Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[C:2]([O:9][CH2:10][CH3:11])(=[O:8])[C:3]([O:5]CC)=O.[C:12]([C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([Cl:24])[CH:22]=2)[NH:17][CH:16]=1)(=[O:14])[CH3:13]>CCO>[CH2:10]([O:9][C:2](=[O:8])[C:3]([OH:5])=[CH:13][C:12]([C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([Cl:24])[CH:22]=2)[NH:17][CH:16]=1)=[O:14])[CH3:11]
Reactant: CC(=O)c1c[nH]c2ccc(Cl)cc12
Reactant: CCOC(=O)C(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(O)=CC(=O)c1c[nH]c2ccc(Cl)cc12
Reaction time: 3 h
Yield: 80.7 %

Procedure:
In 100 ml of EtOH was dissolved 2.99 g (126 mmol) of sodium under heating. The EtOH was evaporated under reduced pressure and the residue was suspended in THF (200 ml). The THF was evaporated. To the suspension of the residue in THF (124 ml) was added 18.1 g (124 mmol) of diethyl oxalate. Subsequently, to the above suspension was added at room temperature, 12 g (62 mmol) of 3-acetyl-5-chloroindole. After stirring for 3 hours, the mixture was stirred at 50° C. for additional 16 hours. The solvent was removed under reduced pressure. The resulting residue was washed with ether, and added to 1N hydrochloric acid (120 ml). The precipitated crystal was collected by filtration, and washed with water and ethyl acetate. Then the crystal was purified by recrystallization from dioxane and dried at 80° C. under reduced pressure to give 14.7 g of the titled compound. Yield: 81%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.CS(O[CH:14]1[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]1)(=O)=O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:18]2[CH2:19][CH2:14][CH2:15][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17]2)=[CH:4][CH:3]=1
Reactant: Sc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC(OS(C)(=O)=O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC(Sc2ccc(Br)cc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 18.2 %

Procedure:
A mixture of 4-bromobenzenethiol (4.697 g, 24.84 mmol), tert-butyl 3-methylsulfonyloxypiperidine-1-carboxylate (6.939 g, 24.84 mmol) and K2CO3 (6.866 g, 49.68 mmol) in DMF (40 mL) were stirred at ambient temperature for 16 hours. The reaction mixture was cooled to 0° C. and diluted with water. The reaction mixture was extracted with ethylacetate (×2) and the combined organic extracts washed with saturated aqueous sodium thiosulphate solution (×2), water (×2), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion, 330 g eluting with 0 to 50% Et2O/Petroleum Ether, loaded in DCM) to give tert-butyl 3-((4-bromophenyl)thio)piperidine-1-carboxylate as a colourless oil (1.68 g, 18% Yield). H NMR (400.0 MHz, CDCl3) δ 0.97-0.86 (m, 2H), 1.44 (s, 9H), 1.80-1.76 (m, 1H), 2.12-2.08 (m, 1H), 2.92-2.86 (m, 1H), 3.14-3.08 (m, 2H), 3.89 (br d, 1H), 4.05 (br s, 1H), 7.30 (d, 2H) and 7.45-7.43 (m, 2H) ppm;
Reaction SMILES: Cl[C:2]1[C:7](Cl)=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:15][CH2:14][CH2:13][N:12]([CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]2[CH:30]=[C:29]3[C:24]([CH:25]=[CH:26][C:27](=[O:31])[NH:28]3)=[CH:23][CH:22]=2)[CH2:11][CH2:10]1.[Na+].[I-].Cl.[CH2:35]([O:37]C1C=CC=CC=1N1CCCNCC1)[CH3:36].C([O-])([O-])=O.[K+].[K+]>CC#N.O>[CH2:35]([O:37][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:15][CH2:14][CH2:13][N:12]([CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]2[CH:30]=[C:29]3[C:24]([CH2:25][CH2:26][C:27](=[O:31])[NH:28]3)=[CH:23][CH:22]=2)[CH2:11][CH2:10]1)[CH3:36]
Reactant: CCOc1ccccc1N1CCCNCC1
Reactant: O=c1ccc2ccc(OCCCCN3CCCN(c4cccc(Cl)c4Cl)CC3)cc2[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Solvent: O
Product: CCOc1ccccc1N1CCCN(CCCCOc2ccc3c(c2)NC(=O)CC3)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.4 %

