Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].N[C:12](N)=[O:13]>C(O)C>[CH3:8][C:6]1[CH:5]=[C:4]([CH3:9])[C:3]2[O:10][C:12](=[O:13])[NH:1][C:2]=2[CH:7]=1
Reactant: Cc1cc(C)c(O)c(N)c1
Reactant: NC(N)=O
Solvent: CCO
Product: Cc1cc(C)c2oc(=O)[nH]c2c1
Temperature: 170 °C
Yield: 74.2 %

Procedure:
A mixture of 2-amino-4, 6-dimethylphenol (6.86 g, 50 mmoles) and urea (6.01 g, 100 mmoles) was heated at 170° C. for 1 hour. After cooling the resulting solid was dissolved in hot ethanol and recrystallized to give 6.05 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[N:6][CH:7]=1.BrC1C=C(N2CCCN([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])CC2)C=NC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:14][CH2:13][CH2:12][N:11]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:10][CH2:9]2)[CH:5]=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2cncc(Br)c2)CC1
Reactant: Clc1cncc(N2CCCNCC2)c1
Product: CC(C)(C)OC(=O)N1CCCN(c2cncc(Cl)c2)CC1

Procedure:
Was prepared from 1-(5-Chloro-3-pyridyl)-homopiperazine according to 1-(5-Bromo-3-pyridyl)-4-tert-butoxycarbonylhomopiperazine.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1Cl)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8])([O-:3])=[O:2].[CH3:19][NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>C(O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[N:20]([CH3:19])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8])([O-:3])=[O:2]
Reactant: CCCCCCCCNC
Reactant: O=C(c1ccccc1)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CCO
Product: CCCCCCCCN(C)c1ccc(C(=O)c2ccccc2)cc1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
A mixture of 9.23 g. of 3-nitro-4-chloro-benzophenone, 10 ml. of ethanol and 10.3 g. of N-methyl-N-octylamine is stirred at 80° to 85°C for 30 minutes, and then the mixture is poured onto 100 ml. of ice water. The aqueous phase is extracted with 2×75 ml. of benzene. The benzene phases are combined, washed with distilled water until chloride-free, dried over anhydrous magnesium sulphate, filtered, and evaporated in vacuo. 11.57 g. of 3-nitro-4-(N-methyl-N-octylamino)-benzophenone are obtained in the form of an oily residue. On the basis of thin layer chromatographical examination, a pure, uniform product is obtained.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]([C:18]2[CH:19]=[C:20]3[NH:29][C:28](=[O:30])[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]3[CH:31]=2)=[O:17])[CH2:11][CH2:10]1)=O)(C)(C)C>CO>[ClH:1].[N:12]1([C:16]([C:18]2[CH:19]=[C:20]3[NH:29][C:28](=[O:30])[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]3[CH:31]=2)=[O:17])[CH2:13][CH2:14][CH2:15][NH:9][CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCCN(C(=O)c2cc3[nH]c(=O)c4ccccc4n3c2)CC1
Agent: Cl
Solvent: CO
Product: O=C(c1cc2[nH]c(=O)c3ccccc3n2c1)N1CCCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
10% hydrogen chloride in methanol (3 mL) was added to a solution of 2-[4-(tert-butoxycarbonyl)homopiperazine-1-carbonyl]pyrrolo[1,2-a]quinazolin-5(4H)-one (the above Compound 1-47, 156 mg, 0.380 mmol) in methanol (1 mL), and the reaction solution was stirred overnight at room temperature. The precipitated solid was collected by filtration, and dried under reduced pressure, to obtain the title compound (102 mg, yield: 87%) as a colorless powder.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][NH2:17])=[N:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([C:21]1[CH:26]=[CH:25][C:24]([C:27](=[CH:32]N(C)C)[C:28](OC)=[O:29])=[CH:23][C:22]=1[F:36])#[N:20].C(O)(=O)C.CCN(C(C)C)C(C)C>CC(O)C.CS(C)=O>[CH2:1]([NH:8][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([N:16]2[C:28]([OH:29])=[C:27]([C:24]3[CH:25]=[CH:26][C:21]([C:19]#[N:20])=[C:22]([F:36])[CH:23]=3)[CH:32]=[N:17]2)=[N:12][CH:11]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(=CN(C)C)c1ccc(C#N)c(F)c1
Reactant: NNc1ccc(C(=O)NCc2ccccc2)cn1
Solvent: CS(C)=O
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(-c2cnn(-c3ccc(C(=O)NCc4ccccc4)cn3)c2O)cc1F
Temperature: 50 °C
Yield: 42.9 %

