Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH:13]=[CH2:14])[C:7]=12.[CH2:15]([OH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([O:22][C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH:13]=[CH2:14])[C:7]=12)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OCc1ccccc1
Reactant: C=Cn1c(C)c(C)c2cnnc(Cl)c21
Product: C=Cn1c(C)c(C)c2cnnc(OCc3ccccc3)c21
Yield: 59.7 %

Procedure:
The title compound was prepared as a white powder in 59.7% yield in a similar procedure to that described in Example 1 by using 7-chloro-2,3-dimethyl-1-vinylpyrrolo[2,3-d]pyridazine and benzyl alcohol.
Reaction SMILES: [CH3:1][NH:2][NH2:3].O.[CH2:5]([O:7][C:8](=[O:19])/[C:9](=[CH:15]\OCC)/[C:10](=O)[CH:11]([F:13])[F:12])[CH3:6]>C1(C)C(C)=CC=CC=1>[F:12][CH:11]([F:13])[C:10]1[C:9]([C:8]([O:7][CH2:5][CH3:6])=[O:19])=[CH:15][N:2]([CH3:1])[N:3]=1
Reactant: CCO/C=C(\C(=O)OCC)C(=O)C(F)F
Reactant: CNN
Solvent: Cc1ccccc1C
Solvent: O
Product: CCOC(=O)c1cn(C)nc1C(F)F
Reaction time: 0.25 h

Procedure:
A 0.25 mol solution of methylhydrazine 40% diluted in 50.0 g xylene and 4.7 g water was prepared. A solution of 0.25 mol of 2-[1-Ethoxy-meth-(Z)-ylidene]-4,4-difluoro-3-oxo-butyric acid ethyl ester in 100.0 g xylene was added to the methylhydrazine over 30-60 minutes at a temperature of 20-25° C. The reaction mixture was stirred for 15 min. The phases of the reaction mass were separated.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:32])[CH2:10][C@@H:11](NC(OC(C)(C)C)=O)[C:12]([NH:14][C@H:15]([C:20](=[O:23])[NH:21][CH3:22])[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)C[C@@H]([C:47]1[CH:51]=[CH:50][N:49]([C:52]2[CH:57]=[CH:56][C:55]([F:58])=[CH:54][CH:53]=2)[CH:48]=1)C(O)=O)C1C=CC=CC=1.CNC(=O)[C@H](C(C)(C)C)N.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CO.C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:32])[CH2:10][C@@H:11]([C:47]1[CH:51]=[CH:50][N:49]([C:52]2[CH:57]=[CH:56][C:55]([F:58])=[CH:54][CH:53]=2)[CH:48]=1)[C:12]([NH:14][C@H:15]([C:20](=[O:23])[NH:21][CH3:22])[C:16]([CH3:17])([CH3:18])[CH3:19])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(C[C@H](C(=O)O)c1ccn(-c2ccc(F)cc2)c1)OCc1ccccc1
Reactant: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)C(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNC(=O)[C@@H](N)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: CO
Solvent: ClCCl
Product: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)c1ccn(-c2ccc(F)cc2)c1)C(C)(C)C
Yield: 82 %

