Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:7]1[C:15]2[S:16][CH:17]=[CH:18][C:14]=2[C:13]([C:19]#[C:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:9]2[S:10][CH:11]=[CH:12][C:8]=12)#[C:2][CH2:3][CH2:4][CH2:5][CH3:6]>C1COCC1.[Pd]>[CH2:1]([C:7]1[C:15]2[S:16][CH:17]=[CH:18][C:14]=2[C:13]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:9]2[S:10][CH:11]=[CH:12][C:8]=12)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCC#Cc1c2ccsc2c(C#CCCCC)c2ccsc12
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCc1c2ccsc2c(CCCCCC)c2ccsc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 49.9 %

Procedure:
To a solution of the above prepared 4,8-dihexynylbenzo[1,2-b:4,5-b′]dithiophene (3 grams, 8.6 mmol) in THF (150 milliliters) in a round-bottomed flask was added 10 percent Pd/C (0.90 gram, 0.86 mmol). The mixture was stirred under a hydrogen atmosphere at room temperature for 24 hours. The solvent was removed by vacuum evaporation, and the residue with the catalyst impurity was purified by column chromatography on silica gel (eluent: hexane/dichloromethane, 2/1, v/v). Recrystallization of the product isolated from column chromatography from 20 milliliters of isopropanol in fridge afforded 1.54 grams (51 percent yield) of needle crystal after drying in vacuo.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([NH:20][CH:21]3[CH2:23][CH2:22]3)[CH2:16][CH2:15]2)=[C:10]([CH2:24][NH:25][CH3:26])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1>>[C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([N:20]([C:32](=[O:33])[C:31]3[CH:35]=[CH:36][C:28]([Cl:27])=[CH:29][CH:30]=3)[CH:21]3[CH2:23][CH2:22]3)[CH2:16][CH2:15]2)=[C:10]([CH2:24][NH:25][CH3:26])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CNCc1cc(C(=O)OC(C)(C)C)ccc1[C@H]1CC[C@H](NC2CC2)CC1
Product: CNCc1cc(C(=O)OC(C)(C)C)ccc1[C@H]1CC[C@H](N(C(=O)c2ccc(Cl)cc2)C2CC2)CC1

Procedure:
from trans-4-(4-tert.butoxycarbonyl-methylaminomethyl-phenyl)-N-cyclopropylcyclohexylamine and 4-chlorobenzoyl chloride. Melting point: 151°-152° C.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:14])=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[CH3:15][NH:16][CH3:17]>CO>[Cl:14][C:5]1[N:4]=[N:3][C:2]([N:16]([CH3:17])[CH3:15])=[C:7]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=1
Reactant: Clc1cc(N2CCNCC2)c(Cl)nn1
Reactant: CNC
Solvent: CO
Product: CN(C)c1nnc(Cl)cc1N1CCNCC1
Reaction time: 4 h
Yield: 113.2 %

Procedure:
23 g 3,6-dichloro-4-piperazin-1-yl-pyridazine and 45 g dimethylamine are suspended in 200 ml of methanol and autoclaved for 4 hours at 100° C. The reaction mixture is evaporated to dryness and the product is extracted with chloroform and washed with sodium hydroxide solution. The hydrochloride is precipitated with an ethereal HCl solution. 27 g product are obtained. M.p.=291° C.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2([CH2:17][CH2:16][N:15]([C:18](=[O:26])[C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)[NH:11][C@@H:10]([CH2:27][CH2:28][S:29][CH3:30])[C:9]1=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C[Si]([Cl:37])(C)C>CC(CC)=O>[ClH:37].[CH2:1]([N:8]1[C:12]2([CH2:17][CH2:16][N:15]([C:18](=[O:26])[C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)[CH2:14][CH2:13]2)[NH:11][C@@H:10]([CH2:27][CH2:28][S:29][CH3:30])[C:9]1=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)Cl
Agent: CSCC[C@@H]1NC2(CCN(C(=O)c3ccc(F)cc3)CC2)N(Cc2ccccc2)C1=O
Solvent: O
Solvent: CCC(C)=O
Product: Cl
Reaction time: 8 h

