Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5](C(O)=O)=[CH:4][N:3]=1.[C:11](Cl)(=[O:15])C(Cl)=O.[F:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1>ClCCl.CN(C)C=O>[F:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][C:11]([C:2]2([Cl:1])[N:3]=[CH:4][CH:5]=[CH:6][NH:7]2)=[O:15])=[CH:20][CH:19]=1
Reactant: O=C(O)c1cnc(Cl)nc1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Nc1ccc(F)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(F)cc1)C1(Cl)N=CC=CN1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68 %

Procedure:
2-Chloro-pyrimidine-5-carboxylic acid 1 (3.16 g, 20 mmol) was suspended in dichloromethane (40 mL), and oxalyl chloride (3.30 g, 26 mmol) was added, followed by dimethylformamide (3 drops) as catalyst. The reaction started to vigorously evolve gas. The reaction was heated to reflux for 1 hour, then allowed to cool to room temperature. 4-fluoroaniline was added, vigorous bubbling was seen again, and the reaction mixture warmed up considerably. Triethylamine was added, and a flocculent precipitate immediately formed. The reaction mixture was heated to reflux once again for another hour, removed from heat, and stirred at room temperature for 18 hours under nitrogen. The reaction was diluted with ethyl acetate (100 mL), and the organic layer washed with water, saturated sodium bicarbonate, water, 1N HCl, water, saturated sodium chloride, then dried over sodium sulfate. The liquid was filtered, and evaporated to yield 3.44 g (68%) of compound 3 as a light yellow solid. ESI-MS m/z=252.0 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH:5]([O:9][CH2:10][CH3:11])[C:6]([OH:8])=O)[CH3:2].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.Cl.[NH2:41][CH2:42][C:43]1[CH:50]=[CH:49][C:46]([C:47]#[N:48])=[CH:45][CH:44]=1.C(N(C(C)C)C(C)C)C>C1COCC1>[CH2:1]([O:3][C:4](=[O:12])[CH:5]([O:9][CH2:10][CH3:11])[C:6]([NH:48][CH2:47][C:46]1[CH:49]=[CH:50][C:43]([C:42]#[N:41])=[CH:44][CH:45]=1)=[O:8])[CH3:2]
Reactant: CCOC(=O)C(OCC)C(=O)O
Reactant: N#Cc1ccc(CN)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(OCC)C(=O)NCc1ccc(C#N)cc1
Reaction time: 24 h
Yield: 78.5 %

Procedure:
A solution under N2 of (RS)-2-ethoxy-malonic acid monoethyl ester (666 mg, 1.0) in THF (37 ml) was prepared. BOP (2.17 g), 4-aminomethyl-benzonitrile hydrochloride (555 mg) and N-ethyldiisopropylamine (733 mg) were added at 0° C. The ice bath was removed and the reaction was let to stir 24 h. THF was evaporated and the mixture was diluted with EtOAc. This organic phase was washed with a sat. aq. NaHCO3 sol. and with brine. The aqueous phases were extracted with one more portion of EtOAc and dried over MgSO4. The solvent was evaporated. The crude product was purified by flash chromatography. (heptane/EtOAc 3:1 to 2:1). 750 mg (68%) of (RS)-N-(4-cyano-benzyl)-2-ethoxy-malonamic acid ethyl ester were isolated as a yellow oil. MS 308.4 (100, [M+NH4]+), 291.1 (88, [M+H]+).
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11](=[O:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][C:3]=1[O:18]C.C(#N)C.[I-].[Na+].[Si](Cl)(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[OH:18][C:3]1[CH:4]=[C:5]([C:11](=[O:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[OH:1]
Reactant: CCOC(=O)C(=O)c1cc(OC)c(O)c([N+](=O)[O-])c1
Agent: Cl[Si](Cl)(Cl)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=O)c1cc(O)c(O)c([N+](=O)[O-])c1

