Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[O:7][CH:6]=1)=[O:4].[N:16]1([CH2:22][CH2:23][CH2:24][NH2:25])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+].C(Cl)[Cl:33]>>[ClH:33].[N:16]1([CH2:22][CH2:23][CH2:24][NH:25][CH:6]=[C:5]2[C:14](=[O:15])[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[O:7][CH2:2][C:3]2=[O:4])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: NCCCN1CCCCC1
Reactant: ClCCl
Reactant: O=C(CBr)c1coc2ccccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cl
Product: O=C1COc2ccccc2C(=O)C1=CNCCCN1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 8.0g (0.03 mole) of 3-(bromoacetyl)chromone, 4.54g (0.032 mole) of piperidinopropylamine, 20g powdered potassium carbonate and 200ml of methylene chloride was stirred vigorously at room temperature for one hour. The red mixture was filtered, and the filtrate was washed well with water to remove the unreacted diamine. The organic phase was dried (K2CO3) and concentrated. The residue was taken-up into ether, and the solution was treated with excess hydrogen chloride to precipitate the crude hydrochloride salt. The ether was decanted, and the residue was dissolved in 100ml of warm 2-propanol. Upon addition of ether, crystals separated; wt. 3.8g (35%) of hygroscopic salt; m.p. 157°-159°. Recrystallization from ethanol-ether gave pure product; m.p. 158°-160°.
Reaction SMILES: [C:1]([OH:15])(=[O:14])[C:2]1[C:3](=[CH:7][C:8](=[CH:12][CH:13]=1)[C:9]([OH:11])=[O:10])[C:4]([OH:6])=[O:5].C(C1C=CC(C(OC)=O)=C(C(O)=O)C=1)(OC)=O.C(C1C=CC(C(O)=O)=C(C(OC2C=CC=CC=2)=O)C=1)(O)=O.[CH2:54]([N:56](CC)[CH2:57]C)C>>[C:1]([OH:15])(=[O:14])[C:2]1[C:3](=[CH:7][C:8](=[CH:12][CH:13]=1)[C:9]([OH:11])=[O:10])[C:4]([OH:6])=[O:5].[NH3:56].[CH3:54][NH:56][CH3:57]
Reactant: CCN(CC)CC
Agent: COC(=O)c1ccc(C(=O)OC)c(C(=O)O)c1
Agent: O=C(O)c1ccc(C(=O)O)c(C(=O)O)c1
Agent: O=C(O)c1ccc(C(=O)O)c(C(=O)Oc2ccccc2)c1
Product: CNC
Product: N

Procedure:
Example of the polyamide-imide powder includes a condensation product of trimellitic acid derivative and aromatic diamine. Example of the trimellitic acid derivative includes trimellitic anhydride; trimellitic anhydride monochloride; 1,4-dicarboxy-3-N,N-dimethyl carbamoyl benzene; 1,4-dicarbomethoxy-3-carboxy benzene; 1,4-dicarboxy-3-carbophenoxy benzene; and ammonium salts formed of trimellitic acid, ammonia, dimethylamine, triethylamine, etc. Among these, trimellitic anhydride, trimellitic anhydride monochloride, etc. are often used with preference. Example of the aromatic diamine includes 2,2-bis[4-(4-aminophenoxy)phenyl] propane; 2,2 bis[4-(4-aminophenoxy)phenyl] butane; 1,1-bis[4-(4-aminophenoxy)phenyl]cyclohexane; 1,1-bis[4-(4-aminophenoxy)phenyl]cyclopentane; bis[4-(4-aminophenoxy)phenyl]sulfone; bis[4-(4-aminophenoxy)phenyl]ether; 4,4′-carbonyl bis(P-phenylene oxy) dianiline, etc.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:12]([C:14]2[CH:22]=[C:21]3[C:17]([CH:18]=[C:19]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[N:20]3[CH2:23][CH2:24][CH2:25][CH2:26][N:27]3[C:35](=[O:36])[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:28]3=[O:37])=[CH:16][CH:15]=2)=[O:13])=[CH:5][C:6]=1[CH2:7][C:8]([O:10][CH3:11])=[O:9].[O-]S(C(F)(F)[F:49])(=O)=O.F[N+]1C=CC=CC=1>C(Cl)Cl.CCOCC>[Br:1][C:2]1[S:3][C:4]([C:12]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([F:49])=[C:19]([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)[N:20]3[CH2:23][CH2:24][CH2:25][CH2:26][N:27]3[C:35](=[O:36])[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:28]3=[O:37])=[CH:16][CH:15]=2)=[O:13])=[CH:5][C:6]=1[CH2:7][C:8]([O:10][CH3:11])=[O:9]
Reactant: O=S(=O)([O-])C(F)(F)F
Reactant: COC(=O)Cc1cc(C(=O)c2ccc3cc(-c4ccccc4)n(CCCCN4C(=O)c5ccccc5C4=O)c3c2)sc1Br
Agent: F[n+]1ccccc1
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)Cc1cc(C(=O)c2ccc3c(F)c(-c4ccccc4)n(CCCCN4C(=O)c5ccccc5C4=O)c3c2)sc1Br
Temperature: 25 °C
Yield: 26.7 %