Procedure:
1-benzyl-8-(4-fluorobenzoyl)-3-(S)-(2-methylsulfanylethyl)-1,4,8-triazaspiro[4,5]decan-2-one (223 mg, 0.5 mmol) was dissolved in ethyl methyl ketone (1.8 mL), water (5 μL) and TMSCl (70 μL) were added and the mixture was stirred overnight. The solid matter was isolated by filtration, washed with ether, and dried in vacuo. The product 1-benzyl-8-(4-fluorobenzoyl)-3-(S)-(2-methylsulfanylethyl)-1,4,8-triazaspiro[4,5]decan-2-one hydrochloride was obtained in a yield of 227 mg (94%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]2[NH:8][CH2:9][C:10]3([CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>CN(C1C=CN=CC=1)C>[Br:1][C:2]1[CH:7]=[C:6]2[N:8]([C:22](=[O:24])[CH3:23])[CH2:9][C:10]3([CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1
Reactant: Brc1ccc2c(c1)NCC21CCOCC1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)N1CC2(CCOCC2)c2ccc(Br)cc21
Temperature: 85 °C

Procedure:
6-Bromo-2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran] (2.53 g, 9.44 mmol) was dissolved in pyridine (8.39 mL, 104 mmol) and acetic anhydride (1.34 mL, 14.2 mmol) was added followed by DMAP (0.0576 g, 0.472 mmol). The reaction was heated to 85° C. for 90 min. After this time the reaction was concentrated in vacuo and the resulting oil was partitioned between EtOAc and 0.5N HCl. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by column chromatography to give 1-(6-bromo-2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran]-1-yl)ethanone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:14]3[CH2:15][CH2:16][CH:10]2[CH2:11][C:12](=O)[CH2:13]3)=[CH:5][CH:4]=1.[CH2:18]([O:20][C:21](=[O:25])[CH2:22][C:23]#[N:24])[CH3:19].N1[CH2:31][CH2:30][CH2:29]CC1.NCCC(O)=O>CN(C)C=O.CCOCC>[C:23]([C:22](=[C:13]1[CH2:12][CH2:11][CH:10]2[N:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH:14]1[CH2:15][CH2:16]2)[C:21]([O:20][CH2:18][CH3:19])=[O:25])#[N:24].[CH:3]([O:2][CH:30]([CH3:29])[CH3:31])([CH3:8])[CH3:4]
Reactant: CCOC(=O)CC#N
Reactant: C1CCNCC1
Reactant: COc1ccc(N2C3CCC2CC(=O)C3)cc1
Agent: NCCC(=O)O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)OC(C)C
Product: CCOC(=O)C(C#N)=C1CCC2CCC1N2c1ccc(OC)cc1
Temperature: 25 °C

Procedure:
3.0 g of 8-(4-methoxyphenyl)-8-azabicyclo[3.2.1]octan-3-one were dissolved in 6 ml of dimethylformamide and treated with 1.8 ml of cyanoacetic acid ethyl ester, 0.2 ml of piperidine and 58 mg of β-alanine. The mixture was heated to 50° for 28 hours while stirring. After cooling to room temperature, the mixture was diluted with ether, washed four times with water, dried over sodium sulfate and concentrated under reduced pressure. Chromatography of the residue on 250 g of silica gel with hexane/ethyl acetate (3:2) yielded ethyl cyano-[8-(4-methoxyphenyl)-8-azabicyclo[3.2.1]octanylidene]acetate as a white solid, melting point 121°-122° (from isopropyl ether).
Reaction SMILES: Cl[C:2](Cl)(Cl)[CH:3]([OH:5])O.[O-]S([O-])(=O)=O.[Na+].[Na+].[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl.Cl.[NH2:24][OH:25]>O>[CH:19]1[CH:20]=[CH:21][C:16]([NH:15][C:3](/[CH:2]=[N:24]/[OH:25])=[O:5])=[CH:17][CH:18]=1
Reactant: OC(O)C(Cl)(Cl)Cl
Reactant: Nc1ccccc1
Reactant: NO
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(/C=N/O)Nc1ccccc1
Temperature: 35 °C

