Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N:2]1([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[N:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Br[CH:28]([OH:30])[CH3:29].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[OH:30][CH2:28][CH2:29][N:5]1[CH2:6][CH2:7][N:2]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][CH:18]=3)[N:9]=2)[CH2:3][CH2:4]1
Reactant: CC(O)Br
Reactant: FC(F)(F)c1ccc(-n2nc(N3CCNCC3)c3ccccc32)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: OCCN1CCN(c2nn(-c3ccc(C(F)(F)F)cc3)c3ccccc23)CC1
Yield: 44.6 %

Procedure:
A stirred mixture of 5.5 g of 3-(1-piperazinyl)-1-[4(trifluoromethyl)phenyl]-1H-indazole hydrochloride, 2.3 g of bromoethanol, 2.5 g of potassium carbonate and 60 ml of dimethylformamide was heated, under nitrogen, at 70°-75° for 16 hours. The reaction mixture was poured into water and the aqueous mixture extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated to an oil. The oil was chromatographed on silica gel utilizing a Water's Model 500 High Pressure Liquid Chromatograph and eluting with dichloromethane/methanol (6%). Evaporation of the appropriate fractions gave an oil which solidified upon standing. Recrystallization of the solid from hexane (2×) gave 2.5 g (40%) of 3-[4-(2-hydroxyethyl)-1piperazinyl-]-1-[4-(trifluoromethyl)phenyl]-1H-indazole, mp 82°-84°.
Reaction SMILES: [S:1]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])(=[O:3])[NH2:2].S(=O)(=O)(O)O.[CH3:19]O>>[S:1]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([O:10][CH3:19])=[O:9])(=[O:3])(=[O:4])[NH2:2]
Reactant: CO
Reactant: NS(=O)(=O)c1cccc(C(=O)O)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(S(N)(=O)=O)c1
Yield: 70.2 %

Procedure:
3-sulfamoylbenzoic acid (150 mg, 0.746 mmol) was refluxed in the presence of concentrated Sulfuric acid (4.82 mg, 0.037 mmol) in methanol (5 mL) at 70° C. for overnight. Reaction was monitored by TLC. After completion of the reaction, Solvent was removed by vacuum and then compound was purified by flash chromatography afforded the methyl 3-sulfamoylbenzoate (115 mg, 0.524 mmol, 70.2% yield) as a solid. 1H NMR (CDCl3, 400 MHz): δ 8.53 (m, 1H), 8.18 (d, 1H, J=8.0 Hz), 8.08 (d, 1H, J=7.6 Hz), 7.57 (t, 1H, J=8.0 Hz), 3.92 (s, 3H). Mass [M+H]+:216.0
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:29])[N:4]([CH2:19][C:20]2[CH:25]=[N:24][C:23]([CH2:26][NH:27][CH3:28])=[CH:22][N:21]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].C([O:33][C:34]([CH3:39])([CH3:38])[C:35](Cl)=[O:36])(=O)C.C(N(CC)CC)C>CN(C=O)C>[Br:1][C:2]1[C:3](=[O:29])[N:4]([CH2:19][C:20]2[N:21]=[CH:22][C:23]([CH2:26][N:27]([CH3:28])[C:35](=[O:36])[C:34]([OH:33])([CH3:38])[CH3:39])=[N:24][CH:25]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: CC(=O)OC(C)(C)C(=O)Cl
Reactant: CNCc1cnc(Cn2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)cn1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1Cc1cnc(CN(C)C(=O)C(C)(C)O)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.2 %

