Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12](=[O:30])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][C:14]=3[NH:19][CH2:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]4[NH:27][CH:28]=[CH:29][C:22]=34)=[CH:8][CH:9]=2)[NH:4][CH2:3]1.C(OC([N:39]1[CH2:42][CH:41]([C:43](O)=[O:44])[CH2:40]1)=O)(C)(C)C>>[NH:39]1[CH2:42][CH:41]([C:43]([N:4]2[C:5]3[C:10](=[CH:9][CH:8]=[C:7]([NH:11][C:12](=[O:30])[C:13]4[CH:18]=[CH:17][CH:16]=[N:15][C:14]=4[NH:19][CH2:20][C:21]4[CH:26]=[CH:25][N:24]=[C:23]5[NH:27][CH:28]=[CH:29][C:22]=45)[CH:6]=3)[C:2]([CH3:31])([CH3:1])[CH2:3]2)=[O:44])[CH2:40]1
Reactant: CC1(C)CNc2cc(NC(=O)c3cccnc3NCc3ccnc4[nH]ccc34)ccc21
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Product: CC1(C)CN(C(=O)C2CNC2)c2cc(NC(=O)c3cccnc3NCc3ccnc4[nH]ccc34)ccc21

Procedure:
The titled compound was prepared from N-(3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-[(1H-pyrrolo[2,3-b]pyridin-4-ylmethyl)amino]nicotinamide (Example 16) and azetidine-1,3-dicarboxylic acid 1-tert-butyl ester by the method described in Example 13. MS (ES+): 496 (M+H). Calc'd. for C28H29N7O2—495.58.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([NH:10][C:11]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([O:19][CH3:20])[CH:12]=1)[CH2:7][CH2:8][CH3:9].C(Cl)(Cl)Cl.CN(C)[CH:27]=[O:28]>>[CH2:6]([N:10]([CH2:6][CH2:7][CH2:8][CH3:9])[C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([CH:27]=[O:28])=[C:13]([O:19][CH3:20])[CH:12]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CN(C)C=O
Reactant: CCCCNc1cc(OC)cc(OC)c1
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCN(CCCC)c1cc(OC)c(C=O)c(OC)c1
Temperature: 7.5 °C
Yield: 80 %

Procedure:
In a stream of argon, to 30 ml of N,N-dimethylformamide was added 16.0 g (104 mmol) of phosphorus oxychloride under cooling at 5 to 10° C. and stirring. After the mixture was well-stirred, 23.5 g (80.1 mmol) of 4-butylamino-2,6-dimethoxybenzene dissolved in 10 ml of N,N-dimethylformamide was added dropwise. The mixture was reacted with stirring for 1.5 hours. After the mixture was poured into 70 ml of ice water, extraction with 200 ml of chloroform, washing with a saturated saline solution, drying over anhydrous magnesium sulfate, and concentration were performed. The residue was purified by silica gel chromatography to give 18.8 g (yield: 80%) of 4-dibutylamino-2,6-dimethoxybenzaldehyde as a dark purple crystal (mp: 55-56° C.)
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH2:9][OH:10])=[C:4]([Cl:11])[CH:3]=1.N12CCCN=C1CCCCC2.[Cl:23][C:24]([Cl:28])([Cl:27])[C:25]#[N:26]>C(Cl)Cl>[Cl:23][C:24]([Cl:28])([Cl:27])[C:25](=[NH:26])[O:10][CH2:9][C:5]1[CH:6]=[C:7]([F:8])[C:2]([Br:1])=[CH:3][C:4]=1[Cl:11]
Reactant: N#CC(Cl)(Cl)Cl
Reactant: OCc1cc(F)c(Br)cc1Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: N=C(OCc1cc(F)c(Br)cc1Cl)C(Cl)(Cl)Cl
Reaction time: 4 h
Yield: 91.6 %

