Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([CH:33]=[CH:34][C:35]=4[CH3:36])[C:24]([NH:26][C:27]4([C:30](O)=[O:31])[CH2:29][CH2:28]4)=[O:25])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[NH:37]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[NH2:38].C(N(CC)C(C)C)(C)C.O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([CH:33]=[CH:34][C:35]=4[CH3:36])[C:24]([NH:26][C:27]4([C:30]([NH:38][NH:37][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[O:31])[CH2:28][CH2:29]4)=[O:25])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NN
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(C(=O)O)CC4)ccc3C)cc12
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(C(=O)NNC(=O)OC(C)(C)C)CC4)ccc3C)cc12
Temperature: 25 °C
Reaction time: 19 h

Procedure:
To a mixture of 1-(3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzamido)cyclopropanecarboxylic acid (41.6 mg, 0.086 mmol), tert-butyl hydrazinecarboxylate (16.95 mg, 0.128 mmol) and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (54.9 mg, 0.171 mmol) in DMF (1 mL) at r.t under N2 was added N,N-diisopropylethylamine (0.060 mL, 0.342 mmol). The mixture was stirred at r.t. for 19 hours. The mixture was added 5 ml H2O. The white precipitates were filtered, washed with 3×2 ml H2O and dried (33.1 mg), and was used without further purification. 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; HPLC Rt=1.750 min.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:10][NH2:11].[BH4-].[Na+]>C1COCC1>[CH3:10][NH:11][CH2:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[Br:1]
Reactant: O=Cc1ccccc1Br
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CNCc1ccccc1Br
Reaction time: 8 h
Yield: 58 %

Procedure:
29.4 g of o-Bromobenzaldehyde and 81 ml of aqueous, 40% methylamine solution are combined with 238 ml of THF and at RT 19 g of NaBH4 are added in batches within 25 minutes. The mixture is left to stand overnight at RT, concentrated using a rotary evaporator, and the residue is stirred into ice water. The aqueous phase is extracted twice with ether and the combined ether phases are evaporated down under reduced pressure. After chromatography on silica gel with ethyl acetate or ethyl acetate/methanol (4:1) as eluant, 18.5 g of N-methyl-2-bromobenzylamine (a) are obtained in the form of a yellowish liquid. Yield: 58%.
Reaction SMILES: C([O:4][C:5]1[CH:18]=[C:17]2[C:8]([NH:9][C:10]3[C:15]([S:16]2(=[O:20])=[O:19])=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:7]2[CH:21]=[CH:22][CH:23]=[CH:24][C:6]=12)(=O)C.[OH-].[Na+].C(O)(=O)C.O>CO>[OH:4][C:5]1[CH:18]=[C:17]2[C:8]([NH:9][C:10]3[C:15]([S:16]2(=[O:20])=[O:19])=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:7]2[CH:21]=[CH:22][CH:23]=[CH:24][C:6]=12
Reactant: CC(=O)Oc1cc2c(c3ccccc13)Nc1ccccc1S2(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: O=S1(=O)c2ccccc2Nc2c1cc(O)c1ccccc21
Temperature: 25 °C
Reaction time: 0.12 h
Yield: 98.2 %

Procedure:
To a suspension of 5-acetoxy-12H-benzo[a]phenothiazine-7,7-dioxide (6.6 g) in methanol (200 ml), kept under a nitrogen atmosphere was added 2N aqueous sodium hydroxide solution (132 ml). The mixture was stirred at room temperature for 7 minutes, then there was added 10% acetic acid (200 ml) and water (300 ml). After 10 minutes of stirring the mixture was filtered to afford the title compound (5.68 g) as a pink solid. The solid was recrystallized from THF, m.p. 334° C. (dec).
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[Br:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1.[N:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:22]>ClCCl>[Br:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]([N:21]([OH:22])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:18])=[CH:15][CH:14]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: O=Nc1ccccc1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(c1ccc(Br)cc1)N(O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
DBU (3.8 mg, 0.025 mmol) was added under argon to a solution of 4-bromobenzaldehyde (185 mg, 1 mmol), nitrosobenzene (107 mg, 1 mmol) and catalyst (1.82 mg, 0.005 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 10 min. The solvent was removed under vacuum, and the residue was purified by flash silica gel column chromatography using hexane and ethyl acetate as the eluents.
Reaction SMILES: Cl[NH:2][C:3](=[NH:8])[C:4]([Cl:7])([Cl:6])[Cl:5].[S-:9][C:10]#[N:11].[K+]>CO>[Cl:5][C:4]([Cl:7])([Cl:6])[C:3]1[N:8]=[C:10]([NH2:11])[S:9][N:2]=1
Reactant: N#C[S-]
Reactant: N=C(NCl)C(Cl)(Cl)Cl
Agent: [K+]
Solvent: CO
Product: Nc1nc(C(Cl)(Cl)Cl)ns1
Reaction time: 1 h