Procedure:
To a cold (5° C.) solution of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-({5-[(methylamino)methyl]pyrazin-2-yl}methyl)pyridin-2(1H)-one (0.24 g, 0.52 mmol) in DMF (2.0 ml), was added 2-acetoxyisobutyryl chloride (0.093 g, 0.56 mmol), followed by the addition of triethylamine (0.072 g, 0.71 mmol). The mixture was stirred at room temperature for an additional 2 h and concentrated in vacuo. The residue was partitioned between water (5.0 mL) and EtOAc (15.0 mL). The EtOAc extract was washed with water, dried (Na2SO4), and concentrated to dryness. The resulting material (0.2 g) was stirred with 1M. LiOH (0.5 mL, MeOH,/Water 1:1 v/v) at room temperature for 3 h, cooled, acidified with trifluoroacetic acid and the product was purified by reverse-phase HPLC using 10-90% CH3CN/Water gradient (60 min) at a flow rate of 70 mL/min. The appropriate fractions (m/z=551 M+H) were combined and freeze dried to give a white powder. This was partitioned between 5% NaHCO3 (10 mL) and EtoAc (15 mL). The organic layer was washed with water, dried (Na2SO4), and concentrated to dryness to afford the title compound (0.075 g) as a white powder: 1H NMR (CD3OD/400 MHz) δ 8.59 (s, 1H), 8.41 (br, 1H), 7.60 (m, 2H), 7.01 (m, 2H), 6.52 (s, 1H), 5.45 (s, 2 h), 5.29 (s, 2H),
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH3:12][O:13][C:14]1[CH:23]=[CH:22][C:17](/[CH:18]=[CH:19]/[CH:20]=[O:21])=[CH:16][CH:15]=1.[N:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:25]>ClCCl>[OH:25][N:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20](=[O:21])/[CH:19]=[CH:18]/[C:17]1[CH:22]=[CH:23][C:14]([O:13][CH3:12])=[CH:15][CH:16]=1
Reactant: COc1ccc(/C=C/C=O)cc1
Reactant: O=Nc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: COc1ccc(/C=C/C(=O)N(O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
DBU (7.5 mg, 0.05 mmol) was added under argon to a solution of (E)-4-methoxycinnamaldehyde (162 mg, 1 mmol), nitrosobenzene (107 mg, 1 mmol) and catalyst (18.2 mg, 0.05 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: N1C=CC=CC=1.Cl.CN(C)CCCN=C=NCC.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[OH:26].[N:27]1([C:33]2[N:34]=[C:35]([CH2:40][C:41]([O-])=[O:42])[NH:36][C:37](=[O:39])[CH:38]=2)[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.[Na+]>CN(C)C=O>[OH:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[NH:19][C:41](=[O:42])[CH2:40][C:35]1[NH:36][C:37](=[O:39])[CH:38]=[C:33]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[N:34]=1
Reactant: Nc1ccccc1O
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1ccccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.5 %

Procedure:
4 ml of pyridine, 550 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride and 700 mg of 2-aminophenol are added to a solution of 500 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate in 4 ml of dimethylformamide. The reaction mixture is stirred at ambient temperature overnight, and is then concentrated under reduced pressure. Water and ethyl acetate are added and the resulting mixture is thus stirred for 30 minutes. The precipitate formed is filtered off, and rinsed with water, ethyl ether and petroleum ether. The solid obtained is dried under vacuum. 370 mg of N-(2-hydroxyphenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are thus obtained in the form of a beige solid, the characteristics of which are the following:
Reaction SMILES: [C:1]1([CH3:22])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[NH:9][C:10](=O)[C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[OH:20])=O.B.[CH2:24]1COCC1.[ClH:29]>CO>[Cl-:29].[C:1]1([CH3:22])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[N+:9]1[CH2:10][CH2:11][N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[OH:20])[CH:24]=1
Reactant: Cc1cc(C)c(NC(=O)C(=O)Nc2ccccc2O)c(C)c1
Reactant: C1CCOC1
Reactant: Cl
Agent: B
Solvent: CO
Product: Cc1cc(C)c([N+]2=CN(c3ccccc3O)CC2)c(C)c1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 55 %