Procedure:
A suspension of 17.2 g of ethyl 4-hydroxy-3-methoxy-5-nitrophenylglyoxylate in 100 of dry acetonitrile and 100 ml of dry toluene is treated with 10.53 g of sodium iodide and 11.9 g of silicon tetrachloride and heated under reflux for 47 hours. The reaction mixture is then evaporated and the residue is distilled six times with 200 ml of toluene each time. The residue obtained is partitioned between water and ether and filtered through a filter aid of diatomaceous earth. The ethereal phase is washed four times with saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated. The oily residue is treated three times with ether and active carbon. There is obtained ethyl 3,4-dihydroxy-5-nitrophenylglyoxylate of m.p. 77°-79° (from ether/n-hexane).
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6](Cl)[N:5]=[C:4]([CH:10]([F:12])[F:11])[N:3]=1.[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.CCN(C(C)C)C(C)C.ClCl.[NH2:31][NH2:32]>CS(C)=O>[F:11][CH:10]([F:12])[C:4]1[N:5]=[C:6]([NH:31][NH2:32])[C:7]([F:8])=[C:2]([N:17]2[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH2:16]2)[N:3]=1
Reactant: CN1CCNCC1
Reactant: NN
Reactant: Fc1c(Cl)nc(C(F)F)nc1Cl
Agent: ClCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2nc(C(F)F)nc(NN)c2F)CC1
Temperature: 25 °C
Yield: 55.9 %

Procedure:
4,6-Dichloro-2-(difluoromethyl)-5-fluoropyrimidine (200 mg, 0.92 mmol) was dissolved in DMSO (5 mL) and stirred at room temperature. N-methylpiperazine (110 μL, 0.96 mmol) was added, followed by DIPEA (500 μL, 2.9 mmol). The resulting mixture was stirred at room temperature for 1 hour, until the N-methylpiperazine displacement of one chlorine was complete as determined by LCMS. Hydrazine (1 mL, 31 mmol) was added and the reaction was stirred overnight at room temperature. The crude reaction mixture was purified by RP-HPLC to provide 2-(difluoromethyl)-5-fluoro-4-hydrazino-6-(4-methyl-1-piperazinyl)pyrimidine (142 mg, 56%). LCMS: (M+H)+: 277.0.
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[CH:7]=[C:6]([CH3:17])[C:3]=1[C:4]#[N:5].Cl.[F:19][C:20]1[CH:29]=[CH:28][C:23]([O:24][CH2:25][CH2:26][NH2:27])=[CH:22][CH:21]=1.C(=O)([O-])O.[Na+].CS(C)=O>O>[F:19][C:20]1[CH:29]=[CH:28][C:23]([O:24][CH2:25][CH2:26][NH:27][C:2]2[N:9]=[C:8]([NH:10][C:11]3[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=3)[CH:7]=[C:6]([CH3:17])[C:3]=2[C:4]#[N:5])=[CH:22][CH:21]=1
Reactant: NCCOc1ccc(F)cc1
Reactant: Cc1cc(Nc2cc(C)c(C#N)c(Cl)n2)n[nH]1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(Nc2cc(C)c(C#N)c(NCCOc3ccc(F)cc3)n2)n[nH]1
Temperature: 100 °C
Reaction time: 27 h
Yield: 4.3 %