Procedure:
To a solution of 5 (170 mg, 0.25 mmol) in 3 mL CH2Cl2 was added 1-fluoropyridinium triflate (75 mg, 0.30 mmol), and then the mixture was stirred at room temperature until no 5 was detected by NMR. The resulting mixture was diluted with 40 mL Et2O, washed with brine (2×10 mL), dried over MgSO4, filtered, and then concentrated in vacuo. MPLC purification (Hex:EtOAc/9:1) gave 6 (45 mg, 26%) as a yellow amorphous solid. 1H NMR (400 MHz, CDCl3) δ 7.94 (s, 1H), 7.78-7.63 (m, 6H), 7.56 (s, 1H), 7.50-7.41 (m, 5H), 4.25 (t, J=7.2 Hz, 2H), 3.71 (s, 3H), 3.69 (s, 2H), 3.49 (t, J=6.8 Hz, 2H), 1.66-1.60 (m, 2H), and 1.50-1.45 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 186.88, 170.13, 168.24, 143.76, 142.84, 140.39, 135.53, 134.70, 133.95, 133.90, 132.08, 132.02, 131.85, 131.39, 129.70, 128.91, 128.87, 128.72, 128.21, 128.18, 127.32, 127.12, 123.20, 121.58, 120.91, 119.94, 119.78, 116.78, 116.76, 112.32, 52.30, 43.37, 36.95, 34.81, 27.06, and 25.51.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[F:15][C:16]1[CH:17]=[C:18]([N:23]2[CH2:27][CH2:26][CH:25]([C:28](O)=[O:29])[C:24]2=[O:31])[CH:19]=[C:20]([F:22])[CH:21]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:28]([CH:25]1[CH2:26][CH2:27][N:23]([C:18]2[CH:19]=[C:20]([F:22])[CH:21]=[C:16]([F:15])[CH:17]=2)[C:24]1=[O:31])=[O:29]
Reactant: O=C(O)C1CCN(c2cc(F)cc(F)c2)C1=O
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)C1CCN(c2cc(F)cc(F)c2)C1=O
Yield: 26 %

Procedure:
This compound was prepared according to method A with 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g; 0.424 mmol), 1-(3,5-difluorophenyl)-2-oxopyrrolidine-3-carboxylic acid (0.110 g; 0.445 mmol), HATU (0.166 g; 0.437 mmol) and N,N-diisopropylethylamine (0.186 mL; 1.06 mmol) in DMF (5 mL). The crude material was purified by flash chromatography on silica gel (eluent: 2 to 20% of ethyl acetate in dichloromethane) to give 0.046 g (26%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-1-(3,5-difluorophenyl)-2-oxopyrrolidine-3-carboxamide as a white solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[CH3:8][O:9][N:10]=[C:11](Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[Cl:27].CCOCC>CN(C=O)C>[CH3:8][O:9][N:10]=[C:11]([N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[Cl:27]
Reactant: CON=C(Cl)c1ccccc1OCc1ccc(Cl)cc1Cl
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CON=C(c1ccccc1OCc1ccc(Cl)cc1Cl)n1ccnc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 48.5 %