Procedure:
11.8 parts (0.06 mol) of N-chloro-trichloroacetamidine are dissolved in 35 parts by volume of 50% strength methanol. A solution of 6.5 parts (0.066 mol) of potassium thiocyanate is added dropwise to the above solution at 0 to 5° C. After standing for one hour at 0° to 5° C, a precipitate forms, which is filtered off after 4 hours and is recrystallised from aqueous alcohol with addition of active charcoal. 8.4 parts of 3-trichloromethyl-5-amino-1,2,4-thiadiazole are isolated. Melting point 192° to 194° C (with decomposition).
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.[C:14](O)(=[O:17])[C:15]#[CH:16].C1C=CC=CC=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[C:14]([O:11][CH2:10][CH2:9][CH2:8][CH2:7][O:6][C:5]1[CH:12]=[CH:13][C:2]([CH3:1])=[CH:3][CH:4]=1)(=[O:17])[C:15]#[CH:16]
Reactant: C#CC(=O)O
Reactant: Cc1ccc(OCCCCO)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: C#CC(=O)OCCCCOc1ccc(C)cc1
Yield: 89.2 %

Procedure:
A mixture of 1 g of 4-(4-methylphenoxy)butanol, 1.1 g of propiolic acid, 0.005 g of p-toluenesulfonic acid and 25 ml of benzene was refluxed with stirring for six hours while water formed was removed by a Dean-Stark water separator. After the reaction was completed, the reaction solution was washed successively with a 5% aqueous sodium bicarbonate solution and a saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. After removal of the solvent under reduced pressure, the obtained residue was subjected to silicagel column chromatography to yield 1.15 g of 4-(4-methylphenoxy)butyl propiolate (compound 11).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[CH3:15][N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([CH2:25]O)[CH:23]=2)[CH:18]=[N:17]1>>[CH3:15][N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([CH2:25][O:1][C:2]3[N:6]([C:7]4[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=4)[N:5]=[CH:4][CH:3]=3)[CH:23]=2)[CH:18]=[N:17]1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: Cn1ncc2ccc(CO)cc21
Product: Cn1ncc2ccc(COc3ccnn3-c3cc(C#N)ccn3)cc21
Yield: 11 %

Procedure:
The title compound was prepared in 11% yield from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (1-methyl-1H-indazol-6-yl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 4.09 (3H, s), 5.40 (2H, s), 5.78 (1H, d, J=1.6 Hz), 7.19-7.17 (1H, m), 7.40 (1H, dd, J=1.2 Hz, J=5.2 Hz), 7.51 (1H, s), 7.58 (1H, d, J=2.0 Hz), 7.75 (1H, s, J=8.4 Hz), 7.99 (1H, d, J=0.4 Hz), 8.07 (1H, s), 8.71 (1H, d, J=8.4 Hz). [M+H] Calc'd for C18H14N6O, 331. Found, 331.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5](Br)[S:4][C:3]=1[C:8]1[S:9][C:10](Br)=[CH:11][C:12]=1[Br:13].O.C(O)(=O)C.Cl>C(O)C.[Zn]>[Br:13][C:12]1[CH:11]=[CH:10][S:9][C:8]=1[C:3]1[S:4][CH:5]=[CH:6][C:2]=1[Br:1]
Reactant: Brc1cc(Br)c(-c2sc(Br)cc2Br)s1
Agent: Cl
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: Brc1ccsc1-c1sccc1Br
Temperature: 25 °C
Yield: 92 %

