Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.Cl.[CH:13]1([C:16]2[C:17]([N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[N:18][CH:19]=[C:20]([CH3:22])[CH:21]=2)[CH2:15][CH2:14]1>>[CH:13]1([C:16]2[C:17]([N:23]3[CH2:28][CH2:27][N:26]([C:6]([C:5]4[CH:4]=[N:3][C:2]([F:1])=[CH:10][C:9]=4[CH3:11])=[O:8])[CH2:25][CH2:24]3)=[N:18][CH:19]=[C:20]([CH3:22])[CH:21]=2)[CH2:14][CH2:15]1
Reactant: Cc1cnc(N2CCNCC2)c(C2CC2)c1
Reactant: Cc1cc(F)ncc1C(=O)O
Agent: Cl
Product: Cc1cnc(N2CCN(C(=O)c3cnc(F)cc3C)CC2)c(C2CC2)c1
Yield: 61.4 %

Procedure:
Using 6-fluoro-4-methylnicotinic acid (139 mg) and a free form (210 mg) of 1-(3-cyclopropyl-5-methylpyridin-2-yl)piperazine hydrochloride described in Preparation Example 85 with a base and by the reaction and treatment in the same manner as in Preparation Example 119, the title compound (180 mg) was obtained.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:9][C@H:10]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:11]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH3:14])=[O:12])[CH:6]=[CH:7][CH:8]=1)#N.C(O)(=[O:33])C>N1C=CC=CC=1.[Ni].O>[CH:1]([C:3]1[CH:4]=[C:5]([CH2:9][C@H:10]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[C:11]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH3:14])=[O:12])[CH:6]=[CH:7][CH:8]=1)=[O:33]
Reactant: CC(=O)O
Reactant: COc1ccc(N(C)C(=O)[C@H](Cc2cccc(C#N)c2)NC(=O)OC(C)(C)C)cc1
Agent: [Ni]
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(N(C)C(=O)[C@H](Cc2cccc(C=O)c2)NC(=O)OC(C)(C)C)cc1
Temperature: 46 °C
Reaction time: 8 h

Procedure:
(S)-tert-Butyl 3-(3-cyanophenyl)-1-((4-methoxyphenyl)(methyl)amino)-1-oxopropan-2-ylcarbamate (2.7 g, 6.60 mmole) was dissolved in pyridine (18.6 ml) and acetic acid (9.3 ml). Raney Nickel (2.7 g of a slurry in H2O) was added and the resulting suspension was stirred at 46° C. overnight. The reaction was confirmed complete by reverse phase HPLC/MS. The reaction was cooled to room temperature and then filtered through celite. The filtrate was concentrated under reduced pressure and then partitioned between EtOAc and H2O. The aqueous layer was extracted with EtOAc (3×). The combined organics were washed with H2O (2×) and brine (2×). The organic layer was dried over MgSO4, filtered and concentrated. The crude produce was dried under high vacuum overnight and used without further purification. Yield was 2.70 g. MS (m/z) 413 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][N:10]([C:13](Cl)=[O:14])[CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21]C(=O)C1C=CC=CC=1>>[OH:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:13]([N:10]1[CH2:11][CH:12]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9]1)=[O:14]
Reactant: O=C(NCCCCO)c1ccccc1
Reactant: O=C(Cl)N1CC=C(c2ccccc2)CC1
Product: O=C(NCCCCO)N1CC=C(c2ccccc2)CC1

Procedure:
4-Phenyl-3,6-dihydro-2H-pyridine-1-carboxylic acid (4-hydroxybutyl)amide (62B) is prepared from 62A as described for 1D. The product is obtained in almost quantitative yield.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4]2([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[NH:3]1.[CH3:20][O:21][C:22](=[O:46])[C@H:23]([CH2:44]O)[NH:24][C:25]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:20][O:21][C:22]([C@@H:23]([NH:24][C:25]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:44][N:6]1[C:5](=[O:7])[C:4]2([CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:12]2)[NH:3][C:2]1=[O:1])=[O:46]
Reactant: COC(=O)[C@H](CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)NC(=O)NC2=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H](CN1C(=O)NC2(CCN(C(=O)OC(C)(C)C)CC2)C1=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 95.1 %