Procedure:
N-(Mesityl)-N′-(2-hydroxyphenyl)-oxalamide (1.47 g, 4.9 mmol, 1 eq), prepared according to the synthesis method described in Example 3, was weighed into an oven-dried round-bottom flask. To this was added BH3-THF (1M in THF) (39 ml, 39.2 mmol, 8 eq). A great deal of bubbling resulted, as the solution turned bright orange. The solution was allowed to reflux overnight. The next day, the solution was observed to have turned clear. The solution was then allowed to cool to room temperature. Methanol was then very slowly added to the solution until all bubbling ceased. Concentrated HCl solution (1.5 ml) was then added, and the solvent was removed under reduced pressure. The resulting solid was dissolved in methanol, and then the solvent was again removed under reduced pressure. This process was repeated twice more. In this way, the remaining boron was removed as B(OMe)3. Triethylorthoformate (15 ml) was then added to the resulting solid, forming a suspension. The suspension was then heated to 100° C. As the suspension was heated, the solid was observed to slowly go into solution. After aproximately one minute at high temperature, a white solid precipitated. It was allowed to stir for five more minutes, and was then filtered. The resulting solid was washed with ether, to provide the desired product as a white powder (0.854 g, 2.7 mmol, 55% yield). 1H NMR (300 MHz, CDCl3) δ 11.43 (s, 1H), 8.84 (s, 1H), 7.54 (dd, J=8.25, 1.2 Hz, 1H), 7.05 (dd, J=8.0, 1.2 Hz, 1H), 6.92 (m, 2H), 6.73 (dt, J=7.7, 0.9 Hz 1H), 4.80 (t, J=11.4 Hz, 2H), 4.37 (t, J=11.7 Hz, 2H), 2.33 (s, 3H), 2.29 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 157.4, 150.0, 141.0, 135.3, 130.7, 130.3, 128.8, 122.8, 120.4, 119.9, 118.8, 51.0, 50.4, 21.3, 18.2. Anal. Calcd for C18H21ClN2O: C, 68.24; H, 6.68; N, 8.84. Found: C, 67.86; H, 6.92; N, 8.52.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][N:6]=1>CO>[CH3:1][O:2][C:5]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][N:6]=1
Reactant: C[O-]
Reactant: COC(=O)c1cnc(Cl)c([N+](=O)[O-])c1
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cnc(OC)c([N+](=O)[O-])c1
Reaction time: 8 h

Procedure:
Sodium methoxide in methanol (82.65 mL of a 1 M solution) is added slowly to a stirred solution of methyl 6-chloro-5-nitronicotinate (17 g) in anhydrous methanol (250 mL) and the mixture stirred for 8 hours. The mixture is concentrated, the residue treated with water and then extracted into ethyl acetate. The extracts are washed with water, treated with decolourising charcoal and dried (MgSO4). Concentration afforded methyl 6-methoxy-5-nitronicotinate (9.8 g) as an orange solid. Recrystallisation from cyclohexane afforded white needles, m.p. 118-9° C.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][N:2]1[C:10]([NH:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=1)=[O:11].CO.[OH-].[Li+]>O1CCCC1>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][N:2]1[C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([OH:19])=[O:18])=[CH:21][CH:22]=1)=[O:11]
Reactant: COC(=O)c1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Temperature: 25 °C

Procedure:
Methyl 4-(isoindoline-2-carboxamido)benzoate (1.65 g, 5.57 mmol) was dissolved in tetrahydrofuran (30 ml) and methanol (15.00 ml) followed by the addition of lithium hydroxide (11.14 ml, 22.27 mmol) and the mixture was allowed to stir at ambient temperature over the weekend. The organic solvent was removed under vacuum, the aqueous layer was adjusted to pH ˜3 with 2N aqueous HCl, and the resulting solid was filtered with water washes to provide the title compound after drying.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.C(O[Na])(C)=O.O.O.O.CC(O)=O>CO.O>[NH2:8][C:7]1[CH:6]=[CH:5][C:4]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:3][C:2]=1[Br:1]
Reactant: COC(=O)Cc1ccc([N+](=O)[O-])c(Br)c1
Agent: CC(=O)O[Na]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: COC(=O)Cc1ccc(N)c(Br)c1
Temperature: 90 °C
Yield: 68.6 %