Procedure:
According to the procedure described in Example 1(b) for the preparation of 3(R)-t-butoxycarbonylamino-N-(2,2-dimethyl-1(S)-(methylcarbamoyl)propyl)succinamic acid benzyl ester, 2(S)-[1-(4-fluorophenyl)-1H-pyrrol-3-yl]-succinic acid 4-benzyl ester and L-t-leucine N-methylamide (see Malon, P.; Pancoska, P.; Budesinsky, M.; Hlavacek, J.; Pospisek, J.; Blaha, K. Coll. Czech. Chem Commun. 1983, 48, 2844-2861) were coupled with TBTU. Flash column chromatography with 0-5% MeOH/CH2Cl2 as gradient eluant provided in 82% yield N-(2,2-dimethyl-1(S)-(methylcarbamoyl)propyl)-3(S)-[1-(4-fluorophenyl)-1H-pyrrol-3-yl]succinamic acid benzyl ester as a crisp foam. 1H NMR: δ 7.34-7.26 (m, 7H), 7.10 (t, 2H, J=8.6 Hz), 6.95 (t, 1H, J=2.4 Hz), 6.89 (t, 1H, J=2.0 Hz), 6.49 (d, 1H, J=8.8 Hz), 6.23 (dd, 1H, J=1.8, 3.0 Hz), 5.76-5.74 (m, 1H), 5.11 (s, 2H), 4.12 (d, 1H, J=9.2 Hz), 4.00 (t, 1H, J=7.2 Hz), 3.20 (dd, 1H, J=7.7, 16.5 Hz), 2.84 (dd, 1H, J=6.6, 16.6 Hz), 2.75 (d, 3H, J=4.8 Hz), 0.95 (s, 9H). Anal. Calculated for C28H32N3O4F: C, 67.89; N, 8.48. Found: C, 67.78; H, 6.52; N, 8.50.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([OH:26])=[C:15]([C:21](OCC)=[O:22])[C:16](=[O:20])[NH:17]2)=[N:12][CH:11]=1.[NH2:27][CH2:28][C:29]([CH3:33])([CH3:32])[CH2:30][OH:31]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([OH:26])=[C:15]([C:21]([NH:27][CH2:28][C:29]([CH3:33])([CH3:32])[CH2:30][OH:31])=[O:22])[C:16](=[O:20])[NH:17]2)=[N:12][CH:11]=1
Reactant: CC(C)(CN)CO
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3F)cc2[nH]c1=O
Product: CC(C)(CO)CNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3F)cc2[nH]c1=O

Procedure:
This compound was prepared from ethyl 7-[(2,4-difluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 3-amino-2,2-dimethylpropanol employing methods similar to those described in Example 9 and was obtained as a white solid: 1H NMR (d6-DMSO) tautomers are observed δ 11.80 (1H, br s ), 10.93 (1H, br s), 10.22 (1H, br s), 8.18 (0.29H, s), 8.13 (0.71H, s), 7.45-7.38 (1H, m), 7.30 (1H, s), 7.27-7.21 (1H, m), 7.09-7.05 (1H, m), 4.59 (1H, m), 4.02 (2H, s), 3.17-3.05 (4H, m), 0.81 (6H, s); HRMS calcd for C21H21F2N3O4+H+: 418.1578. Found 418.1569.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8](O)(=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].S(=O)=O.Cl>S(Cl)(Cl)=O>[C:8]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCC(=O)O
Reactant: Oc1ccccc1
Agent: Cl
Agent: O=S=O
Solvent: O=S(Cl)Cl
Product: CCCCCCCC(=O)Oc1ccccc1

Procedure:
The ester was prepared by slowly adding thionyl chloride (10 ml) to a mixture of pure phenol (6.5 g) and octanoic acid (10 g). The reaction mixture was warmed to drive off the sulfur dioxide and hydrogen chloride gases. The crude mixture was distilled at 95°-100° C./5 mmHg.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6]3[N:7]([C:11](I)=[C:12]([I:14])[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.O1CCCC1.C[Mg]Br>CCOCC.[Cl-].[NH4+]>[F:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([I:14])[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(c1)OCCn1c-2nc(I)c1I
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Fc1ccc2c(c1)OCCn1cc(I)nc1-2
Temperature: -78 °C
Reaction time: 4 h
Yield: 87.8 %

Procedure:
9-fluoro-2,3-diiodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (1.24 g, 2.74 mmol) was dissolved in tetrahydrofuran (25 mL, 310 mmol) and cooled to −78° C. in a dry ice/acetone bath. Added 3.0 Methylmagnesium bromide in ether (1.37 mL and allowed the reaction to warm up to −40° C. and stir for 4 hours. Complete by LCMS. Diluted with 100 mL of saturated ammonium chloride and extracted with ethyl acetate. Dried over magnesium sulfate, concentrated in vacuo and purified by flash chromatography on the ISCO 0-40% ethyl acetate in hexanes to give 9-fluoro-2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (0.794 g, 88% yield)
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10][C:9]1=[NH:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC.[CH:55]1([N:61]=[C:62]=[O:63])[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]1.O>CC(C)=O>[CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10][C:9]1=[N:17][C:62](=[O:63])[NH:61][CH:55]1[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N=c1sc2ccccc2n1Cc1ccccc1
Reactant: O=C=NC1CCCCC1
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: CC(C)=O
Solvent: O
Product: O=C(N=c1sc2ccccc2n1Cc1ccccc1)NC1CCCCC1
Reaction time: 7 h
Yield: 73.1 %