Procedure:
Compound A (200 mg, 813 mmol), 2-(4-fluorophenoxy)ethylamine hydrochloride (466 mg) and sodium hydrogencarbonate (683 mg) were added to DMSO (6 ml), and the mixture was stirred at 100° C. for 27 hr. After stirring, the reaction mixture was added to cold water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and concentrated, and the residue was washed by suspending in ethyl acetate to give the object compound of 2-(2-(4-fluorophenoxy)ethylamino)-6-(5-methyl-1H-pyrazol-3-ylamino)-4-methylnicotinonitrile (38 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:11]=[CH:10][C:9](=[O:12])[N:8]([CH2:13][CH:14]=O)[C:7]=2[N:16]=1.[NH:17]1[CH2:22][CH2:21][CH2:20][C@@H:19]([CH2:23][NH:24][C:25](=[O:34])[O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:18]1.[O-]S([O-])(=O)=O.[Na+].[Na+].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:11]=[CH:10][C:9](=[O:12])[N:8]([CH2:13][CH2:14][N:17]3[CH2:22][CH2:21][CH2:20][C@@H:19]([CH2:23][NH:24][C:25](=[O:34])[O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:18]3)[C:7]=2[N:16]=1
Reactant: COc1ccc2ncc(=O)n(CC=O)c2n1
Reactant: O=C(NC[C@@H]1CCCNC1)OCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc2ncc(=O)n(CCN3CCC[C@@H](CNC(=O)OCc4ccccc4)C3)c2n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
[6-(Methyloxy)-3-oxopyrido[2,3-b]pyrazin-4(3H)-yl]acetaldehyde (for a preparation see Example 126(e)) (0.30 g, 1.36 mmol) was combined with phenylmethyl [(3R)-3-piperidinylmethyl]carbamate (for a preparation see Example 92(b)) (0.337 g, 1.36 mmol) in a 1:1 MeOH/DCM solution (30 mL). Excess Na2SO4 was added as a drying agent and the solution was stirred at ambient temperature for 16 h. NaBH(OAc)3 (0.86 g, 4.08 mmol) was added and the reaction was stirred an additional 2 h. The resulting solution was concentrated onto silica gel under vacuum and the crude residue was purified by column chromatography (silica gel) using a DCM/DCM-MeOH—NH4OH (90:10:1) gradient to yield the desired product as an off white solid (0.37 g, 61%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([NH2:13])=[O:12])=[C:7]2[S:14]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)(=[O:16])=[O:15].C(N(CC)CC)C.[C:30](OC(=O)C)(=[O:32])[CH3:31]>ClCCl>[C:30]([NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([NH2:13])=[O:12])=[C:7]2[S:14]([N:17]1[CH2:18][CH2:19][O:20][CH2:21][CH2:22]1)(=[O:16])=[O:15])(=[O:32])[CH3:31]
Reactant: NC(=O)c1[nH]c2c(N)cccc2c1S(=O)(=O)N1CCOCC1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1cccc2c(S(=O)(=O)N3CCOCC3)c(C(N)=O)[nH]c12
Reaction time: 2 h

Procedure:
To a solution of 7-amino-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide from Example 7 (52 mg, 0.16 mmol) in 1 mL of dichloromethane at 0° C. was added triethylamine (0.067 mL, 0.91 mmol) and acetic anhydride (0.058 mL, 0.52 mmol). After two hours, the mixture was partitioned between ethyl acetate and 3N HCl solution, and the organic layer was washed with saturated NaHCO3 solution and brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide the titled compound. HRMS (ES) exact mass calculated for C15H18N4O5SNa (M+Na+): 389.0890. Found 389.0889.
Reaction SMILES: O[CH2:2][N:3]1[CH:7]=[CH:6][C:5]([CH:8]=[O:9])=[N:4]1.S(Cl)([Cl:12])=O>ClCCl>[ClH:12].[Cl:12][CH2:2][N:3]1[CH:7]=[CH:6][C:5]([CH:8]=[O:9])=[N:4]1
Reactant: O=Cc1ccn(CO)n1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cl
Product: O=Cc1ccn(CCl)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.21 g of 1-(hydroxymethyl)-3-formyl-1H-pyrazole was dissolved to 50 ml of dichloromethane. 2.4 ml of thionyl chloride was added to the solution, followed by stirring at room temperature for overnight. The reaction mixture was concentrated under reduced pressure to obtain 1.57 g of 1-(chloromethyl)-3-formyl-1H-pyrazole hydrochloride.
Reaction SMILES: [CH2:1]([P:5]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[Cl:14][CH:15]([CH3:19])[C:16]([OH:18])=[O:17].P>CC(C)=O>[Cl-:14].[CH2:10]([P+:5]([CH2:1][CH2:2][CH2:3][CH3:4])([CH2:6][CH2:7][CH2:8][CH3:9])[CH:15]([C:16]([OH:18])=[O:17])[CH3:19])[CH2:11][CH2:12][CH3:13]
Reactant: CCCCP(CCCC)CCCC
Reactant: CC(Cl)C(=O)O
Agent: P
Solvent: CC(C)=O
Product: CCCC[P+](CCCC)(CCCC)C(C)C(=O)O
Product: [Cl-]