Procedure:
Combined N-benzyl-6-hydrazinylnicotinamide (30 mg, 0.124 mmol), methyl 2-(4-cyano-3-fluorophenyl)-3-(dimethylamino)acrylate (40.0 mg, 0.161 mmol) and acetic acid (0.021 mL, 0.371 mmol) in 2-propanol (1.0 mL) and stirred at 20° C. for 28 h. Then Hunig's base (0.130 mL, 0.743 mmol) was added and the reaction mixture was heated at 50° C. for 15 h. The reaction mixture was diluted with DMSO (0.1 mL) and purified by prep HPLC to give the title compound (22 mg, 43.0% yield) as a peach solid. 1H NMR (400 MHz, DMSO-d6) 6 ppm 4.53 (d, J=5.8 Hz, 2H) 7.21-7.30 (m, 1H) 7.31-7.39 (m, 4H) 7.85 (t, J=7.7 Hz, 1H) 7.99 (d, J=8.3 Hz, 1H) 8.10 (d, J=11.9 Hz, 1H) 8.42-8.58 (m, 2H) 8.74 (br. s., 1H) 8.97 (d, J=1.5 Hz, 1H) 9.27 (t, J=5.9 Hz, 1H) 13.81 (br. s., 1H). MS m/z 414 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:5]([OH:7])=O.C(N(CC)CC)C.CN1CCOCC1.[Cl:29][C:30]1[CH:40]=[CH:39][C:33]2[NH:34][C:35]([CH2:37][NH2:38])=[N:36][C:32]=2[CH:31]=1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:5]([NH:38][CH2:37][C:35]1[NH:34][C:33]2[CH:39]=[CH:40][C:30]([Cl:29])=[CH:31][C:32]=2[N:36]=1)=[O:7]
Reactant: NCc1nc2cc(Cl)ccc2[nH]1
Reactant: COC(=O)c1ccc(C(=O)O)cc1Cl
Solvent: CCN(CC)CC
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(=O)NCc2nc3cc(Cl)ccc3[nH]2)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1.61 g (7.50 mmol) of 3-chloro-4-methoxycarbonylbenzoic acid is dissolved in 40 mL of N,N-dimethylformamide and combined with 1.30 g (8.00 mmol) of N,N′-carbonyldiimidazole and stirred for 15 minutes at ambient temperature under a nitrogen atmosphere. Then 1.0 mL (7.5 mmol) of triethylamine, 1.5 mL (15 mmol) of N-methylmorpholine, and 1.69 g (7.75 mmol) of C-(5-chloro-1H-benzimidazol-2-yl)methylamine are added successively and stirred for a further 16 hours at ambient temperature under a nitrogen atmosphere. Then the reaction mixture is poured into 1 L of ice water, the precipitate is separated off by filtering, washed with a little demineralized water, and dried at 40° C. Finally the product is recrystallized from petroleum ether/ethyl acetate (2:1). Yield: 2.40 g (85%); Rf value: 0.58 (silica gel; dichloromethane/ethanol=9:1); C17H13Cl2N3O3 (378.22); mass spectrum: (M−H)−=376/78/80 (chlorine isotope).
Reaction SMILES: [CH:1](=[N:8][CH2:9][C:10]#[C:11][Si](C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[Li+].C([Li])CCC.C(NC(C)C)(C)C.CN(C)CCN(C)C.Br[CH2:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH:1](=[N:8][CH:9]([C:10]#[CH:11])[CH2:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C#CCN=Cc1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: CC(C)[N-]C(C)C
Agent: CN(C)CCN(C)C
Agent: [Cl-]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C#CC(CC(=O)OC(C)(C)C)N=Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
A solution of 17.6 g of 1B in 300 ml of dry tetrahydrofuran was added drop-by-drop to a solution of lithium diisopropylamide (prepared by adding 38 ml of a 2.2M solution of n-butyllithium in hexane to a solution of 11 ml of diisopropylamine and 12 ml of tetramethylethylenediamine in 450 ml of tetrahydrofuran) at -78° C. under argon. The resulting solution was held at -78° C. for 40 minutes, then a solution of 13.5 ml of tert-butyl bromoacetate in 50 ml of dry tetrahydrofuran was added. The resulting mixture was stirred at -78° C. for 30 minutes, at 0° C. for 10 minutes, then was poured into 300 ml of ice water containing 4.5 g of ammonium chloride. The resulting mixture was extracted with ether, the extract was washed with water, treated with charcoal and the solvent was evaporated. The residue was stirred in a solution of 7.5 g of sodium methoxide in 700 ml of methanol for 24 hours at room temperature. Then the solvent was evaporated and the residue was mixed with 200 ml of water containing 7.5 g of ammonium chloride. The mixture was extracted with ether, the extract was washed with water, dried (MgSO4) and the solvent was evaporated to give tert-butyl 3-(benzylideneamino)-4-pentynoate (5A), as a brown oil.
Reaction SMILES: C[O:2][CH2:3][C@H:4]([CH3:36])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]3[O:29][C@@H:30]([CH3:35])[C@@H:31]([CH2:33][OH:34])[N:32]=3)=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:14]=[N:15][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][CH:18]=2)[CH:11]=1.B(Br)(Br)Br.C(=O)([O-])O.[Na+]>C(Cl)Cl>[OH:34][CH2:33][C@@H:31]1[C@H:30]([CH3:35])[O:29][C:28]([C:26]2[NH:27][C:23]([C:8]3[CH:7]=[C:6]([CH:11]=[C:10]([O:12][C:13]4[CH:14]=[N:15][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][CH:18]=4)[CH:9]=3)[O:5][C@@H:4]([CH3:36])[CH2:3][OH:2])=[CH:24][CH:25]=2)=[N:32]1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(-c2ccc(C3=N[C@H](CO)[C@H](C)O3)[nH]2)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H]1OC(c2ccc(-c3cc(Oc4ccc(S(C)(=O)=O)nc4)cc(O[C@@H](C)CO)c3)[nH]2)=N[C@@H]1CO
Reaction time: 0.75 h
Yield: 80.9 %