Procedure:
A mixture of intermediate 4 (150 mg, 0.5 mmol) and NaI (150 mg, 1.0 mmol) in CH3CN was heated to reflux for 30 min and then cooled to rt. Intermediate 31 (129 mg, 0.5 mmol) and anhydrous K2CO3 (276 mg, 2.0 mmol) were then added to the mixture. The resulting mixture was heated to reflux and stirred overnight. The reaction solution was diluted with water and extracted with EtOAc. The combined EtOAc layers were washed with brine, dried over anhydrous Na2SO4, concentrated in vacuo and purified by flash chromatography on silica gel column (elution with DCM/MeOH=50:1) to give 7-(4-(4-(2-ethoxyphenyl)-1,4-diazepan-1-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one (compound 12) (95 mg, 44%). 1H NMR (300 MHz, CDCl3) δ 7.75 (bs, 1H), 7.04 (d, J=8.1 Hz, 1H), 6.92-6.83 (m, 4H), 6.52 (dd, J=8.4 Hz, 2.1 Hz, 1H), 6.30 (d, J=2.7 Hz, 1H), 4.04 (q, J=6.9 Hz, 2H), 3.96-3.94 (m, 2H), 3.38-3.29 (m, 4H), 3.02-2.93 (m, 4H), 2.89 (t, J=6.9 Hz, 2H), 2.74-2.70 (m, 2H), 2.61 (t, J=8.1 Hz, 2H), 2.14-2.10 (m, 2H), 1.83-1.79 (m, 4H), 1.45 (t, J=6.9 Hz, 3H). HPLC: 99%, RT 2.438 min. MS (ESI) m/z 438.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][NH2:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Cl[C:14]1[N:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][N:15]=1.CCN(C(C)C)C(C)C>C(O)CCC>[Br:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][NH:12][C:14]2[N:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: CCc1cnc(Cl)nc1
Reactant: COc1ccc(CCN)cc1Br
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cnc(NCCc2ccc(OC)c(Br)c2)nc1
Yield: 67.5 %

Procedure:
A mixture of 2-(3-bromo-4-methoxyphenyl)ethanamine (1 g; 4.35 mmol), 2-chloro-5-ethyl-pyrimidine (0.56 g; 3.92 mmol) and DIEA (0.84 g; 6.53 mmol) in n-butanol was heated to reflux for 14 hr. Upon cooling, the reaction mixture was concentrated and partitioned between 1N HCl and ether. The aqueous phase was basified with 6N NaOH and extracted with ether. The combined organic phases were washed with a saturated solution of NaHCO3, dried over MgSO4, filtered and concentrated to provide a colorless solid, which was triturated with hexane, filtered and dried to provide the title compound as a white crystalline solid (0.89 g; 67% yield).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6]=1[CH2:21]Br)=[O:4].[N:23]1([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C(N(C(C)C)C(C)C)C>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6]=1[CH2:21][N:32]1[CH2:33][CH2:34][CH:29]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:30][CH2:31]1)=[O:4]
Reactant: COC(=O)c1c(CBr)c(-c2ccccc2)nc2ccccc12
Reactant: C1CCN(C2CCNCC2)CC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1c(CN2CCC(N3CCCCC3)CC2)c(-c2ccccc2)nc2ccccc12
Temperature: 50 °C
Yield: 56.4 %