Procedure:
To a solution of 1.8 g of 3-benzyl-2-iminobenzothiazole and a catalytic amount of dibutyltin dilaurate in 30 ml of acetone was added 0.95 g of cyclohexyl isocyanate dropwise. After seven hours, the reaction mixture was poured into approximately 100 ml of water. The crystals precipitated were collected by filtering to thereby obtain 2.0 g of the objective compound.
Reaction SMILES: Cl[S:2]([C:5]1[S:9][C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:18])[CH3:17])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[NH2:19][C:20]1[O:24][N:23]=[C:22]([CH3:25])[C:21]=1[Br:26]>CO.C(Cl)(Cl)Cl>[Br:26][C:21]1[C:22]([CH3:25])=[N:23][O:24][C:20]=1[NH:19][S:2]([C:5]1[S:9][C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:18])[CH3:17])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CC(C)c1ccc(-c2ccc(S(=O)(=O)Cl)s2)cc1
Reactant: Cc1noc(N)c1Br
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1noc(NS(=O)(=O)c2ccc(-c3ccc(C(C)C)cc3)s2)c1Br

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-isopropylphenyl)thiophene-2-sulfonamide was prepared in the same manner as described in Example 2. Reaction of 5-chlorosulfonyl-2-(4-isopropylphenyl)thiophene (260 mg, 0.87 mmol) with 5-amino-4-bromo-3-methylisoxazole (161 mg, 0.91 mmol) yielded after flash chromatography using 10% MeOH/CHCl3 a pale brown solid (265 mg) which was further purified using preparative HPLC to give the pure sulfonamide as a light tan colored solid, m.p. 114-116° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:10][C:11]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[O:12])[CH:6]=[CH:7][C:8]=1[Cl:9].C(N(C(C)C)CC)(C)C.[CH:28]([C@@H:30]1[CH2:35][CH2:34][CH2:33][N:32]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:31]1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:2][C:3]1[CH:4]=[C:5]([NH:10][C:11]([CH:13]2[CH2:14][CH2:15][N:16]([CH2:28][C@@H:30]3[CH2:35][CH2:34][CH2:33][N:32]([C:36]([O:38][C:39]([CH3:40])([CH3:42])[CH3:41])=[O:37])[CH2:31]3)[CH2:17][CH2:18]2)=[O:12])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: O=C(Nc1ccc(Cl)c(Cl)c1)C1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@@H](CN2CCC(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.4 %

Procedure:
To a mixture of N-(3,4-dichlorophenyl)piperidine-4-carboxamide hydrochloride (1.55 g) in dichloromethane (100 mL) was added di-iso-propylethylamine (1.3 mL). The solution was stirred for 15 minutes after which tert-butyl (3R)-3-formylpiperidine-1-carboxylate (1.17 g) and sodium triacetoxyborohydride (1.59 g) was added. The reaction was stirred at room temperature overnight. The reaction mixture was partitioned between dichloromethane and water and the aqueous layer extracted with dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate and evaporated to give the title compound as a white foam (2.34 g, 100%).
Reaction SMILES: S([O:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])(C(F)(F)F)(=O)=O.[F:16][C@@:17]1([CH2:30]O)[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]1.C(N(CC)CC)C>C(Cl)Cl>[F:16][C@@:17]1([CH2:30][O:8][S:9]([C:12]([F:13])([F:14])[F:15])(=[O:10])=[O:11])[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@](F)(CO)C1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@@](F)(COS(=O)(=O)C(F)(F)F)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 106.5 %