Procedure:
A solution of 3.6 g (13.37 mmol) of (34.2) in 15 ml of absolute THF is added to a solution of 3.72 g (10.3 mmol) of (34.3) and 3.5 g (13.34 mmol) of triphenylphosphine in 20 ml of absolute THF. 2.11 ml (13.37 mmol) of diethyl azodicarboxylate (DEAD) are added to this solution and the reaction mixture is stirred at room temperature until the reaction has come to an end. The solvent is removed in vacuo and the residue is chromatographed through silica gel using heptane/ethyl acetate. 6 g (95%) of (34.4) are obtained after concentrating the product fractions.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O.[F:21][C:22]1[C:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)=[CH:28][CH:27]=[CH:26][C:23]=1[CH:24]=O>>[CH3:20][O:19][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=1[CH:2]1[N:1]([CH2:24][C:23]2[CH:26]=[CH:27][CH:28]=[C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)[C:22]=2[F:21])[C:7](=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=Cc1cccc(-c2ccccn2)c1F
Reactant: COC(=O)CCCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCCC(=O)N1Cc1cccc(-c2ccccn2)c1F

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 6-amino-6-(2,6-dimethoxyphenyl)hexanoate with 2-fluoro-3-(pyridin-2-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.72 min.; [M+H]+: 435.13 g/mol.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([S:7]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)(=[O:9])=[O:8])[S:4][C:3]=1[N:16]1[CH2:21][CH2:20][CH:19]([C:22]([OH:24])=[O:23])[CH2:18][CH2:17]1.[Cl:25][C:26]1[CH:36]=[C:35]([F:37])[C:34]([F:38])=[CH:33][C:27]=1[C:28]([N:30]=[C:31]=[O:32])=[O:29]>C(#N)C>[Cl:25][C:26]1[CH:36]=[C:35]([F:37])[C:34]([F:38])=[CH:33][C:27]=1[C:28]([NH:30][C:31](=[O:32])[NH:1][C:2]1[CH:6]=[C:5]([S:7]([N:10]2[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]2)(=[O:9])=[O:8])[S:4][C:3]=1[N:16]1[CH2:17][CH2:18][CH:19]([C:22]([OH:24])=[O:23])[CH2:20][CH2:21]1)=[O:29]
Reactant: O=C=NC(=O)c1cc(F)c(F)cc1Cl
Reactant: Nc1cc(S(=O)(=O)N2CCCCC2)sc1N1CCC(C(=O)O)CC1
Solvent: CC#N
Product: O=C(NC(=O)c1cc(F)c(F)cc1Cl)Nc1cc(S(=O)(=O)N2CCCCC2)sc1N1CCC(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1-[3-Amino-5-(piperidine-1-sulfonyl)thiophen-2-yl]piperidine-4-carboxylic acid (0.2 g of crude product) is dissolved in 2 ml of acetonitrile and admixed with the equimolar solution of 2-chloro-4,5-difluorobenzoyl isocyanate in acetonitrile, and the mixture is stirred at RT. After 3 hours, the solid is filtered off with suction and dried under reduced pressure.
Reaction SMILES: [CH2:1]([N:3]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[F:32])[C:4](=[O:24])[CH2:5][C:6]1[CH:23]=[CH:22][C:9]([CH2:10][O:11][C:12]2[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=2[C:14]([O:16]C)=[O:15])=[CH:8][CH:7]=1)[CH3:2].[OH-].[K+]>CCO>[CH2:1]([N:3]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[F:32])[C:4](=[O:24])[CH2:5][C:6]1[CH:23]=[CH:22][C:9]([CH2:10][O:11][C:12]2[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=2[C:14]([OH:16])=[O:15])=[CH:8][CH:7]=1)[CH3:2]
Reactant: CCN(Cc1ccccc1F)C(=O)Cc1ccc(COc2ccccc2C(=O)OC)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCN(Cc1ccccc1F)C(=O)Cc1ccc(COc2ccccc2C(=O)O)cc1
Yield: 5.6 %