Procedure:
{(4R,5S)-2-[5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]-5-methyl-4,5-dihydro-1,3-oxazol-4-yl}methanol (178 mg, 0.35 mmol) synthesized in Example (91d) was dissolved in methylene chloride (5 mL), and boron tribromide (1.0 mol/L methylene chloride solution, 0.70 mL, 0.70 mmol) was added at −78° C., and subsequently the temperature was brought back to room temperature and stirring was carried out for 45 minutes. To the reaction solution, a saturated aqueous sodium hydrogencarbonate solution was added, and extraction was carried out with methylene chloride. The organic layer was washed with saturated brine, and subsequently dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=0%-4%) to afford the desired compound (142 mg, yield 82%) as a white solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([Cl:13])[C:6]2[CH2:12][NH:11][CH2:10][CH2:9][C:7]=2[N:8]=1.C(N(CC)CC)C.[CH2:21]([N:23]=[C:24]=[O:25])[CH3:22]>C(OCC)(=O)C.O>[Cl:2][C:3]1[N:4]=[C:5]([Cl:13])[C:6]2[CH2:12][N:11]([C:24]([NH:23][CH2:21][CH3:22])=[O:25])[CH2:10][CH2:9][C:7]=2[N:8]=1
Reactant: CCN=C=O
Reactant: Clc1nc(Cl)c2c(n1)CCNC2
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCNC(=O)N1CCc2nc(Cl)nc(Cl)c2C1
Temperature: 25 °C

