in CEM Discover using initial 50 W to 150° C. for 30 mins. The mixture was reheated in the microwave at 150° C. for 1 h. A further aliquot of 4.5M potassium hydroxide (0.05 ml) was added and the mixture was heated in the microwave at 160° C. for 30 mins. A further aliquot of 4.5M potassium hydroxide (0.05 ml) was added and the mixture was heated in the microwave at 160° C. for 1 h. The mixture was filtered through a frit and the filtrate diluted with DMSO to 1 ml. The sample was purified by MDAP (Method A). The solvent was dried under a stream of nitrogen in the Radleys blowdown apparatus to give the product (39.2 mg)
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](I)=[N:7][N:8]2[C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][C:3]=1[N+:31]([O-:33])=[O:32].[CH:34]([C:36]1[CH:44]=[CH:43][C:39]2[O:40][CH2:41][O:42][C:38]=2[CH:37]=1)=[CH2:35].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:40]1[C:39]2[CH:43]=[CH:44][C:36](/[CH:34]=[CH:35]/[C:6]3[C:5]4[C:9](=[CH:10][C:2]([F:1])=[C:3]([N+:31]([O-:33])=[O:32])[CH:4]=4)[N:8]([C:11]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:7]=3)=[CH:37][C:38]=2[O:42][CH2:41]1
Reactant: O=[N+]([O-])c1cc2c(I)nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2cc1F
Reactant: C=Cc1ccc2c(c1)OCO2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=[N+]([O-])c1cc2c(/C=C/c3ccc4c(c3)OCO4)nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2cc1F
Temperature: 100 °C
Reaction time: 5 h
Yield: 13.8 %

Procedure:
Under nitrogen atmosphere, 1 g of 6-fluoro-3-iodo-5-nitro-1-trityl-1H-indazole was dissolved in 10 mL of acetonitrile, added successively with 1.35 g of 5-vinyl-benzo[1,3]dioxole, 81.7 mg of palladium acetate (II), 162 mg of 2-(di-tert-butylphosphino)biphenyl and 2 mL of triethylamine, and stirred at 100° C. for 5 hours. After cooling to room temperature, 5 g of silica gel was added, and the solvent was evaporated, and purified by silica gel column chromatography, to obtain 468 mg of the crude product as yellow crystal. This crude product was washed with 50% diethylether solution in hexane, and the solvent was evaporated, to afford 143 mg of the title compound as yellow crystals.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9](Br)[CH:8]=[CH:7][C:6]=1[O:12][CH3:13])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.C([O:22][B:23](OC(C)C)[O:24]C(C)C)(C)C.Cl>C1COCC1.CCOCC>[C:1]([C:5]1[CH:10]=[C:9]([B:23]([OH:24])[OH:22])[CH:8]=[CH:7][C:6]=1[O:12][CH3:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(Br)cc1C(C)(C)C
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(B(O)O)cc1C(C)(C)C
Temperature: -75 °C
Reaction time: 0.5 h
Yield: 64.2 %

Procedure:
To a mixture of 2-(t-butyl)-4-bromoanisole (23.07 g, 0.0949 mol) in THF (238 mL) cooled to −75° C. under an atmosphere of argon was added n-BuLi (65.3 mL, 1.6 M, 0.1044 mol) dropwise maintaining a temperature below −70° C. The resulting suspension was stirred for 30 minutes and triisopropylborate (34.2 mL, 27.87 g, 0.148 mol) was added dropwise. The mixture was allowed to warm to RT overnight. The resulting mixture was cooled to 0° C. and 1.0 N HCl (150 mL) was slowly added. After warming to RT the mixture was diluted with ether and the layers separated, the aqueous layer was extracted ether (3×) and the organic layers combined. The resulting organic layer was washed with water, brine and dried (Mg2SO4). The mixture was filtered, evaporated and the resulting yellowish residue solidified overnight. The solid was collected and washed with hexane and dried under high vacuum to afford 12.68 g of 3-(t-butyl)-4-methoxyphenyl boronic acid (64%). 1H NMR (300 MHz; DMSO-d6): δ 1.33 (s, 9H), 3.81 (s, 3H), 6.91 (d, J=7.8 Hz, 1H), 7.62–7.79 (m, 2H), 7.78 (brs, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:18]([CH2:19][C:20]([OH:22])=O)[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:12]3[N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:35]([NH:38][CH2:39][CH2:40][CH3:41])[CH2:36][CH3:37]>O1CCCC1>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:18]([CH2:19][C:20]([N:38]([CH2:39][CH2:40][CH3:41])[CH2:35][CH2:36][CH3:37])=[O:22])[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:12]3[N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCCNCCC
Reactant: O=C(O)Cn1c(-c2ccc([N+](=O)[O-])cc2)nc2cccnc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCCN(CCC)C(=O)Cn1c(-c2ccc([N+](=O)[O-])cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.9 %