Procedure:
Tri-n-butyl phosphine (20.27 g, 25 ml, 0.1 mole) was added dropwise to a rapidly stirred solution of 2-chloropropanoic acid (10.85 g, 9.1 ml, 0.1 mole) in 31 ml of acetone. The reaction was, of course, exothermic, and the addition of the phosphine was maintained at a rate such that the temperature did not exceed about 35° C. After the addition was complete, the acetone solvent was removed under reduced pressure leaving a viscous liquid having an infrared spectrum and elemental analysis corresponding to the formula ##STR13##
Reaction SMILES: C[C:2](C)([O-:4])C.[K+].[Cl:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].C(OCC)=O.Cl>C1COCC1.C(OCC)C>[Cl:7][CH:8]([CH:2]=[O:4])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CC(C)(C)[O-]
Reactant: CCOC(=O)CCl
Agent: Cl
Agent: [K+]
Solvent: CCOC=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)C(Cl)C=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a three neck 2 L round bottom flask charged with potassium t-butoxide (0.5 mol, 500 mL of a 1M solution in THF) and 500 mL of dry THF cooled to 0° C. was added dropwise from an addition funnel a solution of ethyl chloroacetate (0.5 mol, 53.5 mL) and ethyl formate (0.5 mol, 40.4 mL), in 200 mL of THF over 3 hours. After completion of addition, the reaction mixture was stirred for 1 hour and allowed to stand overnight. The resulting solid was diluted with diethyl ether and cooled in an ice bath. Then, the pH was lowered to approximately 3 using 6N HCl. The organic phase was separated, and the aqueous layer was washed 3 times with diethyl ether. The combined ethereal portions were dried over NaSO4, and concentrated in vacuo. The crude desired compound was stored at -30° C. and used without further purification.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10](Cl)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:15]1[C:19]2=[N:20][CH:21]=[CH:22][CH:23]=[C:18]2[CH:17]=[CH:16]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CS(C)=O>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]1[CH2:9][N:15]1[C:19]2=[N:20][CH:21]=[CH:22][CH:23]=[C:18]2[CH:17]=[CH:16]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClC1CCCN(Cc2ccccc2)C1
Reactant: c1cnc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: c1ccc(CN2CCCC2Cn2ccc3cccnc32)cc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 60 %

Procedure:
A mixture of 1-benzyl-3-chloropiperidine (3.83 g, 18.3 mmol), 1H-pyrrolo[2,3-b]pyridine (4.4 g, 36.5 mmol) and cesium carbonate (17.8 g, 54.8 mmol) in DMSO is stirred at 80° C. under a nitrogen atmosphere for 24 h. The reaction is monitored by thin layer chromatography. Two additional amounts of 1-benzyl-3-chloro-piperidine (3.83 g and 1.91 g) are added at 12 h intervals. After 48 h, the mixture is cooled, treated with water and extracted with ethyl acetate. The extracts are combined, washed sequentially with water and brine and concentrated in vacuo. The resultant residue is purified by flash chromatography (4-5% methanol in CH2Cl2 as eluent) to afford the title compound as an oil, 6.5 g (60% yield), identified by HNMR and mass spectral analyses.
Reaction SMILES: [N:1]1([C:10](=O)[CH2:11][N:12]2[CH2:17][CH2:16][O:15][C@@H:14]([CH2:18][O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22]N=3)[CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[C:27]1(O)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[N:1]1([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][O:15][C@H:14]([CH2:18][O:19][C:20]3[CH:27]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: Oc1ccccc1
Reactant: O=C(CN1CCO[C@@H](COc2ccccn2)C1)N1CCc2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1ccc(OC[C@@H]2CN(CCN3CCc4ccccc43)CCO2)cc1
Yield: 41.4 %