Procedure:
A mixture of methyl 3-bromo-4-nitrophenylacetate (14.8 g, 53.8 mmol), reduced iron powder (9.62 g, 172 mmol), AcONa.3H2O (7.32 g, 53.8 mmol) and AcOH (20.0 ml) in MeOH/H2O (150/600 ml) was heated at 90° C. for 1 h. After cooled to room temperature, the reaction mixture was filtered through Celite and the filtered cake was washed with MeOH. The combined filtrate were evaporated and extracted with EtOAc. The extracts were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was chromatographed on silica gel [400 g, CHCl3/EtOAc (20/1)] to give methyl 4-amino-3-bromophenylacetate (9.01 g, 69%) as a brown oil. 1H-NMR (CDCl3) δ3.48 (s, 2H), 3.68 (s, 3H), 4.05 (br, 2H), 6.69 (d, J=8.3 Hz, 1H), 7.00 (dd, J=8.1, 2.0 Hz, 1H), 7.32 (d, J=2.0 Hz, 1H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(NC(C)C)(C)C.[CH:15]#[C:16][CH:17]([OH:20])[CH2:18][CH3:19]>CN(C)C=O.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:2]1([C:15]#[C:16][CH:17]([OH:20])[CH2:18][CH3:19])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Ic1ccccc1
Reactant: C#CC(O)CC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: CCC(O)C#Cc1ccccc1
Temperature: 85 °C
Yield: 114.6 %

Procedure:
To a degassed solution of iodobenzene (0.110 mL, 0.980 mmol), bis(triphenylphosphine)palladium(II) chloride (41.3 mg, 0.059 mmol), copper(I) iodide (9.34 mg, 0.049 mmol), and diisopropylamine (0.559 mL, 3.92 mmol) in N,N-dimethylformamide (6 mL) was added pent-1-yn-3-ol (124 mg, 1.47 mmol). The reaction mixture was heated to 85° C. for 6 h. The reaction mixture was diluted with ethyl acetate (50 mL), washed with a 10% aqueous solution of lithium chloride (10 mL), washed with a 2M aqueous ammonium hydroxide (10 mL), washed with brine (10 mL), and dried over anhydrous sodium sulfate. Concentration followed by purification by silica gel chromatography with hexanes/ethyl acetate (3/1) afforded 1-Phenylpent-1-yn-3-ol (180 mg). The compound had an HPLC ret. time=2.74 min.−Column. YMC S5 COMBISCREEN® 4.6×50 mm; Gradient time: 4 min; Flow rate=4 ml/min; Solvent A=10% MeOH−90% Water−0.2% H3PO4; Solvent B=90% MeOH−10% water−0.2% H3PO4; Start % B=0; Final % B=100.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][S:5][C:6]=1[CH:7]=O.[C:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])#[N:10].N1CCCC1.S(C1C=CC(C)=CC=1)(O)(=O)=O.[Cl-].[Na+]>C1(C)C=CC=CC=1>[C:9]([C:11](=[CH:7][C:6]1[S:5][N:4]=[N:3][C:2]=1[CH3:1])[C:12]([O:14][CH2:15][CH3:16])=[O:13])#[N:10]
Reactant: CCOC(=O)CC#N
Reactant: Cc1nnsc1C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCNC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C#N)=Cc1snnc1C
Reaction time: 2 h
Yield: 27.2 %