Procedure:
2,4-Dichloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine hydrochloride (2.0 g, 8.3 mmol) prepared according to Reference Example 1 was dissolved in ethyl acetate (20 mL), and the solution was mixed with triethylamine (1.4 mL) and ethyl isocyanate (0.89 mL), followed by stirring at room temperature for twelve hours. After checking the completion of the reaction by thin layer chromatography, the reaction mixture was diluted with water and was extracted with ethyl acetate. The organic layer was washed with brine, was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure, to thereby yield 2,4-dichloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-6-yl-N-ethylcarboxamide (2.3 g, in a quantitative yield).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][CH:26]=1)[CH2:6][N:7]1[CH2:23][CH2:22][C:10]2([N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:13][NH:12][C:11]2=[O:21])[CH2:9][CH2:8]1.[C:27]1([OH:33])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[C:27]1([O:33][CH2:2][C:3]2[CH:4]=[C:5]([CH:24]=[CH:25][CH:26]=2)[CH2:6][N:7]2[CH2:23][CH2:22][C:10]3([N:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:13][NH:12][C:11]3=[O:21])[CH2:9][CH2:8]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C1NCN(c2ccccc2)C12CCN(Cc1cccc(CCl)c1)CC2
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1NCN(c2ccccc2)C12CCN(Cc1cccc(COc3ccccc3)c1)CC2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 8-(3-chloromethyl-benzyl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4one, prepared as in Example 8 above, (203 mg, 0.500 mmol), phenol (56.8 mg, 0.603 mmol), KI (83.1 mg, 0.500 mmol) and K2CO3 (174 mg, 1.26 mmol) in DMF was stirred at room temperature for 1 day. The reaction mixture was diluted with H2O and a white solid precipitated. The solid was collected by filtration, washed with H2O and dried under house vacuum. The crude product was initially purified by flash chromatography (5% MeOH in CHCl3) and by tapered prep TLC (5% MeOH in CHCl3) to yield the title product as a white amorphous solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].Cl[CH2:23][C:24]#[N:25].CC#N>O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:11]3[CH2:12][CH2:13][N:14]([CH2:23][C:24]#[N:25])[CH2:15][CH2:16]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc2c(N3CCNCC3)n[nH]c2c1
Reactant: N#CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: N#CCN1CCN(c2n[nH]c3cc(F)ccc23)CC1
Yield: 999.9 %

Procedure:
A mixture of 6-fluoro-3-(4-piperazinyl)-1H-indazole (6.0 g, 2.7 mmol), NaHCO3 (2.5 g, 3.0 m-mol) chloroacetonitrile (2.5 g, 3.3 mmol) and CH3CN (150 mol) was stirred at reflux under N2 for 18 hours. The cooled reaction was poured into H2O and the aqueous solution was extracted with EtOAc. The EtOAc extract was washed with H2O washed with brine, dried with MgSO4 and concentrated to yield 7.0 g of a tan solid. A 1.3 g sample was recrystallized from EtOAc to yield 0.65 g of a beige solid, m.p. 154°-156° C.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][NH:6][C:7]([C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][CH:14]=2)=[O:8])[CH2:3][CH2:2]1.[C:16]([N:23]1[CH2:26][CH:25]([NH2:27])[CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].N12CCCN=C1CCCCC2>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCOCC1>[C:19]([O:18][C:16]([N:23]1[CH2:26][CH:25]([NH:27][C:12]2[N:11]=[N:10][C:9]([C:7](=[O:8])[NH:6][CH2:5][CH2:4][CH:1]3[CH2:3][CH2:2]3)=[CH:14][CH:13]=2)[CH2:24]1)=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: O=C(NCCC1CC1)c1ccc(Cl)nn1
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC(Nc2ccc(C(=O)NCCC3CC3)nn2)C1
Yield: 43 %

Procedure:
A mixture of 6-chloropyridazine-3-carboxylic acid (2-cyclopropylethyl)amide (0.350 g, 1.55 mmol), 1-BOC-3-aminoazetidine (0.400 g, 2.32 mmol), tetrabutylammonium bromide (0.120 g, 0.36 mmol) and 1,8-diazabicyclo[5,4,0]undec-7-ene (1.000 g, 6.00 mmol) in 1,4-dioxane (30 mL) was heated under reflux overnight. The solvent was evaporated. The residue was washed with 1 M citric acid (50 mL) and ethyl ether (50 mL) was added. Ultrasonication of the mixture followed by filtration afforded 3-[6-(2-cyclopropylethylcarbamoyl)pyridazin-3-ylamino]azetidine-1-carboxylic acid tert-butyl ester as a white solid in 43% yield (0.240 g).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][C:6]=1[N+:15]([O-:17])=[O:16])(=[O:3])[CH3:2].[OH-].[NH4+:19]>>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH2:19])(=[O:13])=[O:12])=[CH:7][C:6]=1[N+:15]([O-:17])=[O:16])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1[N+](=O)[O-]
Reactant: [NH4+]
Agent: [OH-]
Product: CC(=O)Nc1ccc(S(N)(=O)=O)cc1[N+](=O)[O-]