Procedure:
Chloral hydrate (5.0 g) and Na2SO4 (35.0 g) were dissolved in water (70 mL) in a 300 mL beaker and warmed to 35° C. A warm solution of the appropriate commercial aniline derivative Ia-d (27.6 mmol) in water (20 mL) and aqueous solution of conc. HCl (3 mL) was added (a white precipitate of the amine sulfate was formed), followed by a warm solution of hydroxylamine hydrochloride (6.1 g) in water (27.5 mL). The mixture was stirred by hand and heated on a hot plate (a thick paste formed at 75-70° C.) at 80-90° C. for 2 h, then allowed to cool for 1 h, by which time the temperature had fallen to 50° C., and filtered. The pale cream product was washed by stirring with water (100 mL) and filtered. Drying overnight at 40° C. gave the corresponding isonitrosoacetanilide IIa-d.
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][CH2:4][OH:5].[N+:6]([C:9]1[C:22]2[C:13](=[N:14][C:15]3[C:20]([C:21]=2OC2C=CC=CC=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:12]=[CH:11][CH:10]=1)([O-:8])=[O:7].Cl>C1(O)C=CC=CC=1.CCOCC>[ClH:1].[N+:6]([C:9]1[C:22]2[C:13](=[N:14][C:15]3[C:20]([C:21]=2[NH:2][CH2:3][CH2:4][OH:5])=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:12]=[CH:11][CH:10]=1)([O-:8])=[O:7]
Reactant: NCCO
Reactant: O=[N+]([O-])c1cccc2nc3ccccc3c(Oc3ccccc3)c12
Agent: Cl
Solvent: Oc1ccccc1
Solvent: CCOCC
Product: O=[N+]([O-])c1cccc2nc3ccccc3c(NCCO)c12
Temperature: 80 °C
Yield: 91 %

Procedure:
This compound is synthesized generally using the methods described in EP 38579. Specifically, 2 g of 2-amino-ethanol hydrochloride is added to 6.4 g of 1-nitro-9-phenoxyacridine dissolved in 20 g of freshly distilled phenol. The mixture is heated for 40 minutes at a temperature of 80° C. and then cooled, diluted with ether. It is then poured into dry ether that was acidified with an ethereal solution of hydrogen chloride. The orange colored precipitate of 1-nitro-9-(2-hydroxyethylamino)-acridine hydrochloride, obtained in this way is filtered and crystallized from dry ethanol. The melting point of the compounds obtained was 170° C., with decomposition. Yield 91%. Elementary analysis for the formula: C15H14N3O3Cl:calculated:56.47%; C, 4.42%; H, 13.17%; N. determined: 56.44%; C, 4.40%; H, 13.03%; N.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([O:15]C(C)(C)C)=[O:14])[CH:5]=[C:6]([F:11])[C:7]=1[N+:8]([O-:10])=[O:9].Cl>O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([F:11])[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)Cc1cc(F)c([N+](=O)[O-])c(F)c1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)Cc1cc(F)c([N+](=O)[O-])c(F)c1
Reaction time: 0.17 h

Procedure:
1,1-dimethylethyl (3,5-difluoro-4-nitrophenyl)acetate (150 g) and 4M HCl in 1,4-dioxane (1150 ml) was stirred for 18 h at about 25° C. Nitrogen was bubbled through the mixture to remove excess HCl over 7 hours, then the mixture was concentrated. Toluene (300 ml) was distilled off then the residue was stirred with hexane (300 ml) for 10 minutes. The hexane was decanted off, and the residue stirred with hexane (150 ml) for 10 minutes, then the hexane was decanted off. The residue was stirred with toluene (450 ml) for 2 hours at around 25° C. The solid was filtered and washed with 1:1 toluene/hexane (300 ml), then dried under vacuum to give the title compound as a brown fine powder (41.5 g).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][NH:6][C:7]1([C:10]([OH:12])=[O:11])[CH2:9][CH2:8]1.[CH3:13]O>>[ClH:3].[CH3:5][NH:6][C:7]1([C:10]([O:12][CH3:13])=[O:11])[CH2:9][CH2:8]1
Reactant: CO
Reactant: O=S(Cl)Cl
Reactant: CNC1(C(=O)O)CC1
Product: CNC1(C(=O)OC)CC1
Product: Cl
Reaction time: 5 h
Yield: 86.6 %