Procedure:
To 50 ml of toluene were added 1.5 g (12 mmol) of 4-methyl-1,2,3-thiadiazole-5-carbaldehyde, 1.5 g (13 mmol) of ethyl cyanoacetate, 0.40 g (6.0 mmol) of pyrrolidine and 0.20 g (1.2 mmol) of tosylic acid. In a reactor equipped with a Dean-Stark dehydrating apparatus, the mixture obtained above was stirred for 2 hours with heating under reflux. After the reaction was completed, a saturated aqueous solution of sodium chloride was added to the reaction mixture, the objective product was extracted with ethyl acetate, the organic layer was washed successively with dilute hydrochloric acid, saturated aqueous solution of sodium hydrogen carbonate and saturated aqueous solution of sodium chloride, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography using 3:1 mixture of n-hexane and ethyl acetate. Thus, 0.73 g of the objective compound was obtained.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.[C:27]1([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH:32]=[CH:31][C:30]([CH2:33][O:34][C:35]2[CH:36]=[C:37]3[C:42](=[CH:43][CH:44]=2)[CH2:41][CH:40]([CH2:45][CH2:46]O)[CH2:39][CH2:38]3)=[CH:29][CH:28]=1>C1COCC1.O>[C:27]1([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH:32]=[CH:31][C:30]([CH2:33][O:34][C:35]2[CH:36]=[C:37]3[C:42](=[CH:43][CH:44]=2)[CH2:41][CH:40]([CH2:45][CH2:46][I:25])[CH2:39][CH2:38]3)=[CH:29][CH:28]=1
Reactant: OCCC1CCc2cc(OCc3ccc(-c4ccccc4)cc3)ccc2C1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: ICCC1CCc2cc(OCc3ccc(-c4ccccc4)cc3)ccc2C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 76.8 %

Procedure:
To a solution of triphenylphosphine (12.5 g) in THF (200 ml) were successively added imidazole (3.25 g) and iodine (12.1 g). A solution of 6-(4-biphenylyl) methoxy-2-(2-hydroxyethyl)tetralin (13.15 g) in THF (100 ml) was added to the reaction mixture at room temperature. The reaction mixture was stirred at room temperature for 5 min, diluted with water, and extracted with ethyl acetate. The organic layer was washed with aqueous sodium thiosulfate and saturated aqueous sodium chloride, dried, and concentrated. The residue was purified by silica gel column chromatography (eluent; toluene) to obtain the titled compound (13.2 g).
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][N:5]=[C:4]2[N:9]([S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH:10]=[CH:11][C:3]=12.CS[C:23]1[CH2:24][CH2:25][CH2:26][N:27]=1>CC(O)C>[NH3:5].[N:27]1[CH2:26][CH2:25][CH2:24][C:23]=1[NH:8][C:7]1[C:2]([CH3:1])=[C:3]2[CH:11]=[CH:10][N:9]([S:12]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)(=[O:14])=[O:13])[C:4]2=[N:5][CH:6]=1
Reactant: CSC1=NCCC1
Reactant: Cc1c(N)cnc2c1ccn2S(=O)(=O)c1ccccc1
Solvent: CC(C)O
Product: Cc1c(NC2=NCCC2)cnc2c1ccn2S(=O)(=O)c1ccccc1
Product: N
Temperature: 25 °C
Yield: 37.6 %
Yield: 4 %

Procedure:
A solution of 4-methyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-amine, (775 mg, 2.7 mmol) and 5-(methylthio)-3,4-dihydro-2H-pyrrole (345 mg) in i-PrOH (14 mL) was heated at 105° C. for 3 days. The refluxed mixture was then cooled to room temperature and concentrated. Flash column chromatography (4-6% 7N NH3 in MeOH/DCM) yielded N-(3,4-dihydro-2H-pyrrol-5-yl)-4-methyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-amine, (180 mg) 1H NMR (300 MHZ, CD3OD) δ: 8.10 (d, J=7.6 Hz, 2H), 7.89 (s, 1H), 7.75 (d, J=4.1 Hz, 1H), 7.63 (s, 1H), 7.54 (d, J=8.2 Hz, 2H), 6.77 (d, J=4.1 Hz, 1H), 2.63 (s, 2H), 2.09 (t, J=7.5 Hz, 3H).
Reaction SMILES: [C:1]12([C:11](O)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Br.[C:15]([O:19][C:20](=[O:30])[CH2:21][N:22]1[C:26]([CH3:27])=[C:25]([CH3:28])[S:24][C:23]1=[NH:29])([CH3:18])([CH3:17])[CH3:16]>>[C:15]([O:19][C:20](=[O:30])[CH2:21][N:22]1[C:26]([CH3:27])=[C:25]([CH3:28])[S:24][C:23]1=[N:29][C:11]([C:1]12[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2)=[O:12])([CH3:18])([CH3:16])[CH3:17]
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Reactant: Cc1sc(=N)n(CC(=O)OC(C)(C)C)c1C
Agent: Br
Product: Cc1sc(=NC(=O)C23CC4CC(CC(C4)C2)C3)n(CC(=O)OC(C)(C)C)c1C
Yield: 6.2 %