Procedure:
Methyl 2-[(4-{2-[ethyl(2-fluorobenzyl)amino]-2-oxoethyl}benzyl)oxy]benzoate (0.242 g, 0.555 mmol) was dissolved in EtOH (5 ml, 95%), potassium hydroxide (0.062 g, 1.111 mmol) was added. The reaction was performed in an single node microwave oven (7 min, 150° C.). Work-up by removing the solvent by evaporation and addition of HCl (2 ml, 1 M). The water-phase was extracted with two portions of EtOAc (20 ml) and the organic phase was dried (MgSO4) and the solvent was removed by evaporation. The crude was purified by flash chromatography (started with isocratic DCM 100% and then the MeOH concentration was increased from 0.5% to 20%, (silica gel 60 0.004-0.063 mm). The product containing fractions were pooled and the EtOAc was removed by evaporation to give 0.013 g of 2-[(4-{2-[ethyl(2-fluorobenzyl)amino]-2-oxoethyl}benzyl)oxy]benzoic acid (yield 5.6%).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([N:18]1[CH2:23][CH2:22][C:21]2([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[O:25][CH2:24]2)[CH2:20][CH2:19]1)=[O:17].[CH3:32][C:33]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][C:34]=1[NH2:35]>>[CH3:32][C:33]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][C:34]=1[NH:35][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([N:18]1[CH2:23][CH2:22][C:21]2([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[O:25][CH2:24]2)[CH2:20][CH2:19]1)=[O:17]
Reactant: CCOC(=O)c1cnn2c(Cl)c(C(=O)N3CCC4(CC3)COc3ccccc34)cnc12
Reactant: Cc1ccc(C)c(N)c1
Product: CCOC(=O)c1cnn2c(Nc3cc(C)ccc3C)c(C(=O)N3CCC4(CC3)COc3ccccc34)cnc12
Yield: 88.1 %

Procedure:
In the same manner as in Example 19, step 5 and using 7-chloro-3-ethoxycarbonyl-6-(2H-spiro[benzofuran-3,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine (0.24 g, 0.54 mmol) obtained in Example 128, step 2 and 2,5-dimethylaniline (0.098 g, 0.81 mmol), the title compound (0.25 g, 86%) was obtained.
Reaction SMILES: [C:1]([C:4]1[N:5]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:6]=[C:7]([C:9]([NH:11][C@@H:12]([CH3:29])[CH2:13][N:14]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[C:23]([F:25])[C:22]([C:26]#[N:27])=[C:21]([Cl:28])[CH:20]=3)=[N:15]2)=[O:10])[N:8]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>CO>[Cl:28][C:21]1[CH:20]=[C:19]([C:16]2[CH:17]=[CH:18][N:14]([CH2:13][C@@H:12]([NH:11][C:9]([C:7]3[N:8]=[C:4]([CH:1]([OH:3])[CH3:2])[N:5]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:36])([CH3:35])[CH3:37])[CH:6]=3)=[O:10])[CH3:29])[N:15]=2)[CH:24]=[C:23]([F:25])[C:22]=1[C:26]#[N:27]
Reactant: CC(=O)c1nc(C(=O)N[C@@H](C)Cn2ccc(-c3cc(F)c(C#N)c(Cl)c3)n2)cn1COCC[Si](C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1nc(C(=O)N[C@@H](C)Cn2ccc(-c3cc(F)c(C#N)c(Cl)c3)n2)cn1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(S)-2-Acetyl-N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxamide (290 mg, 0.53 mmol) was dissolved in MeOH (20 ml). NaBH4 (30 mg, 0.79 mmol) was added to the solution in portions at 0° C. and the mixture was stirred at RT for 3 h. The reaction mixture was concentrated and dluted with water. The mixture was extracted with DCM and the organic layer was concentrated. The product was purified by column chromatography. Yield 245 mg. 1H-NMR (400 MHz; DMSO-d6): δ −0.05 (s, 9H), 0.81-0.86 (m, 2H), 1.07-1.1 (m, 3H), 1.49 (d, 3H), 3.47-3.51 (m, 2H), 4.29-4.43 (m, 3H), 4.88-4.91 (m, 1H), 5.4-5.45 (m, 3H), 7.03 (d, 1H), 7.68 (d, 1H), 7.86-8.00 (m, 4H).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[N:4]1.I[CH2:13][CH2:14][CH:15]1[CH2:21][CH2:20][C:19]2[C:22]([O:32][CH3:33])=[C:23]([O:30][CH3:31])[C:24]([O:28][CH3:29])=[C:25]([O:26][CH3:27])[C:18]=2[CH2:17][CH2:16]1>C1COCC1.O>[CH3:27][O:26][C:25]1[C:18]2[CH2:17][CH2:16][CH:15]([CH2:14][CH2:13][N:3]3[C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=4[N:5]=[N:4]3)[CH2:21][CH2:20][C:19]=2[C:22]([O:32][CH3:33])=[C:23]([O:30][CH3:31])[C:24]=1[O:28][CH3:29]
Reactant: COc1c2c(c(OC)c(OC)c1OC)CCC(CCI)CC2
Reactant: c1ccc2[nH]nnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1c2c(c(OC)c(OC)c1OC)CCC(CCn1nnc3ccccc31)CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.3 %