Procedure:
Compound 19s was synthesised by essentially the same procedure as compound 18s (Example 16), using compound 51 (Example 12; 52 mg, 0.2 mmol), phenol (28 mg, 0.3 mmol), triphenylphosphine (78 mg, 0.3 mmol), DEAD (0.05 ml, 0.3 mmol), THF (1 ml). The crude residue was purified twice by flash chromatography to afford the title compound as a colourless oil (28 mg; 41%). Analyses were performed on the free base, and it was converted to the HCl salt for testing.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[S:7]1(=[O:17])=[O:16].C(N(C(C)C)C(C)C)C.[CH2:27]([NH:34][CH2:35][CH:36]1[CH2:45][CH:44]([O:46][Si:47]([C:50]([CH3:53])([CH3:52])[CH3:51])([CH3:49])[CH3:48])[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[O:37]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O>CN1CCCC1=O>[CH2:27]([N:34]([CH2:35][CH:36]1[CH2:45][CH:44]([O:46][Si:47]([C:50]([CH3:53])([CH3:52])[CH3:51])([CH3:48])[CH3:49])[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[O:37]1)[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[S:7]1(=[O:17])=[O:16])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CC(C)(C)[Si](C)(C)OC1CC(CNCc2ccccc2)Oc2ccccc21
Reactant: O=C1c2ccccc2S(=O)(=O)N1CCCCBr
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)OC1CC(CN(CCCCN2C(=O)c3ccccc3S2(=O)=O)Cc2ccccc2)Oc2ccccc21
Temperature: 120 °C
Reaction time: 3 h

Procedure:
380 mg (1.19 mmol) of 2-(4-bromobutyl)-1,1-dioxo-1,2-dihydro-1λ6-benzo[d]isothiazol-3-one and 263 μl (1.51 mmol) of N-ethyldiisopropylamine are added to a solution of 224 mg (0.58 mmol) of benzyl-[4-(tert-butyldimethylsilanyloxy)chroman-2-ylmethyl]amine in 1.25 ml of dry N-methylpyrrolidinone. The reaction mixture is stirred at 120° C. for 3 hours. After cooling to room temperature, 2 ml of water are added, resulting in the precipitation of a dark, viscous product. The supernatant is decanted and the residue is washed twice with in each case 1.5 ml of water. The product is then dissolved in 3 ml of dichloromethane, the residue water is removed by drying and the solution is evaporated to dryness. The crude product is purified by HPLC chromatography under the following conditions: column Nucleosil® 100 C-18, 125×16 mm (particle size 7 μm), column temperature room temperature, mobile phase 85% acetonitrile/15% water (v/v), flow rate 6 ml/min, UV detection at 230 nm. The product-containing fractions are combined and evaporated to dryness. The residue is dissolved in 2.5 ml of ethanol and 6 ml of acetone and again evaporated to dryness. The product is dried in a desiccator over blue gel.
Reaction SMILES: Cl[CH2:2][CH:3]=[C:4]([CH3:7])[CH:5]=[CH2:6].[CH3:8][C:9]([CH3:14])([CH3:13])[C:10](=[O:12])[CH3:11].[OH-].[K+]>C1(C)C=CC=CC=1>[CH3:8][C:9]([CH3:14])([C:10](=[O:12])[CH2:11][CH2:2][CH:3]=[C:4]([CH3:7])[CH:5]=[CH2:6])[CH3:13]
Reactant: CC(=O)C(C)(C)C
Reactant: C=CC(C)=CCCl
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: C=CC(C)=CCCC(=O)C(C)(C)C
Yield: 78.6 %

