Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH:7]([C:10]1[N:11]=[C:12]([C:15]([OH:17])=O)[S:13][CH:14]=1)([CH3:9])[CH3:8].C(N(C(C)C)CC)(C)C.[CH3:27][C:28]1[C:34]([O:35][CH3:36])=[CH:33][CH:32]=[C:31]([C:37](=[O:39])[CH3:38])[C:29]=1[NH2:30]>C1(C)C=CC=CC=1>[C:37]([C:31]1[CH:32]=[CH:33][C:34]([O:35][CH3:36])=[C:28]([CH3:27])[C:29]=1[NH:30][C:15]([C:12]1[S:13][CH:14]=[C:10]([CH:7]([CH3:8])[CH3:9])[N:11]=1)=[O:17])(=[O:39])[CH3:38]
Reactant: CC(C)c1csc(C(=O)O)n1
Reactant: COc1ccc(C(C)=O)c(N)c1C
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(C)=O)c(NC(=O)c2nc(C(C)C)cs2)c1C
Temperature: 25 °C
Yield: 91.3 %

Procedure:
Oxalyl chloride (5.71 g, 45 mmol., 3.0 eq) was added dropwise, at ambient temperature, to a solution of 4-isopropyl-thiazole-2-carboxylic acid (3.85 g, 22.5 mmol., 1.5 eq) in toluene (40 mL). Stirring was continued at ambient temperature until the bubbling stopped. The reaction mixture was then heated under reflux for a further 1 hour. LCMS analysis of an aliquot quenched with methanol revealed full conversion of the acid to the acid chloride. The reaction mixture was left to cool to ambient temperature and the solvent removed under vacuum. The residue was diluted with dry dioxane (40 mL). Diisopropylethylamine (3.9 g, 30 mmol., 2 eq.) was added dropwise followed by 2-methyl-3-methoxy-6-acetyl-aniline (2.7 g, 15.0 mmol., 1.0 eq). The reaction mixture was stirred at ambient temperature for 15 hours. LCMS analysis showed full conversion of the starting material to product. The solvent was removed under vacuum and the residue dissolved with ethyl acetate (75 mL). The organic layer was washed with saturated aqueous sodium hydrogen carbonate (50 mL), water (50 mL), and brine (50 mL), dried over sodium sulphate, filtered and the solvent removed under vacuum. The residue was purified by flash column chromatography using a gradient of heptanes:ethyl acetate (4:1 to 6:4). The relevant fractions were combined and the solvent removed under vacuum to give 4.55 g (91%) of the title compound as a pale yellow solid. 1H NMR (500 MHz, CDCl3) δ ppm 11.28 (br. s, 1 H), 7.76 (d, J=8.70 Hz, 1 H), 7.17 (s, 1 H), 6.79 (d, J=8.70 Hz, 1 H), 3.94 (s, 3 H), 3.23 (spt, J=6.89 Hz, 1 H), 2.59 (s, 3 H), 2.17 (s, 3 H), 1.42 (d, J=6.87 Hz, 6 H). LC-MS: 99% (UV), tR 2.24 min, m/z [M+1]+ 333.05.