Procedure:
To a suspension of sodium hydride (60% oil dispersion, 230 mg) in THF (6 ml) was added a solution of 1,2,3-benzotriazole (680 mg) in THF(6 ml) with cooling with ice. The reaction mixture was warmed to room temperature and stirred at ambient temperature for 30 min. 7-(2-Iodoethyl)-1,2,3,4-tetramethoxy-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene (1.20 g) was added and the stirring was continued for 12 hr. The reaction mixture was heated under reflux for 6 hr, diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride and dried. The solvent was removed in vacuo. The residue was purified by alumina column chromatography(hexane to hexane:ethyl acetate=4:1) and then with recrystallization from hexane-ethyl acetate to obtain the entitled compound (920 mg).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([C:13]([C:28]4[CH:29]=[CH:30][C:31]([C:34](O)=[O:35])=[N:32][CH:33]=4)=[C:14]([C:16]#[C:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.[CH3:37][S:38]([NH2:41])(=[O:40])=[O:39].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:37][S:38]([NH:41][C:34](=[O:35])[C:31]1[CH:30]=[CH:29][C:28]([C:13]2[N:9]3[N:10]=[CH:11][CH:12]=[C:7]([N:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)[C:8]3=[N:15][C:14]=2[C:16]#[C:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)=[CH:33][N:32]=1)(=[O:40])=[O:39]
Reactant: O=C(O)c1ccc(-c2c(C#Cc3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cn1
Reactant: CS(N)(=O)=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)NC(=O)c1ccc(-c2c(C#Cc3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cn1