Procedure:
5 g (14 mmol) of 3-bromomethyl-2-phenyl-quinoline-4-carboxylic acid methyl ester (compound of Description 2), 2.9 g, (15.4 mmol) of 90% [1,4′]Bipiperidinyl (Aldrich), 2.7 ml (15.4 mmol) of ethyl-diisopropyl-amine were dissolved in 100 ml of dry THF and the mixture was stirred for one night at 50° C. The solvent was concentrated, the residue was dissolved in CH2Cl2, washed with water, and the organic phase was dried over MgSO4. After concentration of the solvent, the residue was purified by flash chromatography over 160 g of silicagel (eluting with CH2Cl2/MeOH/NH4OH:95/5/0.5) affording 3.5 g (yield 56%) of the title compound as a white solid.
Reaction SMILES: S(Cl)(Cl)(=O)=O.[F:6][C:7]1[C:15]2C=C[S:12][C:11]=2[C:10]([C:16]#[N:17])=[CH:9][CH:8]=1.[Cl:18][CH2:19][CH2:20][Cl:21]>>[Cl:18][CH:19]1[S:12][C:11]2[C:10]([C:16]#[N:17])=[CH:9][CH:8]=[C:7]([F:6])[C:15]=2[CH:20]1[Cl:21]
Reactant: ClCCCl
Reactant: N#Cc1ccc(F)c2ccsc12
Solvent: O=S(=O)(Cl)Cl
Product: N#Cc1ccc(F)c2c1SC(Cl)C2Cl
Temperature: 60 °C

Procedure:
Sulfuryl chloride (3.0 mL, 37.0 mmol) was added to a solution of 4-fluorobenzo[b]thiophene-7-carbonitrile (1.05 g, 5.93 mmol) in 1,2-dichloroethane (30 mL) at room temperature. The mixture was heated at 60° C. for 24 h and then the solvent was removed and the residue mixed with saturated aq. NaHCO3 solution and extracted with 10% EtOAc in hexanes. These extracts were then washed with saturated aq. NaHCO3 solution, water, brine and dried over Na2SO4. Concentration gave the crude 2,3-dichloro-4-fluoro-2,3-dihydrobenzo[b]thiophene-7-carbonitrile as a brown solid (1.57 g). 1H NMR (400 MHz, CDCl3, δ in ppm) 7.68 (dd, J=4.7, 8.6 Hz, 1H), 7.03 (t, J=8.2 Hz, 1H), 5.82 (s, 1H), 5.74 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([O-:3])=[O:2].[I:13]I.[OH-].[K+].OS([O-])=O.[Na+]>CN(C=O)C>[I:13][C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[NH:9][N:8]=1
Reactant: II
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2[nH]nc(I)c2c1
Reaction time: 96 h
Yield: 98 %

Procedure:
A solution of 5-nitroindazole (8.50 g, 52.13 mmol) in DMF was treated with iodine (26.46 g, 104.27 mmol) and potassium hydroxide pellets (11.70 g, 208.54 mmol) at room temperature, stirred for 4 days, poured into NaHSO3 solution (11.06 g in 200 mL water) and filtered. The filtercake was washed with water and dried in vacuo to provide the title compound as a yellow solid, 14.74 g (98% yield), characterized by NMR and mass spectral analyses.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[C:12]([O:19][CH3:20])[CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[CH:7]=2)=[C:12]([O:19][CH3:20])[CH:11]=1
Reactant: Nc1cc(Cl)ccn1
Reactant: COc1cc(F)ccc1B(O)O
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc(F)ccc1-c1ccnc(N)c1
Temperature: 25 °C
Yield: 235.6 %