Procedure:
3,3′,5,5′-Tetrabromo-2,2′-bithiophene, 10 (15 g, 31.1 mmol) was added in portion within 0.5 h to a refluxing dispersion of zinc powder (7.8 g, 0.12 mol) in 150 mL of ethanol containing 15 mL of water, 72 mL of glacial acetic acid, and 3.1 mL of 3 M HCl. After refluxing for an additional 2 h and then cooling to room temperature, the mixture was filtered and washed three times with ethanol, and the filtrate was collected. The solvent was then removed by evaporation, and 60 mL of H2O was added. The mixture was then extracted with dichloromethane (3×100 mL), and the combined extract was washed with water, dried over anhydrous MgSO4, and filtered. The solvent was removed by evaporation, and the crude product was crystallized from hexane to give colorless crystals of product 9.2 g, 92% yield. 1H NMR (400 MHz, CDCl3, δ) 7.43 (d, J=5.4 Hz, 2H), 7.09 (d, J=5.4 Hz, 2H). 13C NMR (100 MHz, CDCl3, δ) 130.8, 128.8, 127.5, 112.6. MS (FAB): m/z 324.0 (M+).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[N:14]([CH3:15])[C:13](=[O:16])[C:12]3[C:7](=[CH:8][C:9]([C:17]#[C:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)=[CH:10][CH:11]=3)[N:6]=2)[CH2:2]1.Br[CH2:26][C:27]#[N:28].C([O-])([O-])=O.[K+].[K+].CC#N>O>[CH3:15][N:14]1[C:13](=[O:16])[C:12]2[C:7](=[CH:8][C:9]([C:17]#[C:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)=[CH:10][CH:11]=2)[N:6]=[C:5]1[CH:3]1[CH2:2][N:1]([CH2:26][C:27]#[N:28])[CH2:4]1
Reactant: N#CCBr
Reactant: Cn1c(C2CNC2)nc2cc(C#Cc3ccccn3)ccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cn1c(C2CN(CC#N)C2)nc2cc(C#Cc3ccccn3)ccc2c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 44.5 %

Procedure:
The mixture of 2-(azetidin-3-yl)-3-methyl-7-(pyridin-2-ylethynyl)quinazolin-4(3H)-one (100 mg, 0.316 mmol), 2-bromoacetonitrile (0.024 mL, 0.348 mmol), K2CO3 (87 mg, 0.632 mmol) and CH3CN (5 mL) was stirred at room temperature for 3 h, then diluted with water (10 mL). The mixture was then extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated to give the crude product, which was purified by column chromatography to give 50 mg of the desired product. MS (ESI): 356 (MH+); 1H NMR (300 MHz, CDCl3) δ 8.68-8.67 (d, J=4.4 Hz, 1H), 8.27-8.24 (d, J=8.2 Hz, 1H), 7.95 (s, 1H), 7.77-7.71 (m, 1H), 7.67-7.64 (dd, J=8.2, 1.5 Hz, 1H), 7.60-7.58 (d, J=7.8 Hz, 1H), 7.33-7.28 (m, 1H), 3.92-3.89 (m, 5H), 3.56 (s, 2H), 3.50 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.S([O-])([O-])=O.[Na+].[Na+].[S-2].[Na+].[Na+]>>[NH2:1][C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: O=C1c2ccccc2C(=O)c2c1cccc2[N+](=O)[O-]
Agent: O=S([O-])[O-]
Agent: [Na+]
Agent: [S-2]
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O
Temperature: 100 °C
Reaction time: 9 h