Reaction SMILES: [OH-].[K+].N1C=CC=CC=1C1C=CC=CN=1.[C:15]([CH:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1)([CH3:18])([CH3:17])[CH3:16]>CC(O)C>[C:15]([C@@H:19]1[CH2:20][CH2:21][C@H:22]([OH:25])[CH2:23][CH2:24]1)([CH3:18])([CH3:16])[CH3:17].[C:15]([C@H:19]1[CH2:20][CH2:21][C@H:22]([OH:25])[CH2:23][CH2:24]1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)C1CCC(=O)CC1
Agent: [K+]
Agent: [OH-]
Agent: c1ccc(-c2ccccn2)nc1
Solvent: CC(C)O
Product: CC(C)(C)[C@H]1CC[C@@H](O)CC1
Product: CC(C)(C)[C@H]1CC[C@H](O)CC1
Reaction time: 18 h

Procedure:
RuClCp* (cod) (3.8 mg, 0.01 mmol), KOH (0.04 mmol), 2,2′-bipyridyl (3.1 mg, 0.02 mmol) and 4-t-butylcyclohexanone (385.63 mg, 2.5 mmol) were dissolved into 10 ml of 2-propanol, and deaerated by argon substitution, after which the total amount of the resulting mixture was transferred into a 100-milliliter metallic autoclave. Then, the reaction was started at room temperature (28° C.) while conducting argon substitution. After the reaction solution was stirred for 18 hours, the reaction produces, cis-4-t-butylcyclohexanol (yield 8.6%) and trans-4-t-butylcyclohexanol (yield 21.1%), were identified and quantitatively determined by TLC monitor (silica gel: n-hexane/ethyl acetate=4/1) and gas chromatography of the reaction solution. Here, 35.0% of the raw material, 4-t-butylcyclohexanone, was recovered.
Reaction SMILES: N(S([O-])(=O)=O)(S([O-])(=O)=[O:4])[O].[K+].[K+].[N+:13]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])C=1CC#N)([O-:15])=[O:14].C([O:30][CH2:31][CH3:32])C>C(=O)([O-])[O-].[Na+].[Na+].C(#N)C>[N+:13]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[C:32]=1[C:31]([OH:30])=[O:4])([O-:15])=[O:14]
Reactant: N#CCc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: CCOCC
Reactant: [O]N(S(=O)(=O)[O-])S(=O)(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Product: O=C(O)c1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reaction time: 3.5 h
Yield: 90 %

Procedure:
Potassium nitrosodisulfonate (13.4 g, 50 mmol) in 500 mL of 4% aqueous sodium carbonate solution is added to a 1 L Erlenmeyer flask equipped with a large magnetic stir bar. Then, with stirring, a solution of 2,6-dinitrophenylacetonitrile (2.07 g, 10 mmol) in 50 mL of acetonitrile is gradually added over the course of 20 min at ambient temperature. Stirring continued for 3.5 h. Three separate sequential portions of additional potassium nitrosodisulfonate (2.6 g, 9.7 mmol) are added at time points 0.5 h, 1 h and 2 h, and stirred for 3.5 h in total. Diethyl ether (100 mL) is then added to the reaction and is stirred at ambient temperature for 1 h. The layers are separated and the ether layer is discarded. The aqueous layer is cautiously acidified with cone. HCl to pH 2, and 150 mL of diethyl ether is added to the mixture with stirring at ambient temperature for 0.5 h. The layers are separated and the aqueous layer is further extracted with 100 mL and 50 mL portions of diethyl ether. The combined ether layers are dried over magnesium sulfate, filtered and evaporated to afford 1.91 g (90% yield) of the 2,6-dinitrobenzoic acid.
Reaction SMILES: [NH:1]([C:8]1[CH:16]=[C:15]([C:17](O)=[O:18])[C:14]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:13][C:9]=1[C:10](O)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(=O)(O)(O)O.CO>O.CCN1C2C(=CC3N=C4C(=C(Cl)C5C(=C4Cl)OC4C=C6N(CC)C7C(=CC=CC=7)C6=CC=4N=5)OC=3C=2)C2C1=CC=CC=2>[CH:24]1[CH:25]=[C:26]2[C:17]([C:15]3[C:14]([NH:20][C:21]2=[CH:22][CH:23]=1)=[CH:13][C:9]1[C:10]([C:7]2[C:2]([NH:1][C:8]=1[CH:16]=3)=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:11])=[O:18]