Procedure:
2-Amino-4-chloro-pyridine (5.00 g, 38.9 mmol) and 4-fluoro-2-methoxyphenylboronic acid (9.26 g, 54.4 mmol) were taken in 1,2-dimethoxy ethane (100 ml). An aqueous solution of sodium carbonate (80 ml, 2 M) was added and argon gas was purged for 30 min. Bis-(triphenyl phosphine) palladium (II) chloride (Pd(PPh3)2Cl2) (272 mg, 0.39 mmol) was added to the reaction mixture and again purged with argon gas for 20 min. The reaction mixture was slowly heated to 85° C.-90° C. with stirring and maintained for 8 h. On completion of reaction, the reaction mixture was cooled to room temperature and the insoluble solid residue filtered. The filtrate was concentrated until 1,2-dimethoxy ethane was fully evaporated. Excess iced-water was added to precipitate the product which was filtered, washed with copious amount of water, and dried under vacuo at 60° C. Again this solid crude product was washed with ethyl acetate in petroleum ether (10%) and dried to afford 20 g (88%) of compound I.
Reaction SMILES: [CH3:1][N:2](C=O)C.[Br:6][C:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=3)=[CH:13][CH:14]=2)[N:9]([C:25]2[CH:30]=[C:29](Cl)[N:28]=[CH:27][N:26]=2)[CH:8]=1.Cl.CN.C(=O)([O-])[O-].[K+].[K+]>O>[Br:6][C:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=3)=[CH:13][CH:14]=2)[N:9]([C:25]2[N:26]=[CH:27][N:28]=[C:29]([NH:2][CH3:1])[CH:30]=2)[CH:8]=1
Reactant: O=[N+]([O-])c1cccc(-c2ccc3c(Br)cn(-c4cc(Cl)ncn4)c3c2)c1
Reactant: CN(C)C=O
Agent: CN
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Product: CNc1cc(-n2cc(Br)c3ccc(-c4cccc([N+](=O)[O-])c4)cc32)ncn1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
DMF (10 mL) was added to a mixture of 3-bromo-1-(6-chloropyrimidin-4-yl)-6-(3-nitrophenyl)-1H-indole (500 mg, 1.16 mmol), methylamine hydrochloride (393 mg, 5.82 mmol) and potassium carbonate (1.60 g, 11.6 mmol). After stirring at 80° C. for 3 hours and then cooling to room temperature, the reaction solution was added to icy water. After stirring at room temperature for 15 hours, thus produced solid was filtered, washed with water and then dried. The target compound (500 mg) was obtained as yellow solid.
Reaction SMILES: [OH-].[K+].C[O:4][C:5](=[O:21])[C:6](O)([CH3:19])[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[CH2:12][CH:11]([CH:16]([CH3:18])[CH3:17])[CH2:10]2>O.CO>[CH:16]([CH:11]1[CH2:10][C:9]2[C:13](=[CH:14][CH:15]=[C:7]([CH:6]([CH3:19])[C:5]([OH:21])=[O:4])[CH:8]=2)[CH2:12]1)([CH3:18])[CH3:17]
Reactant: COC(=O)C(C)(O)c1ccc2c(c1)CC(C(C)C)C2
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C(=O)O)c1ccc2c(c1)CC(C(C)C)C2