Procedure:
According to the procedure described in Example 7, from 116 g of 1-chloro-3-methyl-2,4-pentadiene and 100 g of 3,3-dimethyl-butan-2-one in the presence of 200 g of powdered potassium hydroxide in 600 ml of toluene there are obtained 141 g of crude 2,2,7-trimethyl-6,8-nonadien-3-one which are subjected to a fractional distillation.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][N:9]([C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=3)[CH2:10]2)=[CH:5][C:4]=1[O:21][CH3:22])=[O:2].S(=O)(=O)(O)[OH:24].C([O-])([O-])=O.[K+].[K+]>>[CH:1]([C:3]1[C:4]([O:21][CH3:22])=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][CH2:10][N:9]([C:13]1[CH:14]=[CH:15][C:16]([C:17]([NH2:18])=[O:24])=[CH:19][CH:20]=1)[CH2:8]2)=[O:2]
Reactant: COc1cc2c(cc1C=O)CN(c1ccc(C#N)cc1)CC2
Reactant: O=S(=O)(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc2c(c1C=O)CCN(c1ccc(C(N)=O)cc1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.7 %

Procedure:
A mixture of 4-(7-formyl-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl)-benzonitrile (200 mg, 0.68 mmol) and 96% (w/w) sulfuric acid (3 mL) was stirred at room temperature overnight. The next day poured onto ice-water (10 mL), the pH was adjusted with K2CO3 to 9 and the mixture was extracted with ethyl acetate. The residue was purified by column chromatography over silica, elating with a 95:5 mixture of chloroform and methanol. In this manner the title compound (85 mg, 0.27 mmol, 39.7%) was obtained as a solid.
Reaction SMILES: Cl[C:2]1[CH:19]=[C:18](F)[C:17]([N+:21]([O-:23])=[O:22])=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[N:12][NH:13]2)=[CH:9][CH:8]=1)=[O:5].[NH4+].[OH-].[NH2:26]C1C=C(F)C([N+]([O-])=O)=CC=1C(NC1C=C2C(C=NN2)=CC=1)=O.[CH3:49][N:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1>O1CCOCC1>[NH2:26][C:18]1[C:17]([N+:21]([O-:23])=[O:22])=[CH:16][C:3]([C:4]([NH:6][C:7]2[CH:15]=[C:14]3[C:10]([CH:11]=[N:12][NH:13]3)=[CH:9][CH:8]=2)=[O:5])=[C:2]([N:53]2[CH2:54][CH2:55][N:50]([CH3:49])[CH2:51][CH2:52]2)[CH:19]=1
Reactant: CN1CCNCC1
Reactant: Nc1cc(F)c([N+](=O)[O-])cc1C(=O)Nc1ccc2cn[nH]c2c1
Reactant: O=C(Nc1ccc2cn[nH]c2c1)c1cc([N+](=O)[O-])c(F)cc1Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CN1CCN(c2cc(N)c([N+](=O)[O-])cc2C(=O)Nc2ccc3cn[nH]c3c2)CC1
Temperature: 25 °C

Procedure:
A solution of 2-chloro-4-fluoro-N-(1H-indazol-6-yl)-5-nitrobenzamide (10 mmol) in dioxane (20 mL) was reacted with aqueous NH4OH using the conditions described in Example 115. After the formation of 2-amino-4-fluoro-N-(1H-indazol-6-yl)-5-nitrobenzamide was complete, the reaction mixture was charged with N-methylpiperazine (40 mmol) (NMP). The contents were heated at reflux for 10 h, and the reaction mixture was cooled to RT. The contents were poured onto ice cold water with vigorous stirring. The solid formed was collected by filtration, washed with water, and dried in vacuo to provide the product, 4-amino-N-(1H-indazol-6-yl)-2-(4-methylpiperazin-1-yl)-5-nitrobenzamide as a yellow solid.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:22])=[CH:7][CH:6]=1)=[O:4].ClO[C:25](C)(C)C.[CH3:29][NH:30]C.O>C(#N)C>[O:22]=[C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20](=[O:21])[N:12]1[CH2:11][C:8]1[CH:7]=[CH:6][C:5]([S:3](=[N:30][CH3:29])([N:2]([CH3:25])[CH3:1])=[O:4])=[CH:10][CH:9]=1
Reactant: CNC
Reactant: CC(C)(C)OCl
Reactant: CNS(=O)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Solvent: O
Solvent: CC#N
Product: CN=S(=O)(c1ccc(CN2C(=O)c3ccccc3C2=O)cc1)N(C)C
Temperature: 0 °C