Reactant: O=C(O)c1cc(Nc2ccccc2)c(C(=O)O)cc1Nc1ccccc1
Agent: CCn1c2ccccc2c2cc3c(cc21)Oc1c(Cl)c2c(c(Cl)c1=N3)Oc1cc3c(cc1N=2)c1ccccc1n3CC
Agent: O=P(O)(O)O
Solvent: CO
Solvent: O
Product: O=c1c2ccccc2[nH]c2cc3c(=O)c4ccccc4[nH]c3cc12
Temperature: 95 °C
Reaction time: 0.25 h
Yield: 92.9 %

Procedure:
To 240 g of polyphosphoric acid (116% phosphoric acid) heated at 85° C. was added 0.15 g of Carbazole Violet followed by 60 g of 2,5-dianilinoterephthalic acid. The mixture was heated at 120°-125° C. for two hours. After the melt was cooled to 95° C., the acid strength was adjusted to 110% by the dropwise addition of phosphoric acid. The resultant melt was stirred for 15 minutes and then slowly poured into 400 g of methanol at 24° C. During the drown, the temperature was allowed to increase to 60° C., with the temperature being controlled by external cooling and adjustment of melt addition rate. The slurry was heated at reflux (68°-72° C.) for one hour, diluted with water, and stirred at 60° C. for 30 minutes. The solid component was collected by filtration and washed with water until acid free. The resultant presscake was reslurried in water. After adjustment of the pH to greater than 7, 5 g of 50% sodium hydroxide was added and the resultant slurry was heated at 90° C. for two hours. The slurry was cooled, filtered, and washed with water until alkali free, then reslurried in water. After adjustment of the pH to greater than 9.0-9.5, 3.2 g of a cycloaliphatic carboxylic acid was added. The resultant slurry was heated at about 140°-145° C. for four hours in a closed system, cooled to less than 45° C., acidified with phosphoric acid, and stirred. The solid component was collected by filtration and washed with water. The wet cake can be dried or used as is for specific applications. Here, the wet cake was dried in an oven at 60° C. to give approximately 50 g of quinacridone as a violet pigment.
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([C:10]1[N:15]=[CH:14][C:13]([NH:16][CH2:17][CH:18]([NH:23]C(=O)OC(C)(C)C)[C:19]([NH:21][CH3:22])=[O:20])=[CH:12][C:11]=1[NH:31][C:32]1[CH:37]=[C:36]([CH3:38])[CH:35]=[C:34]([CH3:39])[N:33]=1)#[N:9]>C(Cl)Cl>[C:8]([C:10]1[N:15]=[CH:14][C:13]([NH:16][CH2:17][C@@H:18]([C:19]([NH:21][CH3:22])=[O:20])[NH2:23])=[CH:12][C:11]=1[NH:31][C:32]1[CH:37]=[C:36]([CH3:38])[CH:35]=[C:34]([CH3:39])[N:33]=1)#[N:9]
Reactant: CNC(=O)C(CNc1cnc(C#N)c(Nc2cc(C)cc(C)n2)c1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(=O)[C@@H](N)CNc1cnc(C#N)c(Nc2cc(C)cc(C)n2)c1
Reaction time: 0.5 h

Procedure:
TFA (1.0 ml, 13 mmol) was added to a solution of tert-butyl [3-({6-cyano-5-[(4,6-dimethylpyridin-2-yl)amino]pyridin-3-yl}amino)-1-(methylamino)-1-oxopropan-2-yl]carbamate (72 mg, 0.16 mmol) in DCM (2 ml) at room temperature. After 30 minutes, the reaction mixture was concentrated under reduced pressure to afford 3-({6-cyano-5-[(4,6-dimethylpyridin-2-yl)amino]pyridin-3-yl}amino)-N-methylalaninamide. The material was used in the next step without purification. MS ESI calc'd. for C17H22N7O [M+H]+ 340. found 340.