Procedure:
A solution of 26.6 g of potassium hydroxide in 50 cc of water is added to a solution of 41.5 g of crude α-hydroxy-2-isopropyl-α-methyl-5-indanacetic acid methyl ester in 500 cc of methanol, and the mixture is boiled at reflux for 11/2 hours. The solution is concentrated, diluted with water and extracted with ether in order to remove the neutral components. The aqueous phase is then acidified with hydrochloric acid, extracted with ether, the ether extract is washed with water, dried over sodium sulphate and concentrated by evaporation. The resulting α-hydroxy-2-isopropyl-α-methyl-5-indanacetic acid is recrystallized from ether/hexane and has a M.P. of 126°-130°.
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[CH2:46]([N:54]1[CH:58]=[C:57]([C:59]2[C:67]3[C:62](=[N:63][CH:64]=[C:65]([C:68]4[CH:69]=[CH:70][C:71]([N:74]5[CH2:79][CH2:78][N:77]([CH2:80][C@@H:81]([OH:83])[CH3:82])[CH2:76][CH2:75]5)=[N:72][CH:73]=4)[CH:66]=3)[N:61](S(C3C=CC(C)=CC=3)(=O)=O)[CH:60]=2)[CH:56]=[N:55]1)[CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.[OH-].[Li+]>C1COCC1.CO.O>[CH2:46]([N:54]1[CH:58]=[C:57]([C:59]2[C:67]3[C:62](=[N:63][CH:64]=[C:65]([C:68]4[CH:69]=[CH:70][C:71]([N:74]5[CH2:79][CH2:78][N:77]([CH2:80][C@@H:81]([OH:83])[CH3:82])[CH2:76][CH2:75]5)=[N:72][CH:73]=4)[CH:66]=3)[NH:61][CH:60]=2)[CH:56]=[N:55]1)[CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(CCc4ccccc4)c3)c3cc(-c4ccc(N5CCN(C[C@H](C)O)CC5)nc4)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](O)CN1CCN(c2ccc(-c3cnc4[nH]cc(-c5cnn(CCc6ccccc6)c5)c4c3)cn2)CC1
Yield: 82.1 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, (S)-1-(4-(5-(3-(1-phenethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)piperazin-1-yl)propan-2-ol (80 mg, 0.12 mmol) was hydrolyzed with lithium hydroxide (25 mg, 0.6 mmol) in THF/methanol/water (2/2/1 mL) to yield 50 mg (83.3% yield) of desired product. 1H NMR (CD3OD, 300 MHz): δ 8.53-8.52 (d, 2H), 8.36-8.35 (d, 1H), 8.12-8.08 (dd, 1H), 7.896-7.893 (d, 1H), 7.818-7.816 (d, 1H), 7.67 (s, 1H), 7.26-7.20 (m, 3H), 7.17-7.12 (m, 3H), 4.47-4.43 (d, 2H), 4.30-4.20 (t, 1H), 3.60-3.40 (bs, 4H), 3.25-3.10 (m, 4H), 1.27-1.25 (d, 3H). MS: m/z=408.6 (M+1), HPLC: 93.50% in method A.
Reaction SMILES: [C:1]1(=O)[C:14]2[C:5](=[N:6][CH:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)[CH:4]=[CH:3][CH2:2]1.[C:16]1(N)[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH2:22].OP(O)(O)=O>O>[CH:4]1[C:5]2[N:6]3[C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[N:22]=[C:7]3[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]=2[CH:1]=[CH:2][CH:3]=1
Reactant: Nc1ccccc1N
Reactant: O=C1CC=Cc2ncc3ccccc3c21
Agent: O=P(O)(O)O
Solvent: O
Product: c1ccc2c(c1)nc1c3ccccc3c3ccccc3n21
Temperature: 300 °C
Reaction time: 8 h
Yield: 57.4 %

Procedure:
97.6 g (0.5 mol) of phenanthridone, 60 g (0.55 mol) of o-phenylenediamine and 15 g of 85% strength H3PO4 (remainder water) are mixed and fused under nitrogen. The elimination of H2O starts from 200° C. The temperature is gradually raised to 300° C over the course of 6 hours, whilst stirring, and is additionally kept at 300° to 330° C for 8 hours. In the course of this time, about 12 g of H2O have distilled over. A fractional distillation in an oil pump vacuum is then carried out and 77 g (57.5% of theory) of benzimidazo-[1,2-f]-phenanthridine of boiling point 227° C/0.4 mm Hg and melting point 153° C are obtained as almost colourless crystals (after recrystallisation from 5 parts of ethanol). ##STR31##
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[N:8][N:9]([OH:11])[CH:10]=1)=[O:5])C.CCO.O>>[OH:11][N:9]1[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=[N:8]1
Reactant: CCOC(=O)c1cn(O)nn1
Solvent: CCO
Solvent: O
Product: O=C(O)c1cn(O)nn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1-Hydroxy-1H-1,2,3-triazole-4-carboxylic acid was prepared by combining 1-hydroxy-1H-[1,2,3]triazole-4-carboxylic acid ethyl ester (2.0 g, 13 mmol), EtOH (25 mL, 430 mmol), and a pre-dissolved solution of LiOH monohydrate (1.6 g, 38.2 mmol) and water (10 mL, 600 mmol). The mixture was stirred at room temperature for 4 hours, then partially concentrated and acidified with HCl to cause precipitation. The solid was filtered and dried under vacuum to give 1.3 g of the desired acid.
Reaction SMILES: C([BH3-])#N.[Na+].[N:5](=[C:7]([C:9]([CH3:20])([CH3:19])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[CH3:8])[OH:6].[ClH:21].CC1C(Br)=C(O)C(Br)=CC=1C1(C2C=C(Br)C(O)=C(Br)C=2C)OS(=O)(=O)C2C=CC=CC1=2>CO>[ClH:21].[F:18][C:15]1[CH:14]=[CH:13][C:12]([O:11][CH2:10][C:9]([CH3:19])([CH3:20])[CH:7]([NH:5][OH:6])[CH3:8])=[CH:17][CH:16]=1
Reactant: CC(=NO)C(C)(C)COc1ccc(F)cc1
Agent: Cc1c(C2(c3cc(Br)c(O)c(Br)c3C)OS(=O)(=O)c3ccccc32)cc(Br)c(O)c1Br
Agent: Cl
Agent: [BH3-]C#N
Solvent: CO
Product: CC(NO)C(C)(C)COc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.1 %