Procedure:
Imidazole (2.04 g) was dissolved in DMF (30 ml), and 60% sodium hydride (1.20 g) was added. The mixture was stirred at room temperature for 10 minutes, then α-chloro-2-(2,4-dichlorobenzyloxy)benzaldehyde O-methyloxime (5.17 g) was added, and the mixture was stirred at 120° C. for 2 hours. After completion of the reaction, ether (200 ml) was added, and the mixture was washed with brine (200 ml) twice, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting crude product was purified by silica gel chromatography and recrystallized from ethyl acetate/n-hexane to give 2-(2,4-dichlorobenzyloxy)-α-(1-imidazolyl)benzaldehyde O-methyloxime (2.74 g) as colorless crystals. mp. 122°-123° C.
Reaction SMILES: [CH3:1][O:2][C:3]1([C:6](Cl)=[O:7])[CH2:5][CH2:4]1.Cl.[CH3:10][NH:11][O:12][CH3:13].N1C=CC=CC=1>ClCCl>[CH3:13][O:12][N:11]([CH3:10])[C:6]([C:3]1([O:2][CH3:1])[CH2:5][CH2:4]1)=[O:7]
Reactant: COC1(C(=O)Cl)CC1
Reactant: CNOC
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CON(C)C(=O)C1(OC)CC1
Temperature: 20 °C
Reaction time: 1 h
Yield: 84.9 %

Procedure:
10 g (74 mmol) of 1-methoxy-cyclopropane-carbonyl chloride are added at 20° C. with stirring to a mixture of 8 g (82 mmol) of N,O-dimethyl-hydroxylamine hydrochloride and 100 ml of absolute dichloromethane. 13 g (164 mmol) of absolute pyridine are then added dropwise at 0° C. The mixture is initially subsequently stirred at 20° C. for one hour and then at 40° C. for one hour, the precipitate is then filtered off and 100 ml of dichloromethane are added. The reaction mixture is washed with water, dried over sodium sulphate and concentrated by stripping off the solvent under reduced pressure. The remaining residue is subjected to a vacuum distillation. 10 g (85% of theory) of N-methoxy-N-methyl-1-methoxy-cyclopropanecarboxamide are obtained in this manner in the form of an oil having a boiling point of b.p.=125° C. at 20 mbar. ##STR35##
Reaction SMILES: [Cl:1][CH2:2][Si:3](Cl)(Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.CC[O:21][CH2:22][CH3:23].[CH2:24]([OH:26])[CH3:25]>>[Cl:1][CH2:2][Si:3]([O:21][CH2:22][CH3:23])([O:26][CH2:24][CH3:25])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: ClC[Si](Cl)(Cl)c1ccccc1
Reactant: CCO
Reactant: CCOCC
Solvent: CCN(CC)CC
Product: CCO[Si](CCl)(OCC)c1ccccc1
Temperature: 25 °C

Procedure:
A solution of 1.0 g (0.0044 mol) of chloromethyl(dichloro)phenylsilane in 8 ml of absolute ethanol was cooled to 0° under nitrogen and stirred while 0.61 ml (0.445 g, 0.0044 mol) of triethylamine was slowly added, giving a slurry that was allowed to warm to room temperature. Addition of 50 ml of ether, filtration to remove precipitated triethylamine/hydrochloride, and evaporation of the filtrate left a residue which was filtered through a short silica gel column (95% petroleum ether:ethyl acetate as the eluent) to give 0.80 (73%) of the title compound as a colorless oil: nmr (CDCl3): δ1.25 (t, 6, J=6 Hz), 3.0 (s, 2), 3.9 (q, 4, J=6 Hz) and 7.2-7.9 (m, 5).
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC1(C)[O:16][C:15](=O)[C:12]2([CH2:14][CH2:13]2)[C:11](=[O:18])[O:10]1>C(O)C>[CH:1]1([N:7]2[CH2:14][CH2:13][CH:12]([C:11]([OH:18])=[O:10])[C:15]2=[O:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Solvent: CCO
Product: O=C(O)C1CCN(C2CCCCC2)C1=O
Yield: 36.7 %