Procedure:
To a solution of (4-bromo-2-chloro-5-fluorophenyl)methanol (3.95 g, 16.49 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (0.5 mL, 3.34 mmol) in methylene chloride (30 mL) was added trichloroacetonitrile (, 2.50 mL, 24.93 mmol) over 5 min at 0° C., stirring was continued for 4 h at 0° C. After concentrated in vacuo, the residue was purified by column chromatography eluting with 5% ethyl acetate in hexanes to give 4-bromo-2-chloro-5-fluorobenzyl 2,2,2-trichloroacetimidate as a colorless solid (5.80 g, 91%): δ 8.49 (s, 1H), 7.59 (d, J=6.3 Hz, 1H), 7.32 (d, J=9.0 Hz, 1H), 5.37 (s, 2H).
Reaction SMILES: N12CCN(CC1)CC2.[OH:9][C:10]1[CH:11]=[N:12][C:13]2[C:18]([C:19]=1[CH:20]=O)=[N:17][C:16]([O:22][CH3:23])=[CH:15][CH:14]=2.C(N(CC)CC)C.CS(Cl)(=O)=O.[CH3:36][O:37][C:38](=[O:41])[CH:39]=[CH2:40]>C(OCC)(=O)C>[CH3:36][O:37][C:38]([C:39]1[CH2:40][O:9][C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[CH:20]=1)=[N:17][C:16]([O:22][CH3:23])=[CH:15][CH:14]=3)=[O:41]
Reactant: C=CC(=O)OC
Reactant: COc1ccc2ncc(O)c(C=O)c2n1
Agent: C1CN2CCN1CC2
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)C1=Cc2c(cnc3ccc(OC)nc23)OC1
Temperature: 25 °C
Yield: 53 %

Procedure:
1,4-Diazabicyclo[2.2.2]octane (522 mg, 4.65 mmol, 1.0 eq) is added at room temperature to a stirred suspension of 3-hydroxy-6-methoxy-[1,5]naphthyridine-4-carbaldehyde (950 mg, 4.65 mmol, 1.0 eq) in acrylic acid methyl ester (20 mL) and the resulting mixture is heated under reflux for 3 hours. The reaction mixture is then cooled down to room temperature, solvent is removed and the residue is dissolved in 1,2-dichloroethane (20 mL). Triethylamine (19.5 mL, 139.6 mmol, 30.0 eq) is then added at 0° C., followed by methanesulfonyl chloride (3.85 mL, 69.8 mml, 15.0 eq) and the resulting mixture is heated under reflux for 4 hours. Solvent is removed and the residue is extracted with dichloromethane (3×40 mL) and water (40 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate, 10:1 to 5:1, v/v) to afford 6-methoxy-2H-1-oxa-5,9-diaza-phenanthrene-3-carboxylic acid methyl ester as a light yellow oil (670 mg, 53% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11](=[O:15])[N:12]([CH3:14])[N:13]=2)=[CH:4][CH:3]=1.[NH:16](C1C=CC(C2C(C)CC(=O)NN=2)=CC=1)N>>[NH:1]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11](=[O:15])[N:12]([CH3:14])[N:13]=2)=[CH:4][CH:3]=1)[NH2:16]
Reactant: Cn1nc(-c2ccc(N)cc2)ccc1=O
Reactant: CC1CC(=O)NN=C1c1ccc(NN)cc1
Product: Cn1nc(-c2ccc(NN)cc2)ccc1=O

Procedure:
The title compound was prepared from 6-(4-aminophenyl)-2-methyl-2H-pyridazin-3-one similarly as 6-(4-hydrazinophenyl)-5-methyl-4,5-dihydro-2H-pyridazin-3-one.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([C:10]2[N:11]=[C:12]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[S:13][C:14]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:22](=[O:24])[CH3:23])[CH:16]=2)[CH:7]=[CH:8][CH:9]=1.[C:31](Cl)(=[O:33])[CH3:32].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>O1CCCC1>[C:31]([N:28]1[CH2:29][CH2:30][CH:25]([C:12]2[S:13][C:14]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:22](=[O:24])[CH3:23])[CH:16]=3)=[C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([Cl:3])[CH:5]=3)[N:11]=2)[CH2:26][CH2:27]1)(=[O:33])[CH3:32]
Reactant: CC(=O)Nc1cc(-c2sc(C3CCNCC3)nc2-c2cccc(Cl)c2)ccn1
Reactant: CC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Nc1cc(-c2sc(C3CCN(C(C)=O)CC3)nc2-c2cccc(Cl)c2)ccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.8 %

Procedure:
To a suspension of N-[4-[4-(3-chlorophenyl)-2-(4-piperidyl)-1,3-thiazol-5-yl]-2-pyridyl]acetamide dihydrochloride (0.41