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([C:13]3[NH:17][N:16]=[N:15][N:14]=3)[CH:10]=[CH:9][C:8]=2[NH:18][C:19]([C:21]2[NH:22][C:23]([C:26]#[N:27])=[CH:24][N:25]=2)=[O:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].Cl.Cl[CH2:36][CH2:37][N:38]([CH3:40])[CH3:39].Cl[CH2:42][CH2:43][N:44]([CH3:46])[CH3:45].CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[C:1]1([C:7]2[CH:12]=[C:11]([C:13]3[N:17]([CH2:36][CH2:37][N:38]([CH3:40])[CH3:39])[N:16]=[N:15][N:14]=3)[CH:10]=[CH:9][C:8]=2[NH:18][C:19]([C:21]2[N:22]([CH2:42][CH2:43][N:44]([CH3:46])[CH3:45])[C:23]([C:26]#[N:27])=[CH:24][N:25]=2)=[O:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CN(C)CCCl
Reactant: N#Cc1cnc(C(=O)Nc2ccc(-c3nnn[nH]3)cc2C2=CCCCC2)[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)CCn1nnnc1-c1ccc(NC(=O)c2ncc(C#N)n2CCN(C)C)c(C2=CCCCC2)c1
Temperature: 70 °C
Reaction time: 3 h
Yield: 21.3 %

Procedure:
To a solution of 5-cyano-1H-imidazole-2-carboxylic acid [2-cyclohex-1-enyl-4-(1H-tetrazol-5-yl)-phenyl]-amide (as prepared in Example 57, step (e), 37 mg, 0.10 mmol) in DMF (0.5 mL) was added K2CO3 (42 mg, 0.30 mmol) followed by 2-chloro-ethyl-dimethyl-amine hydrochloride salt (18 mg, 0.12 mmol). The reaction was heated to 70° C. After 3 h, 2-chloro-ethyl-dimethyl-amine (14.6 mg, 0.102 mmol) was again added, followed by K2CO3 (28 mg, 0.20 mmol) and the resulting mixture heated to 100° C. After 1 h, 2-chloro-ethyl-dimethyl-amine (18 mg, 0.12 mmol) and DIEA (35 μL, 0.20) were added and the resulting mixture stirred at 100° C. overnight. The mixture was poured into EtOAc (20 mL) and washed with saturated aqueous NaHCO3 (2×10 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo. Purification of the residue by preparative TLC (15% MeOH—CHCl3) afforded 10.7 mg (21%) of the title compound as a white solid. 1H-NMR (CDCl3; 400 MHz): δ 9.85 (s, 1H), 8.44 (d, 1H, J=8.5 Hz), 7.98 (dd, 1H, J=8.5, 2.0 Hz), 7.89 (d, 1H, J=1.9 Hz), 7.66 (s, 1H), 5.84 (m, 1H), 4.67 (t, 2H, J=6.7 Hz), 4.60 (t, 2H, J=5.9 Hz), 2.92 (t, 2H, J=6.7 Hz), 2.68 (t, 2H, J=5.9 Hz), 2.25 (s, 6H), 2.22 (s, 6H), 1.81-1.73 (m, 8H). Mass spectrum (ESI, m/z): Calcd. for C26H34N10O, 503.2, found 503.2.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([Br:11])=[CH:4][N:3]=1.O.O.[Sn](Cl)Cl.[BH4-].[Na+].C(OCC)(=O)C>CC(O)(C)C>[Br:11][C:5]1[CH:6]=[C:7]([NH2:8])[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Nc1ncc(Br)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Product: Nc1cc(Br)cnc1N

Procedure:
A procedure similar to that described in Preparation 42 was repeated, except that 12.0 g of 2-amino-5-bromo-3-nitropyridine (prepared as described in Preparation 56), 62.1 g of tin(II) chloride dihydrate, 1.04 g of sodium borohydride and 300 ml of a 9:1 by volume mixture of ethyl acetate and 2-methyl-2-propanol were used, to give the title compound as a crude product. This crude product was crystallized by trituration with a mixture of ethyl acetate and hexane, to give 7.46 g of the title compound, melting at 135°-137° C.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:10]=1[C:11]#[N:12].S(=O)(=O)(O)[OH:22].[OH-].[Na+]>C(O)(=O)C.O>[F:18][C:17]([F:20])([F:19])[C:15]1[CH:14]=[CH:13][C:10]2[C:11](=[O:22])[NH:12][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[S:8][C:9]=2[CH:16]=1
Reactant: N#Cc1ccc(C(F)(F)F)cc1Sc1ccccc1N
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: O=C1Nc2ccccc2Sc2cc(C(F)(F)F)ccc21
Temperature: 0 °C

Procedure:
2-(2-Aminophenylthio)-4-trifluoromethylbenzonitrile (12.5 g, 42.5 mmol) in glacial acetic acid (135 ml), water (135 ml), and concentrated sulphuric acid (135 ml) was heated to 125°-130° C. for 2.5 hr before being cooled and added to 1.5 l of ice-water and adjusted to pH 4 with sodium hydroxide solution (10N, 480 ml). The product was extracted into chloroform (1 l), dried (Na2SO4) and evaporated in vacuo. The light brown oil was placed in xylene (800 ml) and refluxed for 18 hr in a Dean-Stark apparatus. The title compound was obtained as off-white crystals (7.8 g. m.p. 216°-217° C., Rf 0.28, hexane/EtOAc 2:1) after reducing the volume to approximately 450 ml and allowing the solution to cool.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])[N:9]=1)[CH3:3].CS[C:17]1[NH:22][C:21](=[O:23])[C:20]([CH2:24][CH2:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=[CH:19][N:18]=1>N1C=CC=CC=1>[CH3:3][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:17]2[NH:22][C:21](=[O:23])[C:20]([CH2:24][CH2:25][C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)=[CH:19][N:18]=2)[N:9]=1)[CH3:1]
Reactant: CN(C)Cc1nc(CSCCN)cs1
Reactant: CSc1ncc(CCc2cccnc2)c(=O)[nH]1
Solvent: c1ccncc1
Product: CN(C)Cc1nc(CSCCNc2ncc(CCc3cccnc3)c(=O)[nH]2)cs1

Procedure:
Following the procedure of Example 12, a mixture of 1.29 g. of 2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethylamine and 1.37 g. of 2-methylthio-5-[2-(3-pyridyl)ethyl]-4-pyrimidone in 25 ml. of anhydrous pyridine was heated to refluxing temperature for about 4 days. The solvent was removed in vacuo. The residue was dissolved in ethanol and the ethanol evaporated. The residue was purified by high pressure liquid chromatography over silica using a gradient elution technique with an ethyl acetate/ethanol/ammonium hydroxide solvent system as the eluant. Fractions shown by tlc to contain the desired product were combined and the combined fractions rechromatographed on a silica preparative plate using 3% ammoniated ethanol as the solvent. 2-[2-(2-Dimethylaminomethyl-4-thiazolylmethylthio)ethyl]amino-5-[2-(3-pyridyl)ethyl]-4-pyrimidone free base thus prepared was converted by standard procedures to the trihydrochloride salt which melted at 226°-228° C. after recrystallization from an ethanol/ethyl acetate/ether solvent mixture. Yield=1.0 g.
Reaction SMILES: C(O[C:6]([NH:8][C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][N:10]=1)=O)(C)(C)C.C([Li])CCC.CN(C)C=O.Cl>O1CCCC1>[NH:8]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:14]2[CH:15]=[CH:6]1
Reactant: Cc1cccnc1NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: c1cnc2[nH]ccc2c1
Reaction time: 1 h

Procedure:
A solution of 2-(tert-butoxycarbonylamino)-3-methylpyridine (Example 2a) (104.1 g, 0.5 mol) in tetrahydrofuran (2.0 liters) was cooled to -1° C. n-Butyllithium (2.5M, 400 ml, 1.0 mol) was added over 45 minutes (temp. ≤+5° C.) and the mixture aged at 0° C. to +3° C. for 1 hour. Dimethylformamide (39.2 ml, 0.51 mol) was added in one portion (temp. -3° C. to 9.9° C.), the mixture was stirred at +6° C. to +18° C. for 1 hour. The yellow suspension was transferred by canula, over 1 hour, into cooled (2.5° C.), vigorously stirred 5.5M hydrochloric acid (500 ml) at such a rate that the temperature was maintained at ≤10° C. The flask and transfer lines were washed through with 2M hydrochloric acid (200 ml) and the stirred mixture was heated at 45°-50° C. for 2 hours.