Procedure:
Adamantane-1-carboxylic acid (2.2 g, 12 mmol) and the product of Example 82A (2.9 g, 10 mmol) were processed according to the method of Example 77B. Purification by column chromatography (SiO2, 20-35% ethyl acetate/hexanes gradient) afforded 0.25 g (63%) of the title compound. 1H NMR (CDCl3, 300 MHz) δ ppm 1.47 (s, 9H), 1.71-1.75 (m, 6H), 1.96-2.00 (m, 6H), 2.00-2.04 (m, 3H), 2.14 (s, 3H), 2.21 (s, 3H), 4.85-5.02 (m, 2H); MS (DCI/NH3) m/z 405 (M+H)+. Anal. Calculated for C22H32N2O3S: C, 65.31; H, 7.97; N, 6.92. Found: C, 65.38; H, 7.95; N, 6.84.
Reaction SMILES: [C:1]1([CH3:23])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[N:9]1[C:13]2[C:14](=O)[NH:15][N:16]=[C:17]([NH:18][CH2:19][CH2:20][CH3:21])[C:12]=2[CH:11]=[CH:10]1.[CH3:24]I.[C:26](=[O:29])([O-])[O-].[K+].[K+].[H-].[Na+]>O.CN(C=O)C>[C:3]1([CH3:8])[CH:4]=[C:5]([CH3:7])[CH:6]=[C:1]([CH3:23])[C:2]=1[N:9]1[C:13]2[C:26](=[O:29])[N:15]([CH3:14])[N:16]=[C:17]([N:18]([CH3:24])[CH2:19][CH2:20][CH3:21])[C:12]=2[CH:11]=[CH:10]1
Reactant: CCCNc1n[nH]c(=O)c2c1ccn2-c1c(C)cc(C)cc1C
Reactant: O=C([O-])[O-]
Reactant: CI
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCN(C)c1nn(C)c(=O)c2c1ccn2-c1c(C)cc(C)cc1C
Temperature: 60 °C
Reaction time: 4 h
Yield: 20.9 %

Procedure:
A mixture of 1-mesityl-4-(propylamino)-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one (29.8 mg, 0.092 mmol), methyl iodide (0.011 ml, 0.18 mmol), potassium carbonate (25.4 mg, 0.18 mmol) and DMF (1 ml) was stirred at 60° C. for 4 hours. The mixture was diluted with water (30 ml) and extracted with ethyl acetate (30 ml). The extract was washed with water, dried over magnesium sulfate and concentrated in vacuo. A mixture of the residue, methyl iodide (0.1 ml), sodium hydride (60% in oil, 8 mg, 0.2 mmol) and DMF (2 ml) was stirred room temperature for 3 hours. The mixture was diluted with water (30 ml) and extracted with ethyl acetate (30 ml). The extract was washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with hexane/ethyl acetate (10:1-5:1) to give 6.5 mg (20%) of the title compound as crystals.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][CH2:5][CH2:4][CH:3]1[CH2:13][C:14]([OH:16])=[O:15].[ClH:17].CO[C:20]1[CH:25]=[CH:24][C:23]([NH:26][NH2:27])=[CH:22][CH:21]=1>>[Cl:17][C:10]1[CH:11]=[CH:12][C:7]2[S:6][CH2:5][CH2:4][CH:3]([CH2:13][C:14]([OH:16])=[O:15])[C:2](=[O:1])[C:8]=2[CH:9]=1.[ClH:17].[Cl:17][C:20]1[CH:25]=[CH:24][C:23]([NH:26][NH2:27])=[CH:22][CH:21]=1
Reactant: COc1ccc(NN)cc1
Reactant: O=C(O)CC1CCSc2ccccc2C1=O
Agent: Cl
Product: NNc1ccc(Cl)cc1
Product: O=C(O)CC1CCSc2ccc(Cl)cc2C1=O