Procedure:
A suspension of crude 2-(4-nitrophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (3.0 g, 0.0101 mole), 1,1'-carbonyldiimidazole (1.63 g, 0.0101 mole) and dry tetrahydrofuran (100 ml) was stirred at room temperature for three hours with nitrogen bubbling through it and then refluxed under nitrogen overnight. The mixture was cooled to room temperature and a solution of dipropylamine (3.06 g, 0.0302 mole) in tetrahydrofuran (5 ml) was added. The suspension was refluxed over the weekend under nitrogen. The solvents were removed under reduced pressure and the solid residue was triturated in water (100 ml) overnight. The solid was collected by filtration, rinsed twice with water, twice with 5% potassium hydroxide solution and then twice more with water. The solid was dissolved in hot isopropyl alcohol, filtered while hot, and cooled to room temperature to precipitate a solid. Water was added and the solid was collected by filtration, rinsed with water and dried under high vacuum at 70° C. to give 1.23 g (32%) of title compound, mp. 205°-208° C.
Reaction SMILES: [OH:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:21]([C@@H:23]1[O:25][CH2:24]1)Cl>CC(O)C>[O:25]1[CH2:24][C@H:23]1[CH2:21][O:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: ClC[C@H]1CO1
Reactant: Oc1cccc2[nH]c3ccccc3c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: c1ccc2c(c1)[nH]c1cccc(OC[C@@H]3CO3)c12
Temperature: 85 °C
Yield: 52.7 %

Procedure:
To a solution of 4-Hydroxycarbazole (10.98 g, 0.06 mole) dissolved in IPA (60 mL) was added K2CO3 (20.73 g, 0.15 mole), followed by (R)-(−)-epichlorohydrin (7 ml, 0.09 mole) and the reaction mixture was slowly heated to 80-90° C. and then refluxed for 5 hours. Subsequently the reaction mixture was cooled to room temperature, worked up and purified following the procedure similar to one described in step I for the synthesis of example 23, to afford the desired compound as a light brown colored solid (7.56 g, 53%).
Reaction SMILES: C([NH:4][C:5]1[C:17]([F:18])=[C:16]2[C:8]([C:9]3[C:14]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:15]2)[CH2:13][CH2:12][C:11](=[O:23])[C:10]=3[C:24]([F:27])([F:26])[F:25])=[CH:7][C:6]=1[F:28])(=O)C.C(O)(=O)C.Cl.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[NH2:4][C:5]1[C:17]([F:18])=[C:16]2[C:8]([C:9]3[C:14]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:15]2)[CH2:13][CH2:12][C:11](=[O:23])[C:10]=3[C:24]([F:27])([F:25])[F:26])=[CH:7][C:6]=1[F:28]
Reactant: CCCCC12CCC(=O)C(C(F)(F)F)=C1c1cc(F)c(NC(C)=O)c(F)c1C2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCCCC12CCC(=O)C(C(F)(F)F)=C1c1cc(F)c(N)c(F)c1C2
Temperature: 100 °C
Yield: 22.8 %

Procedure:
The crude 7-(acetylamino)-9a-butyl-6,8-difluoro-4-(trifluoromethyl)-1,2,9,9a-tetrahydro-3H-fluoren-3-one from step 2 (about 0.318 mmol) was treated with acetic acid (2 mL) and 6N HCl (2 mL). The resulting solution was stirred and heated in an oil bath at 100° C. for 2 hours. After cooling to room temperature, the mixture was poured into a slurry of solid Na2CO3 in CH2Cl2, dried over MgSO4, then filtered through a pad of silica gel and the product washed off with EtOAc. The filtrate and washings were concentrated under vacuum. The crude product was purified by preparative layer chromatography on a 0.05×20×20 cm silica gel GF plate, developing with 25% EtOAc in hexanes, to afford 7-amino-9a-butyl-6,8-difluoro-4-(trifluoromethyl)-1,2,9,9a-tetrahydro-3H-fluoren-3-one (0.026 g, 23%) as a yellow solid.
Reaction SMILES: [N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=[CH:3][CH:2]=1.[Br:11]NC(=O)CCC(N)=O.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:11][CH:9]1[CH2:8][CH2:7][CH2:6][C:5]2[N:4]=[CH:3][CH:2]=[N:1][C:10]1=2
Reactant: c1cnc2c(n1)CCCC2
Reactant: NC(=O)CCC(=O)NBr
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: BrC1CCCc2nccnc21
Yield: 61.8 %