Procedure:
Triflic anhydride (24.06 ml, 142 mmol) was added to a solution of 1,1-dimethylethyl (3S)-3-fluoro-3-(hydroxymethyl)-1-piperidinecarboxylate (30.2 g, 129 mmol) and triethylamine (23.46 ml, 168 mmol) in DCM (100 ml) at −10° C. over 20 min. The mixture was stirred for 2 h, allowing to warm to 0° C., then washed with water and brine, dried and evaporated to give 1,1-dimethylethyl (3S)-3-fluoro-3-({[(trifluoromethyl)sulfonyl]oxy}methyl)-1-piperidinecarboxylate as a dark brown oil (50.2 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12].[C:13](=O)([O-])[O-].[K+].[K+].CI>O>[Cl:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([F:8])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(O)c(Cl)cc1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: COc1cc([N+](=O)[O-])c(F)cc1Cl
Yield: 157.5 %

Procedure:
To a mixture of 2-chloro-4-fluoro-5-nitrophenol (9.6 g) and potassium carbonate (3.8 g) in acetontrile (50 ml), there was added methyl iodide (14 g), and the resultant mixture was heated under reflux for 3 hours. After being allowed to cool to room temperature (ca. 20° C.), water was added thereto, and the resulting mixture was extracted with ether. The ether extract was washed with water, dried and concentrated. The residue was recrystallized from ethanol to give 8.9 g of 4-chloro-2-fluoro-5-methoxynitrobenzene. M.P., 67.5°-69.8° C.
Reaction SMILES: C[O-].[Na+].[SH:4][C:5]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:13](=[O:21])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1.Cl.Cl[CH2:24][C:25]1[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][N:26]=1.O>CO>[C:15]1([N:14]2[C:13](=[O:21])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]=[C:5]2[S:4][CH2:24][C:25]2[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][N:26]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Cc1ccnc(CCl)c1
Reactant: O=c1c2ccccc2nc(S)n1-c1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1ccnc(CSc2nc3ccccc3c(=O)n2-c2ccccc2)c1
Reaction time: 5 h
Yield: 30.7 %

Procedure:
8.7 ml of 28% methanolic solution of sodium methoxide were added to a solution of 5.0 g of 2-mercapto-3-phenyl-4(3H)-quinazolinone and 4.0 g of 2-chloromethyl-4-methylpyridine hydrochloride in methanol, and the stirring was continued at room temperature for 5 hours. The reaction solution was poured into water and extracted with chloroform. The chloroform layer was washed with an aqueous solution of sodium carbonate and dried over sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography. The fraction eluted with 8% ethyl acetate in chloroform was collected and crystallized from ethyl acetate to give 2.17 g (30.7%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8](OS(C(F)(F)F)(=O)=O)[CH:9]=2)[C:4](=[O:19])[CH2:3]1.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O>>[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[C:4](=[O:19])[CH2:3][C:2]2([CH3:20])[CH3:1]
Reactant: OB(O)c1ccccc1Cl
Reactant: CC1(C)CC(=O)c2ccc(OS(=O)(=O)C(F)(F)F)cc21
Product: CC1(C)CC(=O)c2ccc(-c3ccccc3Cl)cc21

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester and 2-chlorophenyl boronic acid according to the procedure described in example 21. MS (ES) m/z 271.1; HRMS: calcd for C17H15ClO+H+, 271.08842; found (ESI, [M+H]+), 271.088.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:11](=[O:14])[CH2:12][CH3:13]>>[CH3:13][CH:12]([CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH:11]=[O:14]
Reactant: O=CCCc1ccccc1
Reactant: CCC=O
Product: CC(C=O)CCCc1ccccc1