Procedure:
13.1 G. of 4-Acetylamino-3-nitrobenzenesulfonylchloride is suspended in 130 ml. of concentrated ammonium hydroxide and stirred at room temperature for 11/2 hours. The reaction mixture is concentrated to 1/3 of the original volume by boiling, cooling and filtering. The solid material is recrystallized from 70% ethanol/water affording 7.5 g. of 4-acetylamino-3-nitrobenzenesulfonamide, m.p. 182°-183° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[Cl:18][CH2:19][CH2:20][CH2:21][C:22](Cl)=[O:23].C(N(CC)CC)C.CN(C)C=O>O1CCCC1>[Cl:18][CH2:19][CH2:20][CH2:21][C:22]([NH:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1)=[O:23]
Reactant: Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ccn1
Reactant: O=C(Cl)CCCCl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1ccc(Oc2ccnc(NC(=O)CCCCl)c2)cc1
Temperature: 100 °C
Reaction time: 0.33 h

Procedure:
2-Amino-4-(4-nitrophenoxy)pyridine (300 mg), 4-chlorobutyryl chloride (0.18 ml), triethylamine (0.77 ml), dimethylformamide (1 ml) and tetrahydrofuran (1 ml) were stirred at room temperature for 10 minutes, and then silica gel was added to the reaction solution, the solvent was distilled off under reduced pressure and the reaction product was adsorbed onto the silica gel. The silica gel was charged into a dry column packed with silica gel, for column purification (hexane:ethyl acetate=3:1, followed by 2:1 and 1:1). The solvent was distilled off under reduced pressure, and then 300 mg of iron powder, 600 mg of ammonium chloride, 2 ml of DMF, 1 ml of ethanol and 1 ml of water were added to 150 mg of the resulting residue and the mixture was stirred at 100° C. for 20 minutes. After filtration with celite, water and ethyl acetate were added for extraction. The organic layer was washed 5 times with aqueous ammonium chloride solution and then dried over magnesium sulfate. The drying agent was filtered off and the solvent was distilled off under reduced pressure to obtain 110 mg of the target substance as an oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH3:34])[N:8]=[C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH3:20])[C:15]2[N:21]([CH3:33])[C:22](=[O:32])[C:23]([C:25]4[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][CH:26]=4)=[CH:24][C:14]3=2)[CH:10]=1)=O)C.[Li+].[BH4-].[OH-].[Na+]>C(Cl)Cl.C1COCC1>[Br:31][C:28]1[CH:29]=[CH:30][C:25]([C:23]2[C:22](=[O:32])[N:21]([CH3:33])[C:15]3[N:16]([CH3:20])[C:17]4[C:13]([C:14]=3[CH:24]=2)=[CH:12][C:11]([C:9]2[CH:10]=[C:6]([CH2:4][OH:3])[N:7]([CH3:34])[N:8]=2)=[CH:19][CH:18]=4)=[CH:26][CH:27]=1
Reactant: CCOC(=O)c1cc(-c2ccc3c(c2)c2cc(-c4ccc(Br)cc4)c(=O)n(C)c2n3C)nn1C
Agent: [BH4-]
Agent: [Li+]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cn1nc(-c2ccc3c(c2)c2cc(-c4ccc(Br)cc4)c(=O)n(C)c2n3C)cc1CO

Procedure:
5-[3-(4-bromophenyl)-1,9-dimethyl-2-oxo-2,9-dihydro-1H-pyrido[2,3-b]indol-6-yl]-2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester are dissolved in 5 ml of anhydrous CH2Cl2 anhydrous. The mixture is refluxed and then 0.2 ml of 1M LiBH4 in THF is added. The mixture is refluxed for 20 hours, while further adding 3 times 0.2 ml of LiBH4. The mixture is allowed to return to ambient temperature and 1 ml of 2N NaOH is added. The reaction medium is evaporated to dryness. Water is added, and the medium is acidified with 1N HCl and extracted with EtOAc. The organic phase is evaporated to dryness. The product is triturated in water, filtered, and washed with water. The product is taken up in methanol and evaporated to dryness.
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[NH:15][CH2:14][C:9]21[CH2:13]CC[CH2:10]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20]C(N)(CC)CN.CC(C)(O)C#N>>[CH2:1]([N:8]1[CH2:17][C:16]([CH2:18][CH3:20])([CH3:19])[NH:15][CH2:14][C:9]1([CH3:10])[CH3:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(C)(N)CN
Reactant: CC1(C)CN(Cc2ccccc2)C2(CCCC2)CN1
Agent: CC(C)(O)C#N
Product: CCC1(C)CN(Cc2ccccc2)C(C)(C)CN1