Reaction SMILES: F[C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][C:3]=1[N+:20]([O-:22])=[O:21].[NH2:23][CH2:24][C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][CH:26]=1.CCN(C(C)C)C(C)C.O>C(#N)C>[N+:20]([C:3]1[CH:4]=[C:5]([O:6][CH2:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:18]=[CH:19][C:2]=1[NH:30][CH2:29][C:28]1[CH:31]=[CH:32][C:25]([C:24]#[N:23])=[CH:26][CH:27]=1)([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1cc(OCc2ccc3ccccc3n2)ccc1F
Reactant: N#Cc1ccc(CN)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: N#Cc1ccc(CNc2ccc(OCc3ccc4ccccc4n3)cc2[N+](=O)[O-])cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of 2-((4-fluoro-3-nitrophenoxy)methyl)quinoline (298 mg, 1 mmol) and 4-(aminomethyl)benzonitrile (132 mg, 1 mmol) in acetonitrile (1 mL) was added DIPEA (2 mL, 12 mmol). The mixture was stirred at 80° C. overnight. The mixture was cooled to RT, water (20 mL) was added, and the mixture was extracted with DCM (3×20 mL). The organics were combined, washed with brine (20 mL), dried (Na2SO4), filtered and concentrated to dryness. The residue was recrystallized from ethanol to give 4-((2-nitro-4-(quinolin-2-ylmethoxy)phenylamino)methyl)benzonitrile. The recrystallized 4-((2-nitro-4-(quinolin-2-ylmethoxy)phenylamino)methyl)benzonitrile (307 mg, 0.75 mmol) was then dissolved in ethanol (20 mL) and SnCl2.2H2O (1 g, 4.5 mmol) was added. The resulting mixture was stirred at 90° C. overnight. The mixture was cooled to RT and the pH adjusted to ˜pH 8-9 by the addition of sat. aq. NaHCO3. The aqueous mixture was stirred at RT for 30 min. and then extracted with DCM (3×20 mL). The organics were combined, washed with brine (20 mL), dried (Na2SO4), filtered and concentrated to dryness to afford the title compound, which was used without further purification. MS (ESI): mass calcd. for C24H20N4O, 380.16; m/z found, 381.0 [M+H]+.
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([CH:32]=[C:33]([C:35]([CH3:40])([CH3:39])[C:36]([NH2:38])=[O:37])[N:34]=2)[N:31]=1.C(=O)(O)[O-].[Na+]>>[ClH:25].[ClH:25].[C:19]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:26]3[CH:27]=[CH:28][C:29]4[N:30]([CH:32]=[C:33]([C:35]([CH3:40])([CH3:39])[C:36]([NH2:38])=[O:37])[N:34]=4)[N:31]=3)[CH2:11][CH2:10]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C(N)=O)c1cn2nc(Cl)ccc2n1
Reactant: NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(C)(C(N)=O)c1cn2nc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)ccc2n1
Product: Cl
Yield: 137.1 %

Procedure:
1.29 g of 4-(diphenylmethoxy)-1-piperidinepropanamine and 0.478 g of 2-(6-chloroimidazo[1,2-b]pyridazin-2-yl)-2-methylpropionamide were stirred at 190-200° C. for 70 minutes. After cooling, aqueous sodium bicarbonate was added, followed by extraction with ethyl acetate. The extract was washed with saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol:triethylamine (90:10:1). The desired fraction was collected; the residue was dissolved in 10 ml of ethyl acetate; 1.5 ml of a 4 N hydrogen chloride solution in ethyl acetate was added, followed by concentration under reduced pressure. Ethyl acetate was added to the residue; the resulting powder was collected by filtration, washed with ethyl acetate and dried to yield 0.823 g of the title compound.