Procedure:
The 2-methyl-5-phenyl aldehyde derivatives are conveniently prepared by a number of methods known in the art. For example, by an Aldol condensation between 3-phenylpropanal and proprionaldehyde, followed by hydrogenation of the resulting α,β-unsaturated aldehyde to form the saturated aldehyde, 2-methyl-5-phenylpentanal. This aldehyde is the direct precursor for the alcohol, 2-methyl-5-phenylpentan-1-ol via reduction with, e.g. sodium borohydride, as well as the nitrile, 2,4-dimethyl-5-phenyl-pentanitrile via oxidation dehydration chemistry by reaction of hydroxylamine/formic acid as described above. Alternatively, aldehyde derivatives may be prepared by oxidation of the corresponding primary alcohol, i.e. 2-methyl-5-phenylpentan-1-ol, a known compound. The corresponding nitrile, 2-methyl-5-phenylpentanenitrile, is prepared by converting the aldehyde via reaction with hydroxylamine to form the aldoxime intermediate and subsequent formic acid catalyzed dehydration. The primary alcohol may also be converted to the corresponding acid as described above.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:16])[C:8]([CH3:10])([CH3:9])[O:7][B:6]([C:11]2[CH:12]=[N:13][NH:14][CH:15]=2)[O:5]1.[F:17][CH:18]([F:21])[CH2:19]I>CN(C=O)C.[Cl-].[Na+].O>[F:17][CH:18]([F:21])[CH2:19][N:14]1[CH:15]=[C:11]([B:6]2[O:7][C:8]([CH3:9])([CH3:10])[C:4]([CH3:16])([CH3:3])[O:5]2)[CH:12]=[N:13]1
Reactant: FC(F)CI
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OB(c2cnn(CC(F)F)c2)OC1(C)C
Reaction time: 0.25 h

Procedure:
NaH (60%, 128 mg) was added to a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (313 mg, 1.61 mmol) in DMF (4 mL). After stirring for 15 minutes, 1,1-difluoro-2-iodoethane (372 mg, 1.94 mmol) in DMF (1 mL) was added. The resulting solution was stirred at 80° C. under microwave irradiation for 60 minutes. The reaction mixture was diluted with brine and extracted with EtOAc. The combined organic layers were washed with water, dried with Na2SO4, and concentrated in vacuo to afford the title compound as a yellow oil that was used directly in the next step (210 mg, 50%).
Reaction SMILES: CO[C:3]1[CH:26]=[CH:25][C:6]([CH2:7][S:8][C:9]2[N:14]=[C:13]([Cl:15])[CH:12]=[C:11]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=3[CH3:24])[N:10]=2)=[CH:5][CH:4]=1.F[C:28](F)(F)C(O)=O>>[CH2:7]([S:8][C:9]1[N:14]=[C:13]([Cl:15])[CH:12]=[C:11]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[CH3:24])[N:10]=1)[CH2:6][CH2:25][CH2:26][CH2:3][CH2:4][CH2:5][CH3:28]
Reactant: COc1ccc(CSc2nc(Cl)cc(Nc3cccc(C)c3C)n2)cc1
Reactant: O=C(O)C(F)(F)F
Product: CCCCCCCCSc1nc(Cl)cc(Nc2cccc(C)c2C)n1

Procedure:
To a suspension of 2-p-methoxybenzylthio-4-chloro-6-(2,3-xylidino)-pyrimidine (8 g; see example 5) in trifluoroacetic acid (80 ml) anisole (2,7 ml) is added and the mixture is refluxed for 50'. After cooling, the trifluoroacetic acid is evaporated. The residue is dissolved in ethyl ether and the separated solid is filtered, washed with ethyl ether, then with water to neutrality, with cool acetone and again with ethyl ether. 5 G of the desired product (III, 33) are obtained.
Reaction SMILES: [CH3:1][C:2]1[C:11]([C:12]([OH:14])=O)=[CH:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2([OH:41])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)=[CH:31][CH:30]=1.C(Cl)Cl>CCOC(C)=O>[OH:41][C:35]1([C:32]2[CH:31]=[CH:30][C:29]([CH2:28][NH:27][C:12]([C:11]3[C:2]([CH3:1])=[N:3][C:4]4[C:9]([CH:10]=3)=[CH:8][CH:7]=[CH:6][N:5]=4)=[O:14])=[CH:34][CH:33]=2)[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]1
Reactant: NCc1ccc(C2(O)CCCCC2)cc1
Reactant: Cc1nc2ncccc2cc1C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1nc2ncccc2cc1C(=O)NCc1ccc(C2(O)CCCCC2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 17.5 %