Procedure:
To a solution of commercially available 5,6,7,8-tetrahydroquinoxaline (3.08 g, 23.0 mmol) in CCl4 (200 mL) was added N-bromosuccinamide (4.09 g, 23.0 mmol) and a catalytic amount (56 mg) of benzoyl peroxide. The reaction mixture was heated at reflux for 17 hours. Saturated sodium bicarbonate solution was added (100 mL), the layers were separated and the aqueous phase was extracted with CH2Cl2 (2×200 mL). The organic extracts were dried and concentrated. The crude material contained 1:3:1 ratio (GC) of starting material, mono- and dibromo products which were separated by column chromatography on silica gel using a mixture of 1:1 EtOAc:hexanes to give 5-bromo-5,6,7,8-tetrahydroquinoxaline (3.03 g, 54%) as a brown liquid: 1H NMR (CDCl3): δ 1.99-2.03 (m, 1H), 2.20-2.49 (m, 3H), 2.97-3.10 (m, 1H), 3.11-3.20 (m, 1H), 5.48 (t, 1H, J=1.5 Hz), 8.40 (s, 2H). It should be noted that this material is unstable when exposed to air over 2-3 days and was used immediately in the next reaction.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:9]4[C:14]=2[C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:11](=[O:22])[C:10]=4[CH:23]=[CH:24][CH:25]=3)[CH:5]=[CH:4][CH:3]=1.ClCCl.Cl[C:30]([O:32][CH3:33])=[O:31].C(N(CC)CC)C>C(Cl)Cl.CO>[CH3:21][N:19]([CH3:20])[CH2:18][CH2:17][N:12]1[C:11](=[O:22])[C:10]2[CH:23]=[CH:24][CH:25]=[C:8]3[C:9]=2[C:14](=[C:15]2[C:2]([NH:1][C:30](=[O:31])[O:32][CH3:33])=[CH:3][CH:4]=[CH:5][C:6]2=[CH:7]3)[C:13]1=[O:16]
Reactant: COC(=O)Cl
Reactant: CN(C)CCN1C(=O)c2cccc3cc4cccc(N)c4c(c23)C1=O
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: COC(=O)Nc1cccc2cc3cccc4c3c(c12)C(=O)N(CCN(C)C)C4=O
Temperature: 20 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
A solution of 100 mg (0.30 mmole) of 11-amino-2-[2-(dimethylamino)ethyl]-1H-dibenzo[de,h]isoquinoline-1,3(2H)-dione (obtained in example 3), 7 mL of dichloromethane, 23 μL of methyl chloroformate and 41 μL of triethylamine were added. The mixture was magnetically stirred at 20° C. during 4 hours. The solvent was then evaporated under reduced pressure and the residue was submitted to a flash chromatography on silica (eluent: CH2Cl2/methanol in a 97:3 volume ratio) to provide 102 mg (yield: 87%) of the desired product (formula below) as an orange powder
Reaction SMILES: [NH2:1][C:2]1[C:18]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=[CH:15][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)=[O:5].[CH3:27]OC(OC)N(C)C.CN(C=O)C.C(=O)([O-])O.[Na+]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C>[CH3:26][O:25][C:17]1[C:18]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:2]2[C:3]([C:4](=[O:5])[N:6]([CH2:7][CH2:8][C:9]3[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=3)[CH:27]=[N:1]2)=[CH:15][CH:16]=1
Reactant: COC(OC)N(C)C
Reactant: CCCCCOc1c(OC)ccc(C(=O)NCCc2ccncc2)c1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCOc1c(OC)ccc2c(=O)n(CCc3ccncc3)cnc12
Temperature: 130 °C
Reaction time: 5 h
Yield: 55.4 %