Procedure:
86.5 g (1.2 mol) of thionyl chloride were added dropwise to 300 ml of methanol at -10° C., and thereafter 36.9 g (0.32 mol) of 1-methylamino-cyclopropane-1-carboxylic acid were introduced in portions. Stirring was carried out for 5 hours at room temperature, and the mixture was allowed to stand overnight. The mixture was worked up by filtering it, evaporating down the filtrate in vacuo and heating the residue together with 7 g of active carbon for 10 minutes in methanol. After filtration and evaporation, 45.9 g (86.6% of theory) of methyl 1-methylamino-cyclopropane-1-carboxylate hydrochloride were obtained as a yellowish viscous oil of refractive index nD23.5 : 1.4798.
Reaction SMILES: [N:1](C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[OH:19][CH2:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][CH2:30][C:31]([O:33]C)=O)=[O:28])[CH2:23][CH2:22]1.C(P(CCCC)CCCC)CCC.O[C:49]1[CH:58]=[C:57]2[C:52]([CH:53]=[CH:54][CH:55]=[N:56]2)=[CH:51][CH:50]=1>C1C=CC=CC=1.N.CO>[N:56]1[C:57]2[C:52](=[CH:51][CH:50]=[C:49]([O:19][CH2:20][CH:21]3[CH2:22][CH2:23][N:24]([C:27]([O:29][CH2:30][C:31]([NH2:1])=[O:33])=[O:28])[CH2:25][CH2:26]3)[CH:58]=2)[CH:53]=[CH:54][CH:55]=1
Reactant: COC(=O)COC(=O)N1CCC(CO)CC1
Reactant: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Reactant: Oc1ccc2cccnc2c1
Agent: CCCCP(CCCC)CCCC
Agent: N
Solvent: CO
Solvent: c1ccccc1
Product: NC(=O)COC(=O)N1CCC(COc2ccc3cccnc3c2)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 48.5 %

Procedure:
0.26 g (1.03 mmol) of 1,1′-(azodicarbonyl)-dipiperidine (ADDP) is added to a solution of 0.16 g (0.69 mmol) of 2-(methyloxy)-2-oxoethyl 4-(hydroxymethyl)-1-piperidinecarboxylate, prepared in Step 8.1., 0.26 ml (1.03 mmol) of tri-n-butylphosphine and 0.13 g (0.90 mmol) of 7-hydroxyquinoline in 2.5 ml of benzene, which is cooled by means of an ice bath. The mixture is stirred at 0° C. for 15 minutes and then at ambient temperature for 16 hours. It is filtered over celite and rinsed with diethyl ether. The filtrates are evaporated to dryness and purified by chromatography on silica gel, eluting with a 70/30 mixture of ethyl acetate in n-hexane. The product obtained is dissolved in 3 ml (21 mmol) of a 7M solution of ammonia in methanol. The solution is stirred for 3 hours and then evaporated to dryness. The product is purified by chromatography on silica gel, eluting with a 90/10 mixture of ethyl acetate in ethanol, and recrystallized from ethyl acetate, to give 0.115 g of product in white solid form.
Reaction SMILES: [OH:1][C:2]1([CH2:17][CH:18]=O)[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].[C:20](=[O:27])([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH2:21].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(#N)C>[C:23]([O:22][C:20]([NH:21][CH2:18][CH2:17][C:2]1([OH:1])[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:8])=[O:27])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(N)=O
Reactant: O=CCC1(O)CCCC1C(=O)OCc1ccccc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCC1(O)CCCC1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.2 %

Procedure:
To a solution of benzyl 2-hydroxy-2-(2-oxoethyl)cyclopentanecarboxylate (from step C, 120 mg, 0.457 mmol) in acetonitrile (2 mL) was added tert-butyl carbamate (214 mg, 1.830 mmol), triethylsilane (213 mg, 1.830 mmol) and trifluoroacetic acid (0.070 mL, 0.915 mmol). The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated and subjected to preparative HPLC(Shimadzu VP-ODS 20×100 mm, 8 min. gradient, Solvent A: 10% MeOH, 90% H2O, 0.1% TFA; Solvent B: 90% MeOH, 10% H2O, 0.1% TFA; wavelength: 220 nM). The desired fractions were concentrated and freeze dried to yield benzyl 2-(2-(tert-butoxycarbonylamino)ethyl)-2-hydroxycyclopentanecarboxylate (70 mg, 0.193 mmol, 42.1% yield) as a solid. MS (ESI+)=386 (M+Na)+
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[S:19]1[CH:23]=[CH:22][N:21]=[C:20]1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>CN(C)C=O>[CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][C:3]=1[CH2:2][N:27]1[CH2:28][CH2:29][N:24]([C:20]2[S:19][CH:23]=[CH:22][N:21]=2)[CH2:25][CH2:26]1
Reactant: BrCc1ccc2ccccc2c1
Reactant: c1csc(N2CCNCC2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc2cc(CN3CCN(c4nccs4)CC3)ccc2c1
Temperature: 150 °C
Yield: 64.6 %