Procedure:
A mixture of a wet cake of crude 1-nitroanthraquinone (A) (solid content, 28.6 %) (35 parts) and a naphthalenesulfonic acid salt-formalin condensation product (1 part) is finely pulverized by the aid of a wet type pulverizer using stainless steel balls (3 mmφ). The resultant finely pulverized wet cake (36 parts) is charged into a reaction vessel, a 10.8 % aqueous solution of sodium sulfite (28 parts) is added thereto, and the mixture is stirred at 100° C. for 9 hours. After the mixture is cooled to 45° C., sodium sulfide flakes (purity, 60 %) (9.4 parts) are added, and the mixture is treated in the same manner as in Example 7 to obtain 1-aminoanthraquinone with high purity (6.3 parts). The composition is as shown in Table 1.
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.Cl.[NH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([O:22][CH3:23])[CH:16]=1>O1CCCC1>[OH:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][CH2:13][NH:12][CH:1]=[O:2])=[CH:16][C:17]=1[O:22][CH3:23]
Reactant: O=CO
Reactant: COc1cc(CCN)ccc1O
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: COc1cc(CCNC=O)ccc1O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Formic acid (230 g, 5.0 mol) is added dropwise to acetic anhydride (383 g, 3.75 mol) at 0° C. This mixture is stirred for 2 hours at +55° C. and subsequently cooled again to 0° C. Tetrahydrofuran (500 ml) is added at this temperature followed by 4-(2-amino-ethyl)-2-methoxyphenol hydrochloride (50 g, 0.25 mol). The resulting white suspension is stirred for 18 hours at +75° C., changing into a yellow solution. The reaction mixture is evaporated and the residue is submitted to flash-chromatography to yield N-[2-(4-hydroxy-3-methoxy-phenyl)-ethyl]-formamide.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C@@H:18]([NH:23][S:24]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]#[C:36][CH3:37])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:13]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C@@H:18]([NH:23][S:24]([C:27]2[CH:28]=[CH:29][C:30]([O:33][CH2:34][C:35]#[C:36][CH3:37])=[CH:31][CH:32]=2)(=[O:26])=[O:25])[C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:13]=1
Reactant: CC#CCOc1ccc(S(=O)(=O)N[C@@H](C(=O)OC)c2ccc(OCCNC(=O)OC(C)(C)C)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC#CCOc1ccc(S(=O)(=O)N[C@@H](C(=O)OC)c2ccc(OCCN)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 0.300 g (0.564 mmol) of methyl(2R)-(4-{2-[(tert-butoxycarbonyl)amino]ethoxy}phenyl)({[4-(2-butynyloxy)phenyl]sulfonyl}-amino)ethanoate (from Example 199) in 1.5 mL of dichloromethane was added 1.5 mL of trifluoroacetic acid and the resulting mixture was stirred for 2 h at room temperature and then concentrated in vacuo. The residue was diluted with ethyl acetate and the organics were washed with saturated sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated to provide 0.244 g of methyl(2R)-[4-(2-aminoethoxy)phenyl]({[4-(2-butynyloxy)phenyl]sulfonyl}amino)ethanoate pure enough for use in the next step. Electrospray Mass Spec 433.3 (M+H)+.
Reaction SMILES: O.ON1C2C=CC=CC=2N=N1.Cl.CN(CCCN=C=NCC)C.C(N(CC)CC)C.[CH2:31]([N:35]1[C:43]([N:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)=[N:42][C:41]2[C:36]1=[N:37][C:38]([C:56]1[CH:57]=[N:58][C:59]([NH2:62])=[N:60][CH:61]=1)=[N:39][C:40]=2[N:50]1[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1)[CH:32]([CH3:34])[CH3:33].Cl.[CH3:64][N:65]([CH3:70])[CH2:66][C:67](O)=[O:68]>ClCCl.CO.CN(C)C=O>[CH3:64][N:65]([CH2:66][C:67]([N:47]1[CH2:48][CH2:49][N:44]([C:43]2[N:35]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:36]3[C:41]([N:42]=2)=[C:40]([N:50]2[CH2:55][CH2:54][O:53][CH2:52][CH2:51]2)[N:39]=[C:38]([C:56]2[CH:61]=[N:60][C:59]([NH2:62])=[N:58][CH:57]=2)[N:37]=3)[CH2:45][CH2:46]1)=[O:68])[CH3:70]
Reactant: CN(C)CC(=O)O
Reactant: CC(C)Cn1c(N2CCNCC2)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)Cn1c(N2CCN(C(=O)CN(C)C)CC2)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Reaction time: 21 h
Yield: 62 %

Procedure:
1-Hydroxybenzotriazole monohydrate (48.9 mg, 0.32 mmol), 1-(dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (91.8 mg, 0.48 mmol), and triethylamine (164.6 μl, 1.18 mmol) were added to an N,N-dimethylformamide suspension (2.0 ml) of 5-[9-(isobutyl)-6-morpholin-4-yl-8-piperazin-1-yl-9H-purin-2-yl]pyrimidin-2-amine (140.0 mg, 0.32 mmol) and N,N-dimethylglycine hydrochloride (53.5 mg, 0.38 mmol) at room temperature. The resulting mixture was stirred for 21 hour and then the reaction mixture was poured into dichloromethane-methanol (10:1), washed with saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the resulting residue was purified by preparative thin layer silica gel chromatography (dichloromethane:methanol=5:1) to give the title compound (103.9 mg, 62%) as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:17]3[CH:18]=[C:19]([O:24][CH3:25])[C:20]([O:22][CH3:23])=[CH:21][C:16]=3[CH:15]([CH2:26][CH3:27])[C:14]([CH3:28])=[N:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:17]3[CH:18]=[C:19]([O:24][CH3:25])[C:20]([O:22][CH3:23])=[CH:21][C:16]=3[CH:15]([CH2:26][CH3:27])[CH:14]([CH3:28])[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCC1C(C)=NN=C(c2ccc(OC)c(OC)c2)c2cc(OC)c(OC)cc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: CCC1c2cc(OC)c(OC)cc2C(c2ccc(OC)c(OC)c2)=NNC1C
Reaction time: 0.5 h