Procedure:
A solution of compound 40a (0.20 g, 0.42 mmol), methanesulfonamide (60 mg, 0.63 mmol), dicyclohexylcarbodiimide (90.0 mg, 0.44 mmol) and N,N-dimethylpyridin-4-amine (60.0 mg, 0.49 mmol) in DCM (5 mL) was stirred at rt overnight, then concentrated under reduced pressure. The residue obtained was purified by flash column chromatography on silica gel (MeOH/CH2Cl2 (1:20)) to obtain a solid, which was washed with methanol (10 mL) to yield the title compound 28 as a yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 9.50-9.41 (m, 1H), 8.62 (d, J=8.8 Hz, 1H), 8.41 (d, J=8.4 Hz, 1H), 8.30-8.27 (m, 2H), 8.03-7.99 (m, 2H), 7.82 (t, J=7.6 Hz, 1H), 7.73 (t, J=8.8 Hz, 1H), 7.65 (t, J=7.6 Hz, 1H), 6.51 (d, J=5.6 Hz, 1H), 4.08-3.97 (m, 4H), 3.99-3.80 (m, 4H), 2.96 (s, 3H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C28H23N7O4S: 554.2 (M+H). Found: 554.0.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH3:13])=[CH:4][C:3]=1[O:14][CH3:15].Cl[C:17]([O:19][CH3:20])=[O:18].C(N(CC)CC)C>O1CCCC1>[CH3:20][O:19][C:17]([O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH3:13])=[CH:4][C:3]=1[O:14][CH3:15])=[O:18]
Reactant: COc1cc(OC)c2ccccc2c1O
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)Oc1c(OC)cc(OC)c2ccccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1.27 g of 1-hydroxy-2,4-dimethoxynaphthalene, prepared as shown in Preparations 7 and 8, in 50 ml of tetrahydrofuran was added 0.694 g of methyl chloroformate followed by 0.743 g of triethylamine. The mixture was stirred at room temperature for 16 hours, filtered, then the solvent removed under reduced pressure. The residue was dissolved in diethyl ether, washed with dilute hydrochloric acid and dried over anhydrous sodium sulfate. The ether was removed under reduced pressure and the residue chromatographed on silica gel, eluting with a 1:1 mixture of methylene chloride and hexane, to give 1-methoxycarbonyloxy-2,4-dimethoxynaphthalene, m.p. 128°-129° C.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[F:14][C:15]1[CH:28]=[CH:27][C:18]([C:19]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[O:20])=[CH:17][CH:16]=1.C(N(CC)CC)C>C(Cl)Cl>[F:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([CH:21]2[CH2:26][CH2:25][N:24]([C:8](=[O:9])[C:7]3[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[CH2:23][CH2:22]2)=[O:20])=[CH:27][CH:28]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(F)cc1)C1CCN(C(=O)c2ccc([N+](=O)[O-])cc2)CC1
Reaction time: 1 h
Yield: 85.5 %

Procedure:
4-Nitrobenzoyl chloride (3.08 g) was added slowly to a stirred mixture of 4-(4-fluorobenzoyl)piperidine hydrochloride (4.0 g) and triethylamine (4.98 g) in methylene chloride (110 ml) at room temperature. The resulting mixture was stirred at this temperature for 1 hour, washed with 1N hydrochloric acid, saturated sodium bicarbonate solution, and brine, dried over magnesiun sulfate and concentrated in vacuo. The residue was recrystallized from a mixture of acetone and methanol to give 4-(4-fluorobenzoyl)-1-(4-nitrobenzoyl)piperidine (5.0 g) as colourless crystals.
Reaction SMILES: C1(C)C=CC=CC=1.[C:8]([CH2:12][CH2:13][CH2:14][C:15]1[CH:29]=[CH:28][CH:27]=[CH:26][C:16]=1[CH2:17][CH:18]1[C:22](=[O:23])[C:21](=[O:24])[CH2:20][C:19]1=[O:25])([O:10][CH3:11])=[O:9]>CC(O)C.[Pd]>[C:8]([CH2:12][CH2:13][CH2:14][C:15]1[CH:29]=[CH:28][CH:27]=[CH:26][C:16]=1[CH2:17][CH:18]1[C:22](=[O:23])[CH:21]([OH:24])[CH2:20][C:19]1=[O:25])([O:10][CH3:11])=[O:9]
Reactant: COC(=O)CCCc1ccccc1CC1C(=O)CC(=O)C1=O
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: COC(=O)CCCc1ccccc1CC1C(=O)CC(O)C1=O
Reaction time: 72 h