Procedure:
To a solution of 22.1 g (0.1 mole) of 2-bromomethylnaphthalene in 150 ml of dimethylformamide, there were added successively 10.7 g (0.101 mole) of dry potassium carbonate and 17.2 g (0.101 mole) of 1-(2-thiazolyl)-piperazine. The resulting suspension was heated at 150° C. for 10 hours; the salt which had formed was then filtered off and the dimethylformamide was evaporated off under reduced pressure. There was obtained a brown crystalline residue which was washed with water and suction filtered off. The resulting 29 g of crystals were recrystallized in 150 ml of ethanol to give 20 g of 1-(2-naphthylmethyl)-4-(2-thiazolyl)-piperazine as beige crystals melting at 83°-84° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(C1C=CC(S([O-])(=O)=O)=CC=1)(=O)C.[Na+].[CH3:28][NH2:29]>>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:29][CH3:28])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CN
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Agent: CC(=O)c1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Product: CNS(=O)(=O)c1ccc(C(C)=O)cc1

Procedure:
The damp 4-acetylbenzenesulfonyl chloride from 50 g. of sodium 4-acetylbenzenesulfonate is added in portions, with stirring, to 500 ml. of cold 40% aqueous methylamine. The mixture is stirred at room temperature for 16 hours, then cooled and the precipitate collected by filtration. The solid (which proved to be the N-methylimine derivative of the ketosulfonamide) is dissolved in 300 ml. of 6% hydrochloric acid and the solution is heated at 80°-90° C. for 30 minutes, then cooled. The resulting precipitate of 4-acetyl-N-methylbenzenesulfonamide is collected by filtration and crystallized from aqueous ethanol; m.p. 107°-109° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[NH:5][C:6]1[C:7]2[CH:14]=[C:13]([CH2:15][OH:16])[NH:12][C:8]=2[N:9]=[CH:10][N:11]=1.P(Br)(Br)Br.Cl[C:25]1C=C(C=CC=1)NC1C2C=C(CBr)NC=2N=CN=1.C[O-].[Na+]>C(OCC)C.CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[NH:5][C:6]1[C:7]2[CH:14]=[C:13]([CH2:15][O:16][CH3:25])[NH:12][C:8]=2[N:9]=[CH:10][N:11]=1
Reactant: OCc1cc2c(Nc3cccc(Cl)c3)ncnc2[nH]1
Reactant: Clc1cccc(Nc2ncnc3[nH]c(CBr)cc23)c1
Agent: BrP(Br)Br
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: COCc1cc2c(Nc3cccc(Cl)c3)ncnc2[nH]1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To an ice cooled suspension of 82.5 mg (0.30 mmol) of 4-(3-chloro-anilino)-6-hydroxymethyl-7H-pyrrolo[2,3-d]pyrimidin (cf. Example 49) in 5 ml of diethyl ether are added under argon 14 μl (0.15 mmol) of phosphorus tribromide. After stirring for 18 h at 0° C. and 18 h at RT (→4-(3-chloro-anilino)-6-bromomethyl-7H-pyrrolo[2,3-d]pyrimidin), 2 ml of methanol are added. The mixture is stirred for 2 h and then 1 ml of sodium methanolate (5.4 M in methanol) is added dropwise. After 18 h, the mixture is concentrated in vacuo; the residue is redissolved in methanol, silica gel is added and the mixture is evaporated to a dry powder. This powder is put on top of a chromatography column (SiO2 ; CH2Cl2 /ethanol [2:1]). Eluation with CH2Cl2 /ethanol [2:1], concentration and washing with ethyl acetate/diethyl ether/hexane affords the title compound; m.p. 226-230° C.; TLC-Rf =0.59 (CH2Cl2 /methanol [10:1]); HPLC: tRet (Grad20)=9.7.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][C:14]([CH3:47])([CH3:46])[C:15](=[O:45])[CH2:16][N:17]1[C:22](=[O:23])[C:21]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[C:32]([C:37]#[N:38])=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:27][CH:26]=2)=[C:20]([CH2:39][CH2:40][CH3:41])[N:19]2[N:42]=[CH:43][N:44]=[C:18]12>C(OCC)(=O)C>[CH3:47][C:14]([CH3:46])([CH3:13])[C:15](=[O:45])[CH2:16][N:17]1[C:22](=[O:23])[C:21]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]3[NH:3][C:4](=[O:7])[O:5][N:38]=3)=[CH:29][CH:30]=2)=[C:20]([CH2:39][CH2:40][CH3:41])[N:19]2[N:42]=[CH:43][N:44]=[C:18]12
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC(=O)C(C)(C)C)c2ncnn12
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(CC(=O)C(C)(C)C)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 37.7 %