Reaction SMILES: ClC1C=CC=C[C:3]=1[CH:4]=[O:5].[OH-].[Na+].[Cl:12][C:13]1[CH:23]=[CH:22][CH:21]=[CH:20][C:14]=1[CH:15]=[CH:16][C:17](=[O:19])[CH3:18].S(=O)(=O)(O)O>C(O)C.C(OCC)(=O)C.CC(C)=O>[Cl:12][C:13]1[CH:23]=[CH:22][CH:21]=[CH:20][C:14]=1[CH:15]1[CH2:3][C:4](=[O:5])[CH2:18][C:17](=[O:19])[CH2:16]1
Reactant: CC(=O)C=Cc1ccccc1Cl
Reactant: O=Cc1ccccc1Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C1CC(=O)CC(c2ccccc2Cl)C1
Temperature: 90 °C
Yield: 73.7 %

Procedure:
2-Chlorobenzaldehyde (70.3 g) was added to a mixture of acetone (294 ml) and an aqueous solution (1.4 L) of sodium hydroxide (22.0 g) and the mixture was stirred at room temperature for 5 hours. An excessive acetone was distilled off under reduced pressure, and the residue was combined with ethyl acetate (1.4 L) and extracted. The ethyl acetate layer was washed with brine and dried (anhydrous magnesium sulfate), and then ethyl acetate was distilled off under reduced pressure to obtain a crude 2-chlorobenzalacetone (94.6 g) as a yellow oil. This oil was employed in the next step without a further purification. A 20% solution of sodium ethoxide in ethanol (170.1 g) was combined with diethyl malonate (80.1 g) at room temperature (resulting in instantaneous precipitation), and then with a solution of a crude 2-chlorobenzalacetone (94.6 g) in ethanol (40 ml). The reaction mixture was stirred with heating at 90° C. for 2 hours, allowed to stand to cool, and then cooled on ice (1 hour). The precipitate was recovered by a filtration, washed successively with ethyl acetate and isopropyl ether to obtain a crude 6-(2-chlorophenyl)-2-hydroxy-4-oxo-2-cyclohexenene-1-carboxylic acid ethyl ester monosodium salt (151.0 g) as a pale yellow powder. This powder was combined with 2M sodium hydroxide (350 ml) and stirred with heating at 100° C. for 2 hours. After allowing to stand to cool, 2.5 M sulfuric acid (350 ml) was added over a period of 15 minutes, and the mixture was stirred with heating at 100° C. for 2 hours. After allowing to stand to cool, ethyl acetate (1.4 L) was added and extracted. The ethyl acetate layer was washed with brine, dried (anhydrous magnesium sulfate), and then ethyl acetate was distilled off under reduced pressure. The precipitated crystal was washed successively with ethyl acetate-isopropyl ether (1:4) and isopropyl ether to obtain 5-(2-chlorophenyl)cyclohexane-1,3-dione (82.1 g) as a colorless crystal.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([F:11])=[C:4](F)[C:3]=1[CH3:13].O.[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.Cl>C(O)C.C(N(CC)CC)C>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([F:11])=[C:4]([N:19]2[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]2)[C:3]=1[CH3:13]
Reactant: Cc1c(F)c(F)cc([N+](=O)[O-])c1Cl
Reactant: CN1CCNCC1
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1c(Cl)c([N+](=O)[O-])cc(F)c1N1CCN(C)CC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To 2-chloro-5,6-difluoro-3-nitrotoluene (54 mg) are added ethanol (0.3 ml) and water (0.03 ml) at 0° C. and thereto further added dropwise a solution of N-methylpiperazine (0.04 ml) and triethylamine (0.06 ml) in ethanol (0.1 ml) at room temperature. The mixture is stirred at room temperature for 5 hours, at 60° C. for 5 hours and further at 80° C. overnight. The reaction mixture is acidified with 2N hydrochloric acid and washed with a small amount of diethyl ether and then neutralized with aqueous saturated sodium hydrogen carbonate and extracted with dichloromethane. The extract is washed with water and aqueous saturated sodium chloride in this order and dried over anhydrous magnesium sulfate, and then dichloromethane is disilled off to give 2-chloro-5-fluoro-6-(4-methyl-1-piperazinyl)-3-nitrotoluene (35 mg).