Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=O)C=1.[CH3:12][NH:13][C:14](=[O:36])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]1[C:32]2[C:31]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[N:25]=[CH:24][C:23]=2[N:22]=[C:21]1[CH2:33][CH2:34][CH3:35].[OH-].[NH4+:38].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[NH2:38][C:24]1[C:23]2[N:22]=[C:21]([CH2:33][CH2:34][CH3:35])[N:20]([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:14]([NH:13][CH3:12])=[O:36])[C:32]=2[C:31]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N:25]=1
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCCCC(=O)NC
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCCc1nc2c(N)nc3ccccc3c2n1CCCCCC(=O)NC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
mCPBA (5.0 g, 29.03 mmol) was added to a solution of N-methyl-6-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)hexanamide (3.42 g, 9.67 mmol) in chloroform (100 mL). The reaction was stirred for two hours at ambient temperature and then washed with 10% aqueous sodium hydroxide. Ammonium hydroxide (40 mL) and p-toluenesulfonyl chloride (2.39 g, 12.6 mmol) were sequentially added, and the reaction was stirred vigorously for two hours. The organic layer was separated and washed sequentially with 10% sodium hydroxide, saturated aqueous sodium bicarbonate, and brine; dried over magnesium sulfate; filtered; and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting with 95:5 dichloromethane:methanol) followed by recrystallization from methanol:water to provide 1.055 g of 6-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)-N-methylhexanamide as beige needles, mp 158-159° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10](Br)[CH:9]=2)=[O:4].[Cl:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[F:25]>>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([C:21]1[CH:22]=[CH:23][C:24]([F:25])=[C:19]([Cl:18])[CH:20]=1)[CH:9]=2)=[O:4]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: COC(=O)c1c(O)c2ccc(Br)cc2sc1=O
Product: COC(=O)c1c(O)c2ccc(-c3ccc(F)c(Cl)c3)cc2sc1=O

Procedure:
7-(3-Chloro-4-fluoro-phenyl)-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester was prepared from 7-bromo-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester (Example 5e) and 3-chloro-4-fluoro-phenylboronic acid under conditions analogous to Example 7(a). MS ESI(+) m/e: 365.10 (M+1).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][CH:30]=1)[CH2:6][N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@@H:8]1[C:13]([NH:15][C@H:16]([C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[CH:20][CH:19]=1)[CH3:17])=[O:14].O[Li:34].O>>[F:31][C:2]([F:1])([F:32])[C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][CH:30]=1)[CH2:6][N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@@H:8]1[C:13]([NH:15][C@H:16]([C:18]1[CH:19]=[CH:20][C:21]([C:22]([O-:24])=[O:23])=[CH:26][CH:27]=1)[CH3:17])=[O:14].[Li+:34]
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCCCN2Cc2cccc(C(F)(F)F)c2)cc1
Reactant: [Li]O
Solvent: O
Product: C[C@H](NC(=O)[C@H]1CCCCN1Cc1cccc(C(F)(F)F)c1)c1ccc(C(=O)[O-])cc1
Product: [Li+]

Procedure:
The title compound (E5) (5.02 mg) was prepared according to the general procedure for esters hydrolysis starting from methyl 4-((S)-1-((R)-1-(3-(trifluoromethyl)benzyl)piperidine-2-carboxamido)ethyl)benzoate (D22) (19 mg). (LiOH H2O: 1.75 eq; reaction time: 3 hrs)
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:20]([O:22][C:23](=[O:28])[CH2:24][CH2:25][CH2:26]Br)[CH3:21]>CN(C=O)C.C(OCC)C>[CH2:20]([O:22][C:23](=[O:28])[CH2:24][CH2:25][CH2:26][O:13][C:10]1[CH:9]=[CH:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:12][CH:11]=1)[CH3:21]
Reactant: CCOC(=O)CCCBr
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 125.4 %