Procedure:
A 70% benzene solution of 90 ml (0.6 moles) of NaAlH2 (OCH2CH2OCH3)2 is diluted with 90 ml of benzene. The solution thus-obtained is added, within 20 minutes, under stirring, to a solution of 114.6 g (0.3 moles) of 1-(3,4-dimethoxyphenyl)-4-methyl-5-ethyl-7,8-dimethoxy-5H-2,3-benzodiazepine in 1500 ml of benzene. The inner temperature rises to 33° to 35° C. Then the reaction mixture is heated to boiling, within 30 minutes (the gas evolution ceases), recooled to 20° C., and 450 ml of a 20% sodium hydroxide solution (or, in case of compounds containing phenolic hydroxy groups, an aqueous sodium carbonate solution) are dropped to it. A two-phase light yellowish mixture is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:10])=O)=[CH:4][N:3]=1.C(N(CC)CC)C.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][C:21]=1[N:27]1[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]1>S(Cl)(Cl)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[C:21]([N:27]3[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]3)[CH:22]=2)=[O:10])=[CH:4][N:3]=1
Reactant: COc1ccc(N)cc1N1CCN(C)CC1
Reactant: O=C(O)c1ccc(Br)nc1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: COc1ccc(NC(=O)c2ccc(Br)nc2)cc1N1CCN(C)CC1
Reaction time: 18 h

Procedure:
2-Bromo-5-pyridinecarboxylic acid (0.34 g; 1.68 mmol) was heated at reflux in thionyl chloride (8 ml) for 1 hour, cooled, evaporated in vacuo and the residue azeotroped with toluene. The orange residue was redissolved in CH2Cl2 (6 ml) and treated with dry triethylamine (0.24 ml;1.68 mmol) and 4-methoxy-3-(4-methyl-1-piperazinyl)benzenamine (0.372 g;1.68 mmol). The solution was stirred under Ar (18 hours), evaporated in vacuo and partitioned satd. K2CO3 (aq)/EtOAc. The organic phases were combined, dried over Na2SO4, filtered and the filtrate evaporated in vacuo to a brown gum. The gum was purified by flash silica-gel chromatography and eluted with 3%MeOH/CHCl3 to yield the title compound as brown crystals after trituration with acetone/Et2O (0.13 g;19%).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]4[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=4[CH3:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:30][NH2:31]>>[CH3:30][NH:31][CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]3[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:29])[C:15]=2[O:14]1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4c(C)cccc4C)c3O2)cc1
Product: CNCC1Cc2cccc(-c3c(C)cccc3C)c2O1

Procedure:
The title compound was prepared (0.039 g, 63%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.084 g, 0.205 mmol) and methylamine (1.86 g, 60.0 mmol). mp >250° C.
Reaction SMILES: C(C1N=CC2C(C=1)=CC=CC=2)(O)=O.[C:14]([C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[C:20]([N+:27]([O-:29])=[O:28])[CH:21]=[CH:22][CH:23]=2)[N:18]=1)([OH:16])=[O:15]>>[C:14]([C:17]1[N:18]=[CH:19][C:24]2[C:25]([CH:26]=1)=[C:20]([N+:27]([O-:29])=[O:28])[CH:21]=[CH:22][CH:23]=2)([OH:16])=[O:15]
Reactant: O=C(O)c1ccc2cccc([N+](=O)[O-])c2n1
Agent: O=C(O)c1cc2ccccc2cn1
Product: O=C(O)c1cc2c([N+](=O)[O-])cccc2cn1