Procedure:
2-Amino-4-methoxy-3-pentyloxy-N-(2-pyridin-4-ylethyl)benzamide (100 mg, 0.280 mmol) obtained in Example 2-61, dimethyl formamide dimethyl acetal (0.19 ml, 1.4 mmol) and DMF (0.5 ml) were mixed, and p-toluene sulfonate monohydrate (2 mg, 0.011 mmol) was added to this solution. The mixture was stirred at 130° C. for 5 hours, and ethyl acetate (15 ml) and saturated aqueous sodium hydrogencarbonate solution (15 ml) were added to separate the organic layer. The organic layer was washed with saturated bnne (15 ml), and dried over anhydrous magnesium sulfate. The drying agent was filtered off and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (chloroform/methanol=25/1) to give 7-methoxy-8-pentyloxy-3-(2-pyridin-4-ylethyl)-3H-quinazolin-4-one (57 mg, 55%) as a pale-yellow oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([S:11]([N:14]3[CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH2:15]3)(=[O:13])=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:23][NH:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][CH:26]=1.[ClH:33].C(=O)([O-])[O-].[NH4+:38].[NH4+]>C(O)C>[ClH:33].[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([S:11]([N:14]3[CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH2:15]3)(=[O:12])=[O:13])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:23][NH:24][C:25]1[CH:26]=[CH:27][C:28]([C:31](=[NH:38])[NH2:32])=[CH:29][CH:30]=1
Reactant: [NH4+]
Reactant: Cn1c(CNc2ccc(C#N)cc2)nc2cc(S(=O)(=O)N3Cc4ccccc4C3)ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: Cn1c(CNc2ccc(C(=N)N)cc2)nc2cc(S(=O)(=O)N3Cc4ccccc4C3)ccc21
Yield: 33 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-5-(isoindolin-2-yl-sulphonyl)-benzimidazole and ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 33% of theory, Rf value: 0.32 (silica gel; dichloromethane/methanol=4:1) C24H24N6O2S (460.6) EKA mass spectrum: (M+H)+ =461
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6](=[O:15])[NH:7][C:8]3[CH:14]=[CH:13][CH:12]=[N:11][C:9]=3[NH:10][C:4]=2[CH:3]=1.N1C=CC=CC=1.[C:24](Cl)([Cl:26])=[O:25]>O1CCOCC1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6](=[O:15])[NH:7][C:8]3[CH:14]=[CH:13][CH:12]=[N:11][C:9]=3[N:10]([C:24]([Cl:26])=[O:25])[C:4]=2[CH:3]=1
Reactant: O=C(Cl)Cl
Reactant: O=C1Nc2cccnc2Nc2cc(Cl)ccc21
Solvent: c1ccncc1
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: O=C1Nc2cccnc2N(C(=O)Cl)c2cc(Cl)ccc21
Temperature: 45 °C
Reaction time: 2 h

Procedure:
11.6 g (0.0472 mol) of 9-chloro-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one, suspended in a mixture of 450 ml of anhydrous dioxane and 6.4 ml (0.08 mol) of pyridine, were combined at 45° C., within 20 minutes, with 47.1 ml (0.094 mol) of a 20% solution of phosgene in toluene. The reaction mixture was stirred for 2 hours at 45° C. and then for 4 hours at 60° C. The mixture was filtered while hot, the filtrate was evaporated down in vacuo, the crystallising residue remaining was resuspended in 100 ml of dioxane, refluxed for 2 hours, evaporated down once more, mixed with copious amounts of water and suction filtered. After drying in a circulating air dryer the product had an m.p. of 265°-267° C., RF 0.70 (Macherey-Nagel, PolygramRSIL G/UV254, pre-coated plastic sheets for TLC, eluant: dichloromethane/ethyl acetate 1/1 v/v).
Reaction SMILES: Br.[O:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](SCC1C=CC=CC=1)=[NH:8].[CH3:17][N:18]([CH3:32])[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][S:24][C:23]2[CH:27]=[C:28]([NH2:31])[CH:29]=[CH:30][C:22]1=2>CCO>[CH3:17][N:18]([CH3:32])[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][S:24][C:23]2[CH:27]=[C:28]([NH:31][C:7]([C:3]3[O:2][CH:6]=[CH:5][CH:4]=3)=[NH:8])[CH:29]=[CH:30][C:22]1=2
Reactant: N=C(SCc1ccccc1)c1ccco1
Reactant: CN(C)CCN1CCSc2cc(N)ccc21
Agent: Br
Solvent: CCO
Product: CN(C)CCN1CCSc2cc(NC(=N)c3ccco3)ccc21
Reaction time: 48 h
Yield: 89.3 %

Procedure:
Benzyl furan-2-carbimidothioate hydrobromide (1.139 g, 3.82 mmol) was added to a mixture of 4-(2-(dimethylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-amine (0.829 g, 3.49 mmol) in EtOH (20 mL). The mixture was stirred for 2 days under argon atmosphere. The solution was quenched with saturated sodium bicarbonate (50 mL). The solution was transferred to a separatory funnel, diluted with water (50 mL), and extracted with CH2Cl2 (50 mL). The aqueous phase was washed with CH2Cl2 (50 mL). The combined organic fractions were washed with brine (50 mL) and dried (Na2SO4). The crude material was subjected to flash chromatography on silica gel (2.5-5% (2M NH3 in MeOH):CH2Cl2). The collected fractions gave compound 19 as a brown oil (1.03 g, 90%). 1H NMR (CDCl3) δ 7.46 (s, 1H), 7.03 (brs, 1H), 6.73-6.68 (m, 3H), 6.50 (brs, 1H), 5.03 (brs, 2H), 3.62-3.59 (m, 2H), 3.40 (t, J=7.2 Hz, 2H), 3.05-3.02 (m, 2H), 2.52 (t, J=7.5 Hz, 2H), 2.29 (s, 6H); ESI-MS (m/z, %): 333, 331 (MH+, 91), 260, 262 (100).