Procedure:
Substitution in the procedure of Example 4 for the 5-oxo-2,3,4,5-tetrahydro[1]benzothiepine-4-acetic acid and the 4-methoxyphenylhydrazine hydrochloride used therein of 7-chloro-5-oxo-2,3,4,5-tetrahydro[1]benzothiepine-4-acetic acid and 4-chlorophenylhydrazine hydrochloride, respectively, produces 10 chloro-2-(4-chlorophenyl)-4,4a,5,6-hexahydro-[1]benzothiepino[5,4-c]pyridazin-3(2H)-one, melting at 141°-143° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9]3=[C:10]([C:12](=[O:15])C(=O)[N:8]3[CH:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:6][CH2:5]2)[CH:11]=1.[OH-:22].[Na+].OO.Cl>O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]([OH:22])=[O:15])[CH:11]=1)[NH:8][CH:7]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH2:6][CH2:5]2
Reactant: O=C1C(=O)N2c3c(cc(Cl)cc31)CCC2c1ccccc1
Reactant: [OH-]
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc(Cl)cc2c1NC(c1ccccc1)CC2
Temperature: 25 °C
Yield: 96.5 %

Procedure:
To a solution of 8-chloro-5,6-dihydro-4-phenyl-4H-pyrrolo-[3,2,1-ij]quinoline-1,2-dione (3.4 g) and sodium hydroxide (2 g) in water (100 ml) was added 35% aqueous hydrogen peroxide solution (5 ml) and stirred at room temperature for an hour. The reaction mixture was acidified slightly by adding concentrated hydrochloric acid, the resulting precipitate was collected by filtration, washed and dried to give the title compound (3.17 g, 96.7%) as yellow crystals. This crystals was recrystallized from ethanol to pale yellow needles, mp 199°-200 ° C.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[C:29]([O:30][CH3:31])=[C:28]([O:32][CH3:33])[CH:27]=[CH:26][C:5]=1[CH2:6][CH2:7][NH:8][CH2:9][CH:10]([OH:25])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17]CC1C=CC=CC=1.CO>[H][H].[C].[Pd]>[ClH:1].[CH3:2][O:3][C:4]1[C:29]([O:30][CH3:31])=[C:28]([O:32][CH3:33])[CH:27]=[CH:26][C:5]=1[CH2:6][CH2:7][NH:8][CH2:9][CH:10]([OH:25])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[OH:17]
Reactant: COc1ccc(CCNCC(O)c2ccccc2OCc2ccccc2)c(OC)c1OC
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COc1ccc(CCNCC(O)c2ccccc2O)c(OC)c1OC
Yield: 84 %

Procedure:
A mixture of 5 g of α-(2,3,4-trimethoxyphenethylaminomethyl)-2-benzyloxybenzylalcohol hydrochloride, one g of 10% palladium-carbon and 50 ml of 90% aqueous methanol is shaken at room temperature in hydrogen gas atmosphere under atmospheric pressure. After hydrogen uptake is completed, insoluble materials are removed by filtration, and the filtrate is condensed. The residue thus obtained is recrystallized from a mixture of ethanol and ether. 3.4 g of α-(2,3,4-trimethoxyphenethylaminomethyl)-2-hydroxybenzylalcohol hydrochloride are obtained. M.p. 133°-134° C. Yield: 85%