Procedure:
3-Carboxy-5-nitroisoquinoline was prepared from 3-carboxyisoquinoline using a method similar to that used for the preparation of 2-carboxy-8-nitroquinoline in example 10 (Yield: 93%).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:10]=[C:11]([CH:15]=[C:16]([Cl:18])[N:17]=2)[C:12]([NH2:14])=[O:13])[CH2:5][CH2:4]1.[Cl:19][C:20]1[C:24]([Cl:25])=[C:23]([CH2:26][CH3:27])[NH:22][C:21]=1[C:28](O)=[O:29]>>[Cl:18][C:16]1[CH:15]=[C:11]([CH:10]=[C:9]([N:6]2[CH2:5][CH2:4][CH:3]([NH:2][C:28]([C:21]3[NH:22][C:23]([CH2:26][CH3:27])=[C:24]([Cl:25])[C:20]=3[Cl:19])=[O:29])[CH2:8][CH2:7]2)[N:17]=1)[C:12]([NH2:14])=[O:13]
Reactant: NC(=O)c1cc(Cl)nc(N2CCC(N)CC2)c1
Reactant: CCc1[nH]c(C(=O)O)c(Cl)c1Cl
Agent: Cl
Product: CCc1[nH]c(C(=O)NC2CCN(c3cc(C(N)=O)cc(Cl)n3)CC2)c(Cl)c1Cl

Procedure:
Title compound was synthesized by an analogous method to Example 18 by coupling 2-(4-aminopiperidin-1-yl)-6-chloroisonicotinamide hydrochloride (Intermediate 70) with 3,4-dichloro-5-ethyl-1H-pyrrole-2-carboxylic acid (Intermediate 73).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]2[CH:13]=[C:14]([C:16](OCC)=[O:17])[N:15]=[C:5]2[CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]2[CH:13]=[C:14]([CH2:16][OH:17])[N:15]=[C:5]2[CH:4]=1
Reactant: CCOC(=O)c1cn2c(cc(OC)c3ccccc32)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc2nc(CO)cn2c2ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.2 %

Procedure:
A suspension of 19.71 g (73 mmol) of ethyl 5-methoxyimidazo[1,2-a]quinoline-2-carboxylate in 350 ml of freshly distilled anhydrous tetrahydrofuran was stirred under a nitrogen atmosphere at room temperature and 3.33 g (88 mmol) of lithium aluminum hydride were added thereto in portions over 3 hours. The mixture was stirred for 4 hours and excess hydride was destroyed by dropwise addition of wet tetrahydrofuran followed by water. The mixture was poured into 1.5 liters of water and the mixture was extracted with 500 ml of a chloroform-methanol mixture. The mixture was filtered through a celite pad and the aqueous phase was extracted again with a chloroform-methanol mixture. The combined organic phases were dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure. The residue was triturated with ethyl acetate, filtered, washed with ethyl acetate and dried under reduced pressure over P2O5 to obtain 14.87 g (89% yield) of 5-methoxy-imidazo[1,2-a]quinoline-2-methanol as a white crystalline solid melting at 173°-175° C.
Reaction SMILES: [OH-].[Li+].C([O:11][C@H:12]1[CH2:17][CH2:16][C@H:15]2[C@H:18]3[C@H:30]([CH2:31][CH2:32][C@:13]12[CH3:14])[C@:26]1([CH:27]([F:29])[F:28])[C:21]([CH2:22][C:23]2([O:36][CH2:35][CH2:34][O:33]2)[CH2:24][CH2:25]1)=[CH:20][CH2:19]3)(=O)C1C=CC=CC=1>O1CCCC1.CO>[CH2:35]1[CH2:34][O:33][C:23]2([CH2:24][CH2:25][C@@:26]3([CH:27]([F:29])[F:28])[C:21](=[CH:20][CH2:19][C@@H:18]4[C@@H:30]3[CH2:31][CH2:32][C@@:13]3([CH3:14])[C@H:15]4[CH2:16][CH2:17][C@@H:12]3[OH:11])[CH2:22]2)[O:36]1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4CC5(CC[C@@]43C(F)F)OCCO5)[C@@H]1CC[C@@H]2OC(=O)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@]12CC[C@H]3[C@@H](CC=C4CC5(CC[C@@]43C(F)F)OCCO5)[C@@H]1CC[C@@H]2O
Temperature: 25 °C

Procedure:
A solution of this 3,3-ethylenedioxy ester (4.73 g) in 50 ml of tetrahydrofuran is chilled to 0° C., treated with 10 ml of 1N lithium hydroxide in methanol and allowed to warm to room temperature. The reaction is monitored by thin layer chromatography. When all of the ester has been hydrolyzed, the solution is concentrated and diluted with ether. The mixture is washed three times with water and once with brine, dried over magnesium sulfate, and concentrated. The residue is crystallized from ethyl acetate/hexane to yield 3,3-ethylenedioxy-19,19-difluoroandrost-5-en-17β-ol as white crystals.