Procedure:
A mixture of cyclohexylamine (1.02 mL; 8.82 mmol) and 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (0.5 g; 2.94 mmol) in ethanol (3 mL) was irradiated in a microwave oven for 3 minutes at 100° C. and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (eluent 30 to 100% ethyl acetate in heptane with 5% acetic acid) to afford 0.228 g (36%) of 1-cyclohexyl-2-oxopyrrolidine-3-carboxylic acid.
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[C:11]([O:15][C:16]([N:18]1[C:22]2=[N:23][CH:24]=[C:25](O)[CH:26]=[C:21]2[CH:20]=[C:19]1[C:28]([N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)=[O:29])=[O:17])([CH3:14])([CH3:13])[CH3:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[C:11]([O:15][C:16]([N:18]1[C:22]2=[N:23][CH:24]=[C:25]([O:10][CH:7]3[CH2:8][CH2:9][N:4]([CH:1]4[CH2:3][CH2:2]4)[CH2:5][CH2:6]3)[CH:26]=[C:21]2[CH:20]=[C:19]1[C:28]([N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)=[O:29])=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: OC1CCN(C2CC2)CC1
Reactant: CC(C)(C)OC(=O)n1c(C(=O)N2CCOCC2)cc2cc(O)cnc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1c(C(=O)N2CCOCC2)cc2cc(OC3CCN(C4CC4)CC3)cnc21
Temperature: 0 °C
Reaction time: 20 h
Yield: 79.1 %

Procedure:
To the solution of 73 mg (0.5 mmol) N-cyclopropyl-4-piperidinol in 2 ml tetrahydrofuran, 0.15 g (0.43 mmol) 5-hydroxy-2-(morpholine-4-carbonyl)-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester and 0.14 g (0.52 mmol) triphenylphosphine were added and the suspension cooled to 0° C. Then, 0.12 g (0.52 mmol) diisopropyl azodicarboxylate was added and the resulting solution stirred for 20 hours at room temperature. The solvent was evaporated and the residue flash-chromatographed on silica gel with ethyl acetate:methanol (9:1 v/v) as eluant to give 0.16 g (81%) the product as a colorless gum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([CH:12]2[CH:16]=[N:15][N:14]=[N:13]2)=[CH:8][C:4]=1[C:5](O)=[O:6].C(Cl)(=O)C([Cl:20])=O>CN(C)C=O.ClCCl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([CH:12]2[CH:16]=[N:15][N:14]=[N:13]2)=[CH:8][C:4]=1[C:5]([Cl:20])=[O:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc(C2C=NN=N2)cc1C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(C2C=NN=N2)cc1C(=O)Cl
Reaction time: 4 h

Procedure:
Combine 2-methoxy-5-(4H-triazol-4-yl)benzoic acid (5 mmol) and dichloromethane (40 mL). Add dropwise oxalyl chloride (0.72 mL, 8.25 mmol) followed by dimethylformamide (3 drops). After 4 hours, evaporate in vacuo and dry to give the title compound.
Reaction SMILES: N.[C:2]([CH2:5][C:6]12[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[C:13]1[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH:7]2O)([OH:4])=[O:3].[Li].C(O)C>C1COCC1>[C:2]([CH2:5][C:6]12[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[C:13]1[CH2:12][CH:11]=[CH:10][CH2:9][C:8]=1[CH2:7]2)([OH:4])=[O:3]
Reactant: O=C(O)CC12CCCCC1c1ccccc1C2O
Agent: N
Agent: [Li]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)CC12CCCCC1C1=C(CC=CC1)C2