Procedure:
144 mg (0.76 mmol) 2-methyl-1,8-naphthyridine-3-carboxylic acid and 136 mg (0.84 mmol) CDI were refluxed in 5 ml EtOAc for 2 h. The solution was cooled to r.t. and 157 mg (0.76 mmol) 1-(4-(aminomethyl)phenyl)cyclohexanol followed by 5 ml CH2Cl2 was added. The mixture was stirred for 2 days at r.t. Concentrated to dryness and purified by flash chromatography (SiO2, CH2Cl2/MeOH 20:1→10:1) to afford 50 mg (13%) of the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH2:15][CH2:14][C:9]3([NH:13][CH2:12][CH2:11][CH2:10]3)[CH2:8]2)[CH:2]=1.[C:16](=O)(O)[O-].[Na+]>C(O)=O.C=O>[CH3:16][N:13]1[C:9]2([CH2:14][CH2:15][N:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH2:8]2)[CH2:10][CH2:11][CH2:12]1
Reactant: O=C([O-])O
Reactant: c1cncc(N2CCC3(CCCN3)C2)c1
Agent: C=O
Agent: [Na+]
Solvent: O=CO
Product: CN1CCCC12CCN(c1cccnc1)C2
Temperature: 25 °C
Yield: 93.6 %

Procedure:
7-(3-Pyridyl)-1,7-diazaspiro[4.4]nonane (30 mg, 0.15 mmol) was dissolved in 98% formic acid (0.5 mL) and formaldehyde (1 mL, 28% aqueous solution). The reaction mixture was heated to reflux for 8 h. The reaction mixture was cooled to room temperature, basified with saturated aqueous sodium bicarbonate to pH 9-10 and extracted with chloroform (4×3 mL). The combined chloroform extracts were dried (K2CO3), filtered and concentrated on a rotary evaporator to afford 30 mg of the desired compound (93.6%) as a light brown liquid.
Reaction SMILES: [Br:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][CH2:7][C:8]2[S:9][C:10]3[N:11]=[C:12]([NH2:23])[N:13]=[C:14]([N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[C:15]=3[N:16]=2)=[CH:4][CH:3]=1.[CH3:26][O:27][C:28]1[CH:38]=[CH:37][C:31]([O:32][CH2:33][C:34](O)=[O:35])=[CH:30][CH:29]=1>>[NH2:23][C:12]1[N:13]=[C:14]([N:17]2[CH2:18][CH2:19][N:20]([C:34](=[O:35])[CH2:33][O:32][C:31]3[CH:37]=[CH:38][C:28]([O:27][CH3:26])=[CH:29][CH:30]=3)[CH2:21][CH2:22]2)[C:15]2[N:16]=[C:8]([CH2:7][CH2:6][C:5]3[CH:24]=[CH:25][C:2]([Br:1])=[CH:3][CH:4]=3)[S:9][C:10]=2[N:11]=1
Reactant: Nc1nc(N2CCNCC2)c2nc(CCc3ccc(Br)cc3)sc2n1
Reactant: COc1ccc(OCC(=O)O)cc1
Product: COc1ccc(OCC(=O)N2CCN(c3nc(N)nc4sc(CCc5ccc(Br)cc5)nc34)CC2)cc1
Yield: 40 %