Procedure:
To a suspension in dry DMF of 4-phenylphenol (4.99 g,.29.4 mmol) and cesium carbonate (14.35 g, 44.0 mmol) was added ethyl-4-bromobutyrate (8.85 g, 45.3 mmol) in a single portion and the reaction mixture was stirred for 18 hours at ambient temperature. The reaction mixture was diluted with ethyl ether and extracted with pH 7 buffer. The organic phase was washed twice with brine, dried over MgSO4, filtered, and concentrated in vacuo to give 4-(4-phenylphenoxy)butanoic acid ethyl ester (10.48 g) as a white solid.
Reaction SMILES: [C:1]1(=[O:29])[N:5]([CH2:6][C:7]([N:9]2[C@@H:15]3[CH2:16][CH2:17][CH2:18][C@@H:14]3[C:13](=[O:19])[NH:12][C:11]3[CH:20]=[CH:21][CH:22]=[CH:23][C:10]2=3)=[O:8])[C:4](=[O:24])[C:3]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:2]12.[H-].[Na+].Cl[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1.O>CN(C)C=O>[C:4]1(=[O:24])[N:5]([CH2:6][C:7]([N:9]2[C@@H:15]3[CH2:16][CH2:17][CH2:18][C@@H:14]3[C:13](=[O:19])[N:12]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=3)[C:11]3[CH:20]=[CH:21][CH:22]=[CH:23][C:10]2=3)=[O:8])[C:1](=[O:29])[C:2]2=[CH:28][CH:27]=[CH:26][CH:25]=[C:3]12
Reactant: O=C1Nc2ccccc2N(C(=O)CN2C(=O)c3ccccc3C2=O)[C@@H]2CCC[C@H]12
Reactant: ClCc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CC(=O)N1c2ccccc2N(Cc2ccccn2)C(=O)[C@H]2CCC[C@H]21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 48 %

Procedure:
In a mixture of water (0.5 mL) and ethyl acetate (1 mL)was dissolved 2-(chloromethyl)pyridine hydrochloride (246 mg, 1.5 mmol). This solution was neutralized with the addition of sodium hydrogencarbonate. The organic layer was separated, and the remaining aqueous layer was subjected to extraction twice with ethyl acetate. The organic layers were combined and dried over magnesium sulfate, followed by concentration under reduced pressure to give 2-(chloromethyl)pyridine. To a suspension of (3aR*,10aS*)-4-(phthalimidoacetyl)-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta[e][1,4]diazepin-10(1H)-one (389 mg, 1.0 mmol) in N,N-dimethylformamide (3 mL), which was cooled to 0° C., was added sodium hydride (60% liquid paraffin dispersion, 44 mg, 1.1 mmol). The mixture was stirred for 3 minutes at the same temperature and for 10 minutes at room temperature. To this mixture was added a solution of the 2-(chloromethyl)pyridine, which was produce by the above-mentioned procedure, in N,N-dimethylformamide (0.5 mL). The mixture was stirred for 3 hours at room temperature. To the reaction mixture was added water, and resulting precipitate was collected by filtration, which was recrystallized from chloroform-ethanol-diisopropylether to give 232 mg (yield 48%) of the titled compound, m.p. 227°-229° C.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][S:14]([CH2:17][C:18](NC1N=NN(CCCCCCCCCCCC)N=1)=[O:19])(=[O:16])=[O:15])([CH3:3])[CH3:2].[CH2:38]([SH:56])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55]>>[CH2:38]([S:56][C:18](=[O:19])[CH2:17][S:14](=[O:16])(=[O:15])[NH:13][C:5]1[C:6]([CH:10]([CH3:11])[CH3:12])=[CH:7][CH:8]=[CH:9][C:4]=1[CH:1]([CH3:2])[CH3:3])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55]
Reactant: CCCCCCCCCCCCn1nnc(NC(=O)CS(=O)(=O)Nc2c(C(C)C)cccc2C(C)C)n1
Reactant: CCCCCCCCCCCCCCCCCCS
Product: CCCCCCCCCCCCCCCCCCSC(=O)CS(=O)(=O)Nc1c(C(C)C)cccc1C(C)C

Procedure:
This compound was prepared in the same manner as for the title compound of Example 2, except that 2-DAT was replaced with octadecanthiol.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:17].[F:18][C:19]1[CH:20]=[CH:21][C:22]([O:28][CH3:29])=[C:23](B(O)O)[CH:24]=1>>[C:11]1([S:8]([C:5]2[CH:6]=[CH:7][C:2]([C:21]3[CH:20]=[C:19]([F:18])[CH:24]=[CH:23][C:22]=3[O:28][CH3:29])=[C:3]([F:17])[CH:4]=2)(=[O:10])=[O:9])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=S(=O)(c1ccccc1)c1ccc(Br)c(F)c1
Reactant: COc1ccc(F)cc1B(O)O
Product: COc1ccc(F)cc1-c1ccc(S(=O)(=O)c2ccccc2)cc1F