Procedure:
To 500 ml of liquid NH3 is added a solution of 9.84 g (0.04 mole) of 9a-carboxymethyl-1,2,3,4,4a,9a-hexahydrofluoren-9-ol (JACS 82 2561 (1960)) in 100 ml of THF. The mixture is then treated portionwise with 7 g of lithium cut in small pieces followed dropwise by sufficient absolute ethanol to discharge the blue color. After NH3 has evaporated, the cooled mixture is treated with water and carefully acidified. The desired 9a-carboxymethyl-1,2,3,4,5,8,4a,9a-octahydrofluorene is isolated by extraction with ether, drying and solvent removal.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH3:13])=[C:8]([N+:14]([O-])=O)[C:7]=1[CH3:17])(=[O:3])[CH3:2].[Cl-].[NH4+]>CO.[Zn]>[C:1]([O:4][CH2:5][C:6]1[C:7]([CH3:17])=[C:8]([C:9]([CH3:13])=[CH:10][C:11]=1[CH3:12])[NH2:14])(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1c(C)cc(C)c([N+](=O)[O-])c1C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: CC(=O)OCc1c(C)cc(C)c(N)c1C
Yield: 72.8 %

Procedure:
To a solution of 1-acetoxymethyl-3-nitro-2,4,6-trimethybenzene (6.0 g, 25.2 mmol) in methanol (100 mL) were sequentially added ammonium chloride (2.7 g in 25 mL of water), zinc powder (11 g). The exothermic reaction was vigorously stirred until it was back to RT (2 h). To work up the crude mixture was filtered off and the cake was washed with methanol. The methanolic solutions were concentrated to a volume of 20 mL, added 1N HCl (300 mL). The insoluble material was removed by filtration, the solution was basified with solid NaHCO3. The semicrystalline precipitate was taken into ethyl acetate. The extract was concentrated and the residual product purified by means of column chromatography (25% ethyl acetate/hexane) to give 3-Acetoxymethyl-2,4,6-trimethylaniline as a pink oil (3.8 g, 75%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:17]1[N:22]=[CH:21][N:20]=[C:19]2[N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[N:24]=[CH:25][C:18]=12.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([N:14]([CH3:15])[C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[N:24]=[CH:25][C:18]=23)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN[C@@H]1CCCN(Cc2ccccc2)C1
Reactant: C[Si](C)(C)CCOCn1ncc2c(Cl)ncnc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(c1ncnc2c1cnn2COCC[Si](C)(C)C)[C@@H]1CCCN(Cc2ccccc2)C1
Temperature: 60 °C
Reaction time: 8 h
Yield: 50.6 %

Procedure:
To a solution of (R)-1-benzyl-N-methylpiperidin-3-amine (500 mg, 2.4 mmol) and 4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidine (697 mg, 2.4 mmol) in DMF (10 mL) was added DIEA (1.26 g, 9.7 mmol) and the reaction mixture was stirred at 60° C. overnight. The reaction mixture was diluted with EtOAc (40 mL) and was washed with water (3×20 mL). The EtOAc layer was dried over Na2SO4 and evaporated in vacuo to give a residue that was purified by column chromatography (silica gel, gradient EtOAc in hexanes) to afford the titled intermediate (550 mg, 49%). 1H NMR (400 MHz, CDCl3): δ 8.37 (s, 1H), 7.98 (s, 1H), 7.34-7.20 (m, 5H), 5.71 (s, 2H), 3.62 (t, J=8.0 Hz, 2H), 3.55 (m, 2H), 3.24 (s, 3H), 2.91 (m, 2H), 2.17 (m, 1H), 1.99 (m, 2H), 1.79 (m, 2H), 1.41 (m, 1H), 1.27 (m, 1H), 0.92 (t, J=8.0 Hz, 2H), −0.054 (s, 9H). LC-MS: m/z [M+1]=453.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.CO[CH:14](OC)[CH2:15]Br.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C@@H:26]2[C@:28]3([C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[NH:30][C:29]3=[O:37])[CH2:27]2)=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C@H:26]2[C@@:28]3([C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]([CH2:14][CH2:15][N:8]4[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][N:2]([CH3:11])[CH3:1])[CH2:6][CH2:7]4)[C:29]3=[O:37])[CH2:27]2)=[CH:24][CH:25]=1
Reactant: O=C1Nc2ccccc2[C@@]12C[C@@H]2c1ccc(Cl)cc1
Reactant: COC(CBr)OC
Reactant: CN(C)CCN1CCNCC1
Product: CN(C)CCN1CCN(CCN2C(=O)[C@@]3(C[C@H]3c3ccc(Cl)cc3)c3ccccc32)CC1