Procedure:
A mixture of 4-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-benzenesulfinic acid methylamide (preparation 60b, 250 mg, 0.795 mmol) in acetonitrile is cooled at 0° C. in an ice bath and treated with tert-butyl hypochlorite (100 μL, 0.88 mmol). After 15 min dimethylamine (2 M in tetrahydrofuran, 600 μL, 1.2 mmol) is added and the mixture is warmed to room temperature. Water is added, and the mixture is extracted twice with dichloromethane. The combined organic layers are dried over Na2SO4 and concentrated under reduced pressure. The residue is purified by flash chromatography on silica (gradient cyclohexane/ethyl acetate 7:3 to ethyl acetate). Yield: 284 mg (99% of theory). ESI mass spectrum: [M+H]+=358; r.t. HPLC: 0.43 min (X012_S01).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH2:4][CH:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][C:8](=O)[CH2:7][CH2:6]2.[CH2:14]([NH:17][CH2:18][CH2:19][CH3:20])[CH2:15][CH3:16].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>O>[CH2:14]([N:17]([CH2:18][CH2:19][CH3:20])[CH:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:9]1)[CH2:15][CH3:16]
Reactant: CCCNCCC
Reactant: COC1=CC=C2CC(=O)CCC2C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCCN(CCC)C1CCc2cc(OC)ccc2C1

Procedure:
20 g of 6-methoxytetrahydronaphthalen-2-one, 20 ml of dipropylamine and 200 mg of para-toluenesulphonic acid are introduced into 300 ml of benzene under a nitrogen atmosphere. The mixture, which has become black, is then heated under reflux for 12 hours, the water of condensation being removed by azeotropic distillation. The solution, which contains the compound (IV), is then concentrated to a volume of about 100 ml. For the hydrogenation, 150 ml of ethanol and 300 mg of PtO2 are added thereto and hydrogenation is carried out, under a pressure of about 0.3 MPa, until the absorption has stopped.
Reaction SMILES: C1[C:6]([CH2:7][C:8]2C=C[C:11]([N:14]=C=O)=CC=2)=[CH:5][CH:4]=[C:3]([N:17]=C=O)[CH:2]=1>C1(C)C=CC=CC=1>[CH:11]#[N:14].[N:17]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:2]
Reactant: O=C=Nc1ccc(Cc2ccc(N=C=O)cc2)cc1
Solvent: Cc1ccccc1
Product: C#N
Product: Cc1cccc(C)n1
Reaction time: 0.5 h

Procedure:
A solution of 21 grams (0.75 mole) of hydrogen cyanide and 85 grams of dry toluene and 10 grams of 2,6-lutidine was prepared at ice bath temperatures. To the solution, 62.5 grams (0.25 mole) of 4,4'-diphenylmethane diisocyanate in 135 grams of dry toluene were added dropwise over a period of two hours. While keeping the temperature below 10° C., a solid began to come out of solution. The reaction solution was stirred an additional 30 minutes after completion of the addition. The product (76 grams) was collected on a filter. The product was purified by dissolving it in acetone and filtering the solution into petroleum ether. The pure product melted at 208° C. Analysis calculated for C17H12N4O2 : C, 67.10; H, 3.97; N, 18.41. Found: C, 66.98; H, 4.22; N, 18.20.