Procedure:
A mixture of hydroxylammonium chloride (0.9 g), sodium hydrogen carbonate (1.4 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[4-(3,3-dimethyl-2-oxobutyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.4 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.17 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.14 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.17 g, 37%).
Reaction SMILES: C(N(CC)CC)C.Cl.Cl.[NH2:10][C:11]1[C:20]2[N:21]=[C:22]([CH2:32][CH3:33])[N:23]([CH2:24][C:25]3([OH:31])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[C:19]=2[C:18]2[N:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1.[N:34]1([C:40](Cl)=[O:41])[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>ClCCl>[NH2:10][C:11]1[C:20]2[N:21]=[C:22]([CH2:32][CH3:33])[N:23]([CH2:24][C:25]3([OH:31])[CH2:30][CH2:29][N:28]([C:40]([N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)=[O:41])[CH2:27][CH2:26]3)[C:19]=2[C:18]2[N:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: CCc1nc2c(N)nc3cccnc3c2n1CC1(O)CCNCC1
Reactant: O=C(Cl)N1CCOCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nc2c(N)nc3cccnc3c2n1CC1(O)CCN(C(=O)N2CCOCC2)CC1
Temperature: -5 °C
Reaction time: 48 h
Yield: 88.3 %

Procedure:
Under a nitrogen atmosphere triethylamine (1.39 mL, 10.0 mmol) was added to a suspension of 4-[(4-amino-2-ethyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]piperidin-4-ol dihydrochloride (1.00 g, 2.50 mmol) in dichloromethane (25 mL). The mixture was cooled to −5° C. 4-Morpholinecarbonyl chloride (292 μL, 2.50 mmol) was added and the reaction mixture was allowed to slowly warm to ambient temperature. The reaction mixture was stirred at ambient temperature for 2 days and then at 30° C. for 2 days. More 4-morpholinecarbonyl chloride (30 μL) was added and the reaction mixture was stirred at 30° C. for 5 days. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between chloroform (150 mL) and saturated aqueous sodium carbonate (30 mL). The organic was washed with saturated aqueous sodium carbonate (20 mL) and brine (20 mL), dried over sodium sulfate, filtered, and then concentrated under reduced pressure to provide an off white solid. This material was triturated with acetonitrile, recrystallized from chloroform/hexanes, isolated by filtration, washed with hexanes, and dried under high vacuum at 130° C. to provide 0.97 g of 4-[(4-amino-2-ethyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]-1-(morpholin-4-ylcarbonyl)piperidin-4-ol as a white powder, mp>255.0° C. Anal. Calcd for C22H29N7O3.0.25H2OC, 59.51; H, 6.70; N, 22.08. Found: C, 59.32; H, 6.36; N, 22.00.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:18]3[C:13](=[CH:14][C:15]([NH2:19])=[CH:16][CH:17]=3)[NH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:20][N:21]1[C:29]2[C:24](=[CH:25][C:26]([C:30](O)=[O:31])=[CH:27][CH:28]=2)[CH:23]=[CH:22]1.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.O>[CH3:20][N:21]1[C:29]2[C:24](=[CH:25][C:26]([C:30]([NH:19][C:15]3[CH:14]=[C:13]4[C:18]([C:10]([C:7]5[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=5)=[CH:11][NH:12]4)=[CH:17][CH:16]=3)=[O:31])=[CH:27][CH:28]=2)[CH:23]=[CH:22]1
Reactant: Nc1ccc2c(-c3ccc([N+](=O)[O-])cc3)c[nH]c2c1
Reactant: Cn1ccc2cc(C(=O)O)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1ccc2cc(C(=O)Nc3ccc4c(-c5ccc([N+](=O)[O-])cc5)c[nH]c4c3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.7 %

Procedure:
A mixture of 3-(4-nitrophenyl)-1H-indol-6-amine (66.3 mg, 0.26 mmol), 1-methyl-1H-indole-5-carboxylic acid (50.4 mg, 0.29 mmol), hydroxybenzotriazole (3.5 mg, 0.03 mmol) and triethylamine (40.1 μL, 0.29 mmol) in DMF (1.00 mL) was stirred for 5 min before 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (55.2 mg, 0.29 mmol) was added. The reaction was stirred overnight at room temperature and was then diluted with water (5.0 mL). The precipitate that formed was filtered off and sequentially washed with excess methylene chloride and methanol. The solid was recrystallized using hot methanol and gave a bright yellow solid for 1-methyl-N-(3-(4-nitrophenyl)-1H-indol-6-yl)-1H-indole-5-carboxamide (59.8 mg, 0.15 mmol, 56%) after filtration.