Procedure:
19.6 g (0.29 mol) of sodium cyanoborohydride (95%) are added in portions to a solution of 66.8 g (0.29 mol) of 2-hydroximino-3,3-dimethyl-4-(4-fluorophenoxy)-butane in 500 ml of methanol, which is kept at pH 3 with concentrated hydrochloric acid against bromocresol green. When the addition has ended, the pH value is kept at 3 with hydrochloric acid for a further 3 hours and the mixture is then subsequently stirred at room temperature for 16 hours. The reaction mixture is acidified to pH 1 and concentrated in vacuo. The residue is taken up in chloroform/water, the organic phase is separated off and dried over sodium sulphate and the solvent is distilled off in vacuo. 52.3 g (67.1% of theory) of 4-(4-fluorophenoxy)-3,3-dimethyl-2-butyl-hydroxylamine hydrochloride of melting point 99° C. are obtained. ##STR95##
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[CH:21]1([C:27]([Cl:29])=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>C(Cl)Cl>[ClH:29].[CH:21]1([C:27]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: NCCCSc1ccncc1
Reactant: O=C(Cl)C1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCCSc1ccncc1)C1CCCCC1
Yield: 68.1 %

Procedure:
To a solution of 1.00 g (4.15 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 2.77 ml (19.8 mmol) of triethylamine in 40 ml of methylene chloride was added 0.66 ml (4.96 mmol) of cyclohexanoyl chloride under ice-cooling with stirring and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and water and dried. The solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain 890 mg of the desired compound (free base) (77.0% colorless prisms), mp: 93.0°-94.0° C.
Reaction SMILES: [NH:1]([S:8]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:23][CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)=[C:13]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH:12]=1)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCOCC.[ClH:41]>CO>[ClH:41].[N:17]1([C:14]2[CH:15]=[CH:16][C:11]([S:8]([NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)(=[O:10])=[O:9])=[CH:12][C:13]=2[NH:31][S:32]([CH3:35])(=[O:33])=[O:34])[CH2:23][CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(S(=O)(=O)Nc3ccccc3)cc2NS(C)(=O)=O)CC1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: CS(=O)(=O)Nc1cc(S(=O)(=O)Nc2ccccc2)ccc1N1CCCNCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 48 %