Procedure:
The subtitle compound was prepared by the method of example 2 step (ii) using the product of step (i) and 5-fluoro-2-methoxyphenylboronic acid.
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[NH:6][C:5](=[O:7])[CH2:4][NH:3]1.C(=O)([O-])[O-].[K+].[K+].[Br:15][CH2:16][C:17](Br)=[O:18]>O>[Br:15][CH2:16][C:17]([N:3]1[CH2:4][C:5](=[O:7])[NH:6][C:2]1([CH3:8])[CH3:1])=[O:18]
Reactant: CC1(C)NCC(=O)N1
Reactant: O=C(Br)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC1(C)NC(=O)CN1C(=O)CBr
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(1) To an ice-cold stirred solution of 2,2-dimethyl-4-imidazolidinone (7 g) and potassium carbonate (12.8 g) in water (80 ml), bromoacetyl bromide (5.4 ml) was added dropwise. The reaction mixture was stirred at the same temperature for 1 hour, then at room temperature for 2 hours. The obtained suspension was extracted three times with ethyl acetate and the organic phase was washed with 3% hydrochloric acid, dried and evaporated under reduced pressure to give a residue which was crystallized from xylene to afford 1-(2-bromoacetyl)-2,2-dimethyl-4-imidazolidinone as a white crystalline powder, m.p. 137°-138° C.
Reaction SMILES: [C:1]([S-:3])#[N:2].[K+].CC1C=CC(S(O[CH2:16][C:17]2([CH3:21])[CH2:20][O:19][CH2:18]2)(=O)=O)=CC=1.C(OCC)(=O)C>C(O)C.CCCCCC>[CH3:16][C:17]1([CH2:21][S:3][C:1]#[N:2])[CH2:20][O:19][CH2:18]1
Reactant: N#C[S-]
Reactant: Cc1ccc(S(=O)(=O)OCC2(C)COC2)cc1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CCCCCC
Product: CC1(CSC#N)COC1
Temperature: 85 °C
Yield: 304.4 %

Procedure:
KSCN (0.75 g, 7.81 mmol) was added to a solution of (3-methyloxetan-3-yl)methyl 4-methylbenzenesulfonate (1 g, 3.90 mmol) in ethanol (25 mL) and the resulting reaction mass was heated at 85° C. overnight. The reaction was monitored by TLC (30% ethyl acetate in hexane). The reaction mass was concentrated under reduced pressure to afford 1.7 g of the crude product which was used for the next step without further purification.
Reaction SMILES: [CH:1]1([C@@:7]([OH:17])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([OH:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:18]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O.O>[CH:11]1([C@@:7]([OH:17])([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]([O:10][CH3:18])=[O:9])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: O=C(O)[C@](O)(c1ccccc1)C1CCCCC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)[C@](O)(c1ccccc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To a mixture of (R)-α-cyclohexyl-α-hydroxybenzeneacetic acid (III) (12.2 g, 52.1 mmol) and K2CO3 (10.8 g, 78.2 mmol) in 100 mL of acetone was added methyl iodide (MeI) (13.0 mL, 208 mmol) dropwise at 0° C. (ice bath). After the addition (ca. 1 h) of MeI, the reaction mixture was stirred at room temperature overnight. The mixture was filtered through a pad of Celite and rinsed with acetone twice. The filtrate was concentrated to give a white slurry which was diluted with water and extracted with heptane. The combined extracts were washed with water, brine, dried and concentrated to give the product (R)-IV (11.9 g, 92% yield) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[NH2:9].Cl[CH2:11][CH:12]=O>C(O)C>[Br:1][C:2]1[C:3]2[N:4]([CH:11]=[CH:12][N:9]=2)[N:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=CCCl
Reactant: Nc1nnc(Cl)cc1Br
Solvent: CCO
Product: Clc1cc(Br)c2nccn2n1
Yield: 107.5 %