Procedure:
The title compound was prepared in analogy to Example 74 starting from 1-(2-Dimethylamino-ethyl)-piperazine, bromoacetaldehyde dimethyl acetal (commercially available), (1R,2S) and (1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3′-indolin]-2′-one prepared as in Scheme 1. LC/MS m/e calcd. for C26H33ClN4O: 452, observed (M+H)+: 453.1 1HNMR (400 MHz, MeOD-d4) δppm 2.15-2.33 (m, 3 H) 2.86 (t, J=5.81 Hz, 3 H) 2.96 (s, 6 H) 3.27 (t, J=8.59 Hz, 3 H) 3.45-3.76 (m, 3 H) 4.32 (d, J=48.76 Hz, 3 H) 6.12 (d, J=7.58 Hz, 1 H) 6.81 (t, J=7.20 Hz, 1 H) 7.11-7.19 (m, 1 H) 7.20-7.28 (m, 3 H) 7.30-7.41 (m, 2 H).
Reaction SMILES: OC[C:3]1[N:7]([C:8]2[CH:9]=[C:10]([C:14]3[CH2:20][C:19](=[O:21])[NH:18][C:17]4[CH:22]=[C:23]([CH3:32])[C:24]([N:26]([CH2:28][CH:29]([CH3:31])[CH3:30])[CH3:27])=[CH:25][C:16]=4[N:15]=3)[CH:11]=[CH:12][CH:13]=2)[N:6]=[N:5][CH:4]=1.S(Cl)(Cl)=O.[Cl-].N1[CH2:42][CH2:41][CH2:40][CH2:39]1.[CH3:43][N:44](C=O)C>ClCCl>[CH2:28]([N:26]([CH3:27])[C:24]1[C:23]([CH3:32])=[CH:22][C:17]2[NH:18][C:19](=[O:21])[CH2:20][C:14]([C:10]3[CH:11]=[CH:12][CH:13]=[C:8]([N:7]4[C:3]([CH2:4][N:5]5[CH2:39][CH2:40][CH2:41][CH2:42]5)=[N:44][CH:43]=[N:6]4)[CH:9]=3)=[N:15][C:16]=2[CH:25]=1)[CH:29]([CH3:31])[CH3:30]
Reactant: C1CCNC1
Reactant: CN(C)C=O
Reactant: Cc1cc2c(cc1N(C)CC(C)C)N=C(c1cccc(-n3nncc3CO)c1)CC(=O)N2
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1cc2c(cc1N(C)CC(C)C)N=C(c1cccc(-n3ncnc3CN3CCCC3)c1)CC(=O)N2

Procedure:
The title compound was prepared from 4-[3-(5-hydroxymethyl-[1,2,3]triazol-1-yl)-phenyl]-7-(isobutyl-methyl-amino)-8-methyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 132) (180 mg, 0.42 mmol) by reaction with thionylchloride in dichloromethane and subsequent treatment of the corresponding chloride with pyrrolidine in DMF according to the method described in Example 45. Obtained as an off-white solid (106 mg, 52%).
Reaction SMILES: [C:1]1(=O)[O:5][CH2:4][CH2:3][O:2]1.[F:7][C:8]([F:32])([F:31])[C:9]1[N:13]2[N:14]=[C:15]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:29]=[CH:28]C(O)=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)[CH:16]=[CH:17][C:12]2=[N:11][N:10]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:32][C:8]([F:7])([F:31])[C:9]1[N:13]2[N:14]=[C:15]([N:18]3[CH2:19][CH2:20][CH:21]([C:24]4[CH:29]=[CH:28][C:1]([O:2][CH2:3][CH2:4][OH:5])=[CH:26][CH:25]=4)[CH2:22][CH2:23]3)[CH:16]=[CH:17][C:12]2=[N:11][N:10]=1
Reactant: O=C1OCCO1
Reactant: Oc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCOc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Temperature: 80 °C
Reaction time: 20 h
Yield: 71.6 %