Procedure:
A toluene solution of 30.5 g (0.1 mol) of 2-[2-(3-carbomethoxypropyl)benzyl]-1,3,4-cyclopentanetrione, XIIa, was thoroughly dried by azeotropic distillation. Removal of the toluene gave a red oil that was taken up in 200 ml of 2-propanol. Five grams of Pd/C was added and the compound hydrogenated at 0.25 psi for 3 days. The catalyst was filtered and the solvent evaporated to give the crude product. This was chromatographed on silicic acid and eluted with 4:1 benzene:ethyl acetate. The major fraction amounted to 20 g of the hydroxy dione XIIIa as a clear, light tan oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14]O)=[CH:4][CH:3]=1.P(Br)(Br)[Br:17]>COCCOC>[Br:17][CH2:14][C:9]1[C:10]([CH3:13])=[N:11][O:12][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: BrP(Br)Br
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CO
Solvent: COCCOC
Product: Cc1noc(-c2ccc(Br)cc2)c1CBr
Temperature: 25 °C
Reaction time: 1 h

Procedure:
[5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-methanol (2.88 g, 10.74 mmol) in DME (23 mL) was treated with phosphorus tribromide (1.5 mL, 16.11 mmol), and the reaction was stirred at room temperature for 1 hour. Aqueous workup provided the title compound.
Reaction SMILES: [C:1]([CH:4]([CH2:9][CH:10]=[C:11]([CH3:22])[CH2:12][CH2:13][CH:14]=[C:15]([CH3:21])[CH2:16][O:17][CH2:18][O:19][CH3:20])C(OC)=O)(=[O:3])[CH3:2].[Cl-].[Na+].O>CS(C)=O>[CH3:22][C:11]([CH2:12][CH2:13][CH:14]=[C:15]([CH3:21])[CH2:16][O:17][CH2:18][O:19][CH3:20])=[CH:10][CH2:9][CH2:4][C:1](=[O:3])[CH3:2]
Reactant: COCOCC(C)=CCCC(C)=CCC(C(C)=O)C(=O)OC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COCOCC(C)=CCCC(C)=CCCC(C)=O
Temperature: 150 °C
Reaction time: 5 h
Yield: 102.7 %

Procedure:
To a solution of methyl 2-acetyl-5,9-dimethyl-10-(methoxymethyl)oxy-4,8-decadienate (420 mg, 1.37 mmol) in methylsulfoxide (4 ml) were added sodium chloride (160 mg, 2.74 mmol) and water (0.1 ml), and the mixture was stirred at 150° C. After five hours, the reaction mixture was allowed to cool to room temperature, and water (10 ml) was added thereto. The product was extracted with ether (20 m1×2). The extract was dried over Na2SO4, and concentrated to give a residue, which was then purified with silica gel column chromatography to obtain 6,10-dimethyl-11-(methoxymethyl)oxy- 5,9-undecadien-2-one (358 mg, 67%).
Reaction SMILES: [OH:1][N:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[N:13][N:14]([CH:16]4[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]4)[CH:15]=3)[CH:9]=2)[CH:4]=[CH:3]1.Br[C:30]1[N:35]=[CH:34][CH:33]=[CH:32][N:31]=1>>[NH:19]1[CH2:20][CH2:21][CH:16]([N:14]2[CH:15]=[C:11]([C:8]3[CH:9]=[C:10]4[N:2]([O:1][C:30]5[N:35]=[CH:34][CH:33]=[CH:32][N:31]=5)[CH:3]=[CH:4][C:5]4=[N:6][CH:7]=3)[CH:12]=[N:13]2)[CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc4ccn(O)c4c3)cn2)CC1
Reactant: Brc1ncccn1
Product: c1cnc(On2ccc3ncc(-c4cnn(C5CCNCC5)c4)cc32)nc1

Procedure:
The entitled compound is prepared from tert-butyl 4-[4-(1-hydroxy-1H-pyrrolo[3,2-b]pyridin-6-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate and 2-bromo-pyrimidine as described in the last 2 steps of Example 18.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[N:6][NH:7][CH:8]=1.Br[CH2:10][C:11]1([CH3:15])[CH2:14][O:13][CH2:12]1>CN(C=O)C.C([O-])(O)=O.[Na+]>[Br:3][C:4]1[CH:5]=[N:6][N:7]([CH2:10][C:11]2([CH3:15])[CH2:14][O:13][CH2:12]2)[CH:8]=1
Reactant: Brc1cn[nH]c1
Reactant: CC1(CBr)COC1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(Cn2cc(Br)cn2)COC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94.2 %

Procedure:
To a suspension of NaH (98 mg, 55% in mineral oil, 2.25 mmol) in DMF (1.2 ml) was added a solution of 4-bromopyrazole (300 mg, 2.04 mmol) in DMF (2 ml). The reaction mixture was stirred at room temperature for 15 minutes before a solution of 3-bromomethyl-3-methyloxetane (404 mg, 2.45 mmol) in DMF (2 ml) was added slowly. The mixture was stirred at room temperature for 1.5 h, then diluted with saturated NaHCO3 solution and extracted with 3 times with EtOAc. The combined organic layers were washed 2 times with water and with brine, dried (Na2SO4) and evaporated. The remaining colorless oil was purified by silica gel chromatography (heptane/EtOAc 80:20-50:50) to obtain the title compound (444 mg, 94%) as colorless oil. MS (EI): 231.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:12]=2)=[O:10])=[CH:4][C:3]=1[NH:23][C:24](=[O:35])[C:25]1[CH:30]=[C:29](Cl)[CH:28]=[CH:27][C:26]=1[N+:32]([O-:34])=[O:33].[CH3:36][NH:37][CH2:38][CH2:39][CH2:40][NH:41][CH3:42]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:12]=2)=[O:10])=[CH:4][C:3]=1[NH:23][C:24](=[O:35])[C:25]1[CH:30]=[C:29]([N:37]([CH2:38][CH2:39][CH2:40][NH:41][CH3:42])[CH3:36])[CH:28]=[CH:27][C:26]=1[N+:32]([O-:34])=[O:33]
Reactant: CNCCCNC
Reactant: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1NC(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Product: CNCCCN(C)c1ccc([N+](=O)[O-])c(C(=O)Nc2cc(NC(=O)c3ccnc(N4CCOCC4)c3)ccc2C)c1

Procedure:
In an analogous procedure to that described in the fifth paragraph of the portion of Note a) which is concerned with the preparation of starting materials, N-[2-methyl-5-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]-5-chloro-2-nitrobenzamide was reacted with N-(3-methylaminopropyl)-N-methylamine to give N-[2-methyl-5-(2-morpholinopyrid4-ylcarbonylamino)phenyl]-5-[N-(3-methylaminopropyl)-N-methylamino]-2-nitrobenzamide: NMR Spectrum: (DMSOd6) 1.61–1.74 (m, 2H), 2.35 (s, 3H), 2.26 (m, 3H), 2.38–2.44 (m, 2H), 3.09 (s, 3H), 3.5–3.55 (m, 6H), 3.7–3.74 (m, 4H), 6.78 (s, 1H), 6.84 (d, 1H), 7.14 (d, 1H), 7.21 (d, 1H), 7.27 (s, 1H), 7.6 (d, 1H), 7.9 (s, 1H), 8.04 (d, 1H), 8.27 (d, 1H), 9.83 (s, 1H), 10.55 (s, 1H); Mass Spectrum: M+H+ 562.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:12][CH3:13])[C:10]=1[OH:11])[C:6]#[N:7].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>CC(N(C)C)=O>[CH3:13][O:12][C:9]1[CH:8]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:10]=1[O:11][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)[C:6]#[N:7]
Reactant: COc1cc(C#N)cc(OC)c1O
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cc(C#N)cc(OC)c1OCCN1CCOCC1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
6.06 g 3,5 Dimethoxy-4-hydroxy-benzonitrile was dissolved in 20 mL dimethylacetamide, 5.2 g potassium carbonate and 6.7 g N-(2-chloroethyl)morpholine hydrochloride was added and the mixture was stirred at 100° C. for 6 h. The solvent was distilled off and the residue was co-evaporated twice with toluene. The residue was suspended in dichloromethane, filtered and the filtrate was concentrated.