Procedure:
A solution of 4-bromo-6-chloropyridazin-3-amine (5.0 g, 24 mmol) and 2-chloroacetaldehyde (12 g, 75 mmol) in ethanol (100 mL) was heated at reflux for 15 h. The reaction mixture was concentrated and washed with acetone (75 mL) to give 104a as a yellow solid (6.0 g, 71%). MS: [M+H]+ 234.
Reaction SMILES: [CH3:1][S:2]([OH:5])(=[O:4])=[O:3].C(N([CH2:11][CH3:12])CC)C>C(OCC)(=O)C>[CH3:1][S:2]([O:5][CH:11]([CH2:12][O:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:12][CH2:11][O:5][S:2]([CH3:1])(=[O:4])=[O:3])(=[O:4])=[O:3]
Reactant: CCN(CC)CC
Reactant: CS(=O)(=O)O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)OCCC(COS(C)(=O)=O)OS(C)(=O)=O
Temperature: 2.5 °C
Reaction time: 2 h

Procedure:
A solution of 18.1 ml of methanesulphonic acid in 45 ml of ethyl acetate was added dropwise within 2 hours under argon to a solution, cooled to 0-5° C., of 7.96 g of S-1,2,4-butanetriol and 33.5 ml of triethylamine in 90 ml of ethyl acetate. The white suspension was stirred at 0-5° C. for a further 2 hours and thereafter the suspension was filtered and the yellow filtrate was washed in succession with 75 ml of 1N hydrochloric acid, 75 ml of saturated NaHCO3 solution and 75ml of saturated NaCl solution. The organic phase was dried over Na2SO4, filtered and the filtrate was concentrated. 21.79 g of yellow oil were obtained.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[C:16]([CH3:17])=[C:15]([CH3:18])[C:14]([CH3:19])=[C:13]2[C:9]=1[CH2:10][CH:11]([NH:20][C:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:12]2>O1CCCC1>[CH2:21]([NH:20][CH:11]1[CH2:12][C:13]2[C:9](=[C:8]([CH3:7])[C:16]([CH3:17])=[C:15]([CH3:18])[C:14]=2[CH3:19])[CH2:10]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Cc1c(C)c(C)c2c(c1C)CC(NC(=O)c1ccccc1)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(C)c(C)c2c(c1C)CC(NCc1ccccc1)C2
Temperature: 50 °C
Reaction time: 20 h

Procedure:
1M Lithium aluminium hydride (2.4 ml) in tetrahydrofuran is added dropwise to a solution of N-(4,5,6,7-tetramethyl-indan-2-yl)-benzamide (352 mg) in anhydrous THF (10 ml) under nitrogen at room temperature. The reaction mixture is allowed to stir at 50° C. for 20 hours. After 4 hours more 1M Lithium aluminium hydride (1.2 ml, 1.20 mmole) in THF is added. On cooling the reaction mixture is quenched with ice water. The aqueous phase is washed with diethyl ether (x3) and the organic layers combined, treated with magnesium sulphate, filtered and the solvent removed in vacuo.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C@H:11]([N:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:19](=[O:22])[CH2:20][CH3:21])[CH2:10][C@@H:9]2[CH3:29])=[O:7])=[CH:4][CH:3]=1.[CH2:32]([CH:34]([CH2:37][CH3:38])[CH:35]=O)[CH3:33].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl>[CH2:32]([CH:34]([CH2:37][CH3:38])[CH2:35][NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C@H:11]([N:18]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:19](=[O:22])[CH2:20][CH3:21])[CH2:10][C@@H:9]2[CH3:29])=[O:7])=[CH:30][CH:31]=1)[CH3:33]
Reactant: CCC(C=O)CC
Reactant: CCC(=O)N(c1ccccc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(N)cc2)c2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCC(=O)N(c1ccccc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(NCC(CC)CC)cc2)c2ccccc21
Temperature: 25 °C
Yield: 83 %