Procedure:
1-Benzyl-5-ethyl-2,2,5-trimethyl-piperazine was synthesized in analogy to 6-benzyl-8,8-dimethyl-6,9-diaza-spiro[4.5]decane starting from 2-methylbutane 1,2-diamine and acetone cyanohydrin.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][SH:8].[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:28]OS(C)(=O)=O)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>CCO>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:28][S:8][CH3:7])[CH2:18][CH2:17]1)=[O:15])([CH3:11])([CH3:10])[CH3:12]
Reactant: CS
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2COS(C)(=O)=O)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Product: CSCc1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Potassium t-butoxide (159 mg, 1,42 mmol) in 15 mL of abs. EtOH was saturated with methyl mercaptan gas. To this mixture was added 1-t-butoxycarbonyl-4-(2-(methanesulfonyloxymethyl)phenyl)-piperazine (0.94 mmol, which was generated according to the procedure described in Step C of Example 9). The resulting mixture was refluxed for 50 min and concentrated. The residue was purified by preparative TLC (20% EtOAc in Hex) to give the title compound (157 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:32])[CH2:16][N:17]2[CH:20]([S:21][CH2:22][CH2:23][CH2:24][C:25]([O:27]CC=C)=[O:26])[CH2:19][C:18]2=[O:31])=[CH:4][CH:3]=1.N1CCCC1>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:32])[CH2:16][N:17]2[CH:20]([S:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])[CH2:19][C:18]2=[O:31])=[CH:4][CH:3]=1
Reactant: C=CCOC(=O)CCCSC1CC(=O)N1CC(=O)NCCCCCCc1ccc(F)cc1
Solvent: ClCCl
Solvent: C1CCNC1
Product: O=C(O)CCCSC1CC(=O)N1CC(=O)NCCCCCCc1ccc(F)cc1
Yield: 52 %

Procedure:
N-[6-(4-Fluorophenyl)hexyl]-[4-(3-allyloxycarbonylpropyl)thio-2-oxo-azetidin-1-yl]-acetamide (1.4 g) was dissolved in dry dichloromethane (30 ml) and the resulting solution treated with pyrrolidine (0.3 g) and (tetrakistriphenylphosphino)palladium (0.2 g) at room temperature until TLC analysis showed absence of starting material. The mixture was washed with dilute HCl, brine, dried (MgSO4) and evaporated. The residue was purified by chromatography on silica gel (dichloromethane:methanol:acetic acid, 90:9:1) to give the title compound as an oil, 0.7 g, 52% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:3]=1[O:4][CH:5]([CH3:11])[C:6]([O:8]CC)=O.[CH2:19]([NH2:21])[CH3:20]>C(O)C>[CH2:19]([NH:21][C:6](=[O:8])[CH:5]([O:4][C:3]1[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:2]=1[Cl:1])[CH3:11])[CH3:20]
Reactant: CCOC(=O)C(C)Oc1cc([N+](=O)[O-])ccc1Cl
Reactant: CCN
Solvent: CCO
Product: CCNC(=O)C(C)Oc1cc([N+](=O)[O-])ccc1Cl

Procedure:
A mixture of 2.74 g. of ethyl α-(2-chloro-5-nitrophenoxy)propionate, 0.77 g. of 70% aqueous solution of ethylamine and 15 ml. of ethanol was kept at room temperature for one night. The precipitate was separated by a filtration and recrystallized from a mixture of benzene-cyclohexane to obtain 2.5 g. of the object compound (melting point of 148° to 149° C.).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3([CH2:23][NH2:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>>[N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3([CH2:23][NH:24][C:25](=[O:27])[CH3:26])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:16]=2)[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1
Reactant: NCC1(c2ccc(OCCCN3CCSCC3)cc2)CCOCC1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)NCC1(c2ccc(OCCCN3CCSCC3)cc2)CCOCC1
Yield: 100 %

Procedure:
The title compound (1.16 g, 100%) was prepared using 1-{4-[4-(3-thiomorpholin-4-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}methanamine and acetic anhydride similarly to the procedure used for example 140. 1H NMR (400 MHz, CDCl3) δ 1.82-1.86 (m, 2H), 1.87 (s, 3H), 2.00-2.04 (m, 4H), 2.58-2.85 (m, 10H), 3.45 (d, 2H), 3.56-3.61 (m, 2H), 3.79-3.84 (m, 2H), 4.02 (t, 2H), 4.97 (brs, 1H), 6.91 (d, 2H), 7.19 (d, 2H). LRMS APCI+ m/z 393 [MH]+.