Procedure:
A solution of ethylene carbonate (18.18 g, 206.42 mmol) in DMF (30 mL) was added dropwise to a stirred suspension of 4-{1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenol (obtained as described in Example 4.2, preparation of starting materials) (15 g, 41.28 mmol) and potassium carbonate (11.41 g, 82.57 mmol) in DMF (30 mL) at 80° C. over a period of 10 minutes under nitrogen. The resulting mixture was stirred at 80° C. for 20 hours. The reaction mixture was cooled to room temperature then concentrated and diluted with DCM (500 mL), and washed sequentially with water (500 mL) and saturated brine (250 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 70 to 100% EtOAc in isohexane. Pure fractions were evaporated to dryness to give 2-(4-{1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenoxy)ethanol (12.04 g, 71.6%) as a solid.
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[CH3:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[Cl:16])[CH2:9][C:8]1=O.CN([CH:21]=[O:22])C>>[CH3:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[Cl:16])[C:9]([CH:21]=[O:22])=[C:8]1[Cl:3]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN(C)C=O
Reactant: CN1C(=O)Cc2cccc(Cl)c21
Product: Cn1c(Cl)c(C=O)c2cccc(Cl)c21
Yield: 72 %

Procedure:
Prepared from POCl3 (17 ml), DMF (17 ml), (44) (7.5 g), yielding (47) 6.8 g (72%). M.p. 185°-187° C. In this reaction the reaction time was 48 h instead of 3 h.
Reaction SMILES: O.[N:2]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][C:6]=1[C:15]([OH:17])=[O:16])=[N+:3]=[N-:4].O[N:19]1[C:23](=[O:24])[CH2:22][CH2:21][C:20]1=[O:25]>CN(C=O)C>[N:2]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][C:6]=1[C:15]([O:17][N:19]1[C:23](=[O:24])[CH2:22][CH2:21][C:20]1=[O:25])=[O:16])=[N+:3]=[N-:4]
Reactant: [N-]=[N+]=Nc1c(C(=O)O)cnc2ccccc12
Reactant: O=C1CCC(=O)N1O
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=Nc1c(C(=O)ON2C(=O)CCC2=O)cnc2ccccc12
Reaction time: 0.5 h

Procedure:
4-Azido-3-quinolinic acid monohydrate (2.3 g; 0.01 M) was suspended at ambient temperatures in dry DMF (25 ml). N-hydroxysuccinimide (1.2 g; 0.01 M) was added and the resulting mixture cooled to 0°-5° C. N,N-dicyclohexylcarbodi-imide (2.3 g; 0.11 M) was added and the mixture stirred at 0°-5° C. for 1/2 hr. then at ambient temperatures for 4 days. The insoluble material was removed by filtration and the filtrate evaporated to dryness in vacuo. The residual solid was recrystallized from iso-propyl alcohol as a light-brown, crystalline solid, 2.5 g. (80%), m.p. 173°-5° C. (dec.)(Found: C, 53.71; H, 2.80; N, 22.47%. C14H9N5O4 requires: C, 54.02; H, 2.89; N, 22.47%), νmax (KBr), 2120, 1790, 1760, 1730, 1490, 1390, 1370, 1202, 890, 780, 640cm-1, δ[(CD3)2SO] 2.9(s)(CH2CH2), 7.57-8.4(m), 9.18(s) (aromatic protons), m/e 311(M+)
Reaction SMILES: [Li].[N:2]([N:4]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:5][CH2:6][OH:7])=O.O1CCCC1.CO>O>[C:8]([N:4]([CH2:5][CH2:6][OH:7])[NH2:2])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)N(CCO)N=O
Agent: [Li]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C)N(N)CCO
Temperature: 60 °C

Procedure:
A total of 12.2 g of lithium alanate are added in portions to a mixture of 23 g of N-nitroso-tert.-butyl-(2-hydroxy-ethyl)amine and 200 ml of anhydrous tetrahydrofuran at 60° C. When the addition has ended, the mixture is heated at 60° C. for a further hour and cooled in an ice bath and the excess lithium alanate is hydrolysed by careful dropwise addition of methanol and then water. The solids are removed by filtration with suction and the filtrate is concentrated. A colourless oil (14 g) remains and is subsequently used without further purification.