Procedure:
(±)-Cis-N-{1-[4-(2-ethyl-butylamino)-benzoyl]-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl}-N-phenyl-propionamide was prepared from (±)-cis-N-[1-(4-amino-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-N-phenyl-propionamide. To a solution of (±)-cis-N-[1-(4-Amino-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-N-phenyl-propionamide (75 mg, 0.145 mmol) in dichloromethane (3 mL) was added 2-ethylbutyraldehyde (26 uL, 0.2 mmol) in one portion. The mixture was stirred at room temperature for a 0.5 h before a solution of sodium triacetoxyborohydride (74 mg, 0.348 mmol) 1 ml DCM was added slowly. A single drop of acetic acid was added and the reaction was allowed to stir at room temperature over night. Excess reagent was quenched by the addition of saturated aqueous sodium bicarbonate. The resulting mixture was extracted three times with 20 mL dichloromethane. The combined extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. Crude product was purified by HPLC to afford the title compound (60 mg, 83%).
Reaction SMILES: [CH3:1][N:2]([CH3:23])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[O:16])=[CH:10][CH:9]=2)[CH2:4]1.Cl[C:25]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:26]=1[C:27]#[N:28]>>[CH3:1][N:2]([CH3:23])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:25]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:26]=4[C:27]#[N:28])[CH2:19][CH2:18]3)=[O:16])=[CH:12][CH:13]=2)[CH2:4]1
Reactant: CN(C)C1CCN(c2ccc(NC(=O)C3CCNCC3)cc2)C1
Reactant: N#Cc1cc(Cl)ccc1Cl
Product: CN(C)C1CCN(c2ccc(NC(=O)C3CCN(c4ccc(Cl)cc4C#N)CC3)cc2)C1

Procedure:
Piperidine-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide was reacted with 2,5-dichlorobenzonitrile as described in example 323. This resulted in the product with the molecular weight of 452.00 (C25H30ClN5O); MS (ESI): 452 (M+H+).
Reaction SMILES: O[C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1
Reactant: O=C(O)c1cnc(O)c([N+](=O)[O-])c1
Reactant: O=P(Cl)(Cl)Cl
Product: O=C(O)c1cnc(Cl)c([N+](=O)[O-])c1
Temperature: 105 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
A suspension of 6-hydroxy-5-nitronicotinic acid (8 g, 43.5 mmol) (prepared by literature nitration of 6-hydroxynicotinic acid) in phosphorus oxychloride (24.3 mL, 261.0 mmol) was heated to reflux (105° C.) for 3 h under a nitrogen atmosphere. At the end of this time period all of the solids had dissolved. The reaction was cooled to rt and poured over 500 mL crushed ice, and stirring was continued for 30 minutes until all of the ice had melted. The aqueous mixture was extracted with a 1:2 mixture of THF in diethyl ether (3×150 mL). The pooled organic extracts were washed with brine (1×), dried (MgSO4), and concentrated on a rotary evaporator to afford intermediate 56 as a light brown solid (8.37 g, 95%). ESI-MS m/e 405.3 (2M−1).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]4[C:19]=3[CH:18]=[CH:17][CH:16]=[N:15]4)[CH:8]=[CH:7][N:6]=2)[CH2:3][CH2:2]1.[H-].[Na+].[CH3:22]I>CN(C=O)C>[CH:1]1([N:4]([CH3:22])[C:5]2[N:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]4[C:19]=3[CH:18]=[CH:17][CH:16]=[N:15]4)[CH:8]=[CH:7][N:6]=2)[CH2:2][CH2:3]1
Reactant: c1cnn2ncc(-c3ccnc(NC4CC4)n3)c2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(c1nccc(-c2cnn3ncccc23)n1)C1CC1
Reaction time: 1 h
Yield: 75.1 %