Procedure:
A mixture of tert-butyl 4-[2-amino-4-(anilinosulfonyl)phenyl]-1,4-diazepane-1-carboxylate (176 mg, 0.39 mmol), methylsulfonyl chloride (0.040 mL, 0.47 mmol) and pyridine (0.285 mL, 3.51 mmol) in CH2CL2 (5 mL) was stirred at room temperature overnight. The reaction mixture was quenched with NaHCO3 aq (3×30 mL). The organic phase was separated, dried (MgSO4) and filtered. The volatiles were evaporated followed by purification of the oily residue by chromatography (SiO2, hexane/EtOAc 4:1) to give 110 mg of tert-butyl 4-{4-(anilinosulfonyl)-2-[(methylsulfonyl)amino]phenyl}-1,4-diazepane-1-carboxylate (yield 58%). 1H NMR (CDCl3) δ 7.90-7.85 (m, 1H), 7.50-7.43 (m, 1H), 7.30-7.24 (m, 2H), 7.20-7.08 (m, 4H), 6.84-6.79 (m, 1H), 3.65-3.51 (m, 4H), 3.12-3.06 (m, 1H), 3.04-2.96 (m, 6H), 2.04-1.91 (m, 2H), 1.49 (s, 3H); MS (posEI-DIP) m/z=524 (M+H+). tert-Butyl 4-{4-(anilinosulfonyl)-2-[(methylsulfonyl)amino]phenyl}-1,4-diazepane-1-carboxylate (0.077 g, 0.147 mmol) was dissolved in MeOH, and ether saturated with HCl gas was added. The mixture was stirred at room temperature for 4 h and then concentrated. The crude solid was dissolved in a small amount of MeOH, and ether was added. The precipitate was collected and dried to give 30 mg of the pure product as the HCl salt (yield 48%): 1H NMR (DMSO-d6) δ 7.72-7.70 (m, 1H), 7.46-7.42 (m, 1H), 7.25-7.20 (m, 3H), 7.14-7.09 (m, 2H), 7.03-6.99 (m, 1H), 3.45-3.15 (m, partly obscured by solvent signal, HDO, 6H), 2.96 (s, 3H), 2.02-1.95 (m, 2H); MS (posES-FIA) m/z=425 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:14]([O-:16])=[O:15])=[C:5]([CH:8]=[C:9]([O:12][CH3:13])[C:10]=1[OH:11])[CH:6]=O.C([O-])(=O)C.[NH4+].[N+:22]([CH3:25])([O-:24])=[O:23]>C(OC(=O)C)(=O)C>[CH3:1][O:2][C:3]1[C:4]([N+:14]([O-:16])=[O:15])=[C:5]([CH:8]=[C:9]([O:12][CH3:13])[C:10]=1[OH:11])[CH:6]=[CH:25][N+:22]([O-:24])=[O:23]
Reactant: C[N+](=O)[O-]
Reactant: COc1cc(C=O)c([N+](=O)[O-])c(OC)c1O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)OC(C)=O
Product: COc1cc(C=C[N+](=O)[O-])c([N+](=O)[O-])c(OC)c1O
Yield: 58.5 %

Procedure:
A suspension of 20 g (0.088 mole) of 3,5-dimethoxy-4-hydroxy-2-nitrobenzaldehyde and 21 g (0.27 mole) of dry ammonium acetate in 400 cm3 of acetic anhydride and 15.8 g (0.26 mole) of nitromethane is heated under reflux for 2 hours. The reaction mixture is cooled, then the precipitate is filtered off. After washing with water, recrystallization from an ethanol-water mixture and drying under vacuum, 13.9 g of the desired product is obtained in the form of orangeish-yellow crystals (yield =58% ).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH:5]=[C:6]1[CH2:9][CH2:8][CH2:7]1)[CH3:2].[N+:11]([CH3:14])([O-:13])=[O:12].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:10])[CH2:5][C:6]1([CH2:14][N+:11]([O-:13])=[O:12])[CH2:9][CH2:8][CH2:7]1)[CH3:2]
Reactant: C[N+](=O)[O-]
Reactant: CCOC(=O)C=C1CCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1(C[N+](=O)[O-])CCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.1 %

Procedure:
The unsaturated ester (2) (5.79 g, 41.4 mmol) was dissolved in tetrahydrofuran (20 mL) and stirred at 70° C. with nitromethane (4.67 mL, 86.4 mmol) and tetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 55 mL, 55.0 mmol). After 18 hours, the mixture was cooled to room temperature, diluted with ethyl acetate (150 mL), and washed with 2N HCl (60 mL) followed by brine (100 mL). The organic phase was collected, dried (MgSO4), and the solvent removed in vacuo. The residue was purified by flash chromatography (silica, ethyl acetate:heptane 1:1) to give 4.34 g (52%) of a clear oil.