Procedure:
This compound was prepared from 2-(4-bromophenethyl)-7-(piperazin-1-yl)thiazolo[5,4-d]pyrimidin-5-amine using 4-methoxyphenoxyacetic acid in a yield of 40%, according to the procedure for the synthesis of example 50. 1H NMR (300 MHz, CDCl3, 25° C.): δ=7.40 (d, 2H, PhH), 7.07 (d, 2H, PhH), 6.82-6.93 (m, 4H, PhH), 4.71 (s, 2H, NH2), 4.70 (s, 2H, OCH2), 4.23 (br s, 2H, NCH2), 4.19 (br s, 2H, NCH2), 3.77 (s, 3H, CH3), 3.67-3.75 (m, 4H, N(CH2)2), 3.23 (t, 2H, CH2), 3.05 (t, 2H, CH2) ppm
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[CH:10]=[C:11]3[N:17]([N:18]=2)[C:16]2[CH:19]=[C:20]([C:23]([OH:25])=O)[CH:21]=[CH:22][C:15]=2[O:14][CH2:13][CH2:12]3)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].Cl.Cl.[F:28][C:29]([F:38])([F:37])[CH2:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[CH:1]([N:4]1[C:8]([C:9]2[CH:10]=[C:11]3[N:17]([C:16]4[CH:19]=[C:20]([C:23]([N:34]5[CH2:33][CH2:32][N:31]([CH2:30][C:29]([F:37])([F:38])[F:28])[CH2:36][CH2:35]5)=[O:25])[CH:21]=[CH:22][C:15]=4[O:14][CH2:13][CH2:12]3)[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:2])[CH3:3]
Reactant: FC(F)(F)CN1CCNCC1
Reactant: CC(C)n1ncnc1-c1cc2n(n1)-c1cc(C(=O)O)ccc1OCC2
Agent: Cl
Product: CC(C)n1ncnc1-c1cc2n(n1)-c1cc(C(=O)N3CCN(CC(F)(F)F)CC3)ccc1OCC2

Procedure:
Following the procedure for 116, 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-9-carboxylic acid was reacted with 1-(2,2,2-trifluoroethyl)piperazine dihydrochloride to give 124 as a white solid. 1H NMR (CDCl3, 400 MHz): δ 8.02 (d, J=2.1 Hz, 1H); 7.95 (s, 1H); 7.35 (dd, J=8.3, 2.1 Hz, 1H); 7.23 (d, J=8.3 Hz, 1H); 6.88 (s, 1H); 5.73-5.60 (m, 1H); 4.58 (t, J=5.8 Hz, 2H); 3.94-3.44 (br m, 4H); 3.20 (t, J=5.8 Hz, 2H); 3.04 (q, J=9.4 Hz, 2H); 2.74 (br s, 4H); 1.58 (d, J=6.6 Hz, 6H). LCMS: RT=10.93 min, M+H+=490
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([CH:13]2[CH2:17][NH:16][C:15](=[O:18])[CH2:14]2)=[CH:7][C:6]=1[O:19][CH3:20])[CH3:4].[CH3:21]I>O1CCCC1.CN(C)C=O>[CH2:3]([C:5]1[C:6]([O:19][CH3:20])=[CH:7][C:8]([CH:13]2[CH2:17][N:16]([CH3:21])[C:15](=[O:18])[CH2:14]2)=[CH:9][C:10]=1[O:11][CH3:12])[CH3:4]
Reactant: CCc1c(OC)cc(C2CNC(=O)C2)cc1OC
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCc1c(OC)cc(C2CC(=O)N(C)C2)cc1OC
Temperature: 25 °C
Yield: 86.4 %

Procedure:
3.12 g (78 mmol) of a sodium hydride dispersion (60% in oil) were added using a spatula and while stirring to a suspension of 8.85 g (35.5 mmol) of 4-(4-ethyl-3,5-dimethoxy-phenyl)-pyrrolidin-2-one in 250 ml of tetrahydrofuran and 2 ml of dimethylformamide and the mixture was stirred at room temperature for a further hour. Thereafter, the reaction mixture was treated with 3.52 ml (106.5 mmol) of methyl iodide and left to stir at room temperature for a further 16 hours. Subsequently, the reaction mixture was poured on to 400 ml of ice-water and extracted twice with 600 ml of ethyl acetate each time. The combined organic phases were washed twice with 300 ml of saturated sodium chloride solution each time, dried (MgSO4) and concentrated in a vacuum. The crude product was purified by column chromatography on silica gel (methylene chloride/methanol 39:1). 8.08 g (86%) of 4-(4-ethyl-3,5-dimethoxy-phenyl)-1-methyl-pyrrolidin-2-one were obtained as a beige solid.