Procedure:
To a solution of N-cyclopropyl-4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinamine (25 mg, 0.1 mmol) in DMF (2 mL) was added sodium hydride (6 mg, 0.25 mmol) and methyl iodide (0.013 mL, 0.15 mmol). The reaction was allowed to stir for about 1 hour. The reaction was concentrated in vacuo. Water (10 mL) was added and the aqueous layer was extracted with EtOAc (2×30 mL). The combined organic layers were dried (MgSO4) filtered and concentrated in vacuo. The residue was triturated with diethylether to give the title compound as light orange solid (20 mg, 80%). 1H-NMR (400 MHz, CDCl3) δ 9.07 (d, 1H, J=8.8 Hz), 8.46 (s, 1H), 8.35 (m, 2H) 7.12 (dd, 1H, J=8.8, 4.4 Hz), 6.89 (d, 1H, J=5.6 Hz), 3.23 (s, 3H), 2.85 (m, 1H), 0.94 (m, 2H), 0.73 (m, 2H); MS (ESI) (M+H)+ 267.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH:22]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]([CH3:33])[CH3:32])[C:26]=1[N:34]=[C:35]=[O:36])([CH3:24])[CH3:23]>C1C=CC=CC=1>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=2)[C:35]([NH:34][C:26]2[C:25]([CH:22]([CH3:23])[CH3:24])=[CH:30][CH:29]=[CH:28][C:27]=2[CH:31]([CH3:33])[CH3:32])=[O:36])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(NCc2ccc(N(C)C)cc2)cc1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Solvent: c1ccccc1
Product: CCCCc1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)Nc2c(C(C)C)cccc2C(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (4-butylphenyl)[(4-dimethylaminophenyl)methyl]amine (0.6 g) in benzene (5 mL) was added 2,6-diisopropylphenyl isocyanate (0.46 mL) and the mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give N-(4-butylphenyl)-N′-(2,6-diisopropylphenyl)-N-[(4-dimethylaminophenyl)methyl]urea (0.34 g).
Reaction SMILES: CO.[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[C:10]([CH2:17][C:18](OC)=[O:19])[N:9]=[C:8]2[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=1.[BH4-].[Na+].O1CCCC1>O>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[C:10]([CH2:17][CH2:18][OH:19])[N:9]=[C:8]2[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=1
Reactant: COC(=O)Cc1nc(-c2ccc(OC)c(OC)c2)c2cc(OC)c(OC)cc2n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2nc(CCO)nc3cc(OC)c(OC)cc23)cc1OC
Yield: 80.7 %

Procedure:
Methanol (15 ml) was added dropwise under reflux to a mixture of methyl 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-quinazoline-2-acetate (4.0 g), sodium borohydride (1.9 g) and tetrahydrofuran (80 ml). The mixture was stirred under reflux for 2 hours, poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-(2-hydroxyethyl)quinazoline (3.0 g, 81%) which was then recrystallized from ethyl acetate. Colorless needle crystals. mp. 165°-166° C.
Reaction SMILES: [CH2:1]([N:4]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[S:5]1(=[O:7])=[O:6])[C:2]#[CH:3].[CH3:16][O:17][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:27]=1[CH2:26][CH:25]([NH:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:23]2.[CH2:32]=O>O1CCOCC1.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:16][O:17][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:27]=1[CH2:26][CH:25]([N:28]([CH2:32][C:3]#[C:2][CH2:1][N:4]1[C:14](=[O:15])[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[S:5]1(=[O:7])=[O:6])[CH2:29][CH2:30][CH3:31])[CH2:24][CH2:23]2
Reactant: C=O
Reactant: C#CCN1C(=O)c2ccccc2S1(=O)=O
Reactant: CCCNC1CCc2cccc(OC)c2C1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Solvent: O
Product: CCCN(CC#CCN1C(=O)c2ccccc2S1(=O)=O)C1CCc2cccc(OC)c2C1
Reaction time: 5 h
Yield: 75.2 %

Procedure:
2.21 g of propargylsaccharine in 20 ml of dioxane were added dropwise to 2.19 g (10 mmol) of 8-methoxy-2-propylamino-1,2,3,4-tetrahydronaphthalene, 0.36 g (12 mmol) of paraformaldehyde and 0.1 g of copper(II) acetate monohydrate in 10 ml of dioxane at 50° C. After 5 hours at 80° C., the mixture was freed from solvent. The crude product remaining was purified by flash chromatography on silica gel using toluene/ethyl acetate gradients. 3.4 g (75%) of the title compound were obtained as a solidifying oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)=[O:5])[CH3:2].[O-]CC.[Na+].Br[CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22].O>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c[nH]1
Reactant: CC(C)CCBr
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc([N+](=O)[O-])cn1CCC(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 29 %

Procedure:
4-Nitro-1H-pyrrole-2-carboxylic acid ethyl ester (3.69 g, 20.04 mmol) was dissolved in 100 ml of hot anhydrous ethanol and the solution was cooled to room temperature. 30 ml of sodium ethoxide (about 1M) in ethanol was added. The reaction mixture was stirred at room temperature for 20 min and 1-bromo-3-methylbutane (8 ml) was added. The mixture was stirred at reflux for 6 h and cooled to room temperature and then poured into water. The pale yellow precipitates were collected by filtration, washed with water, and dried to give the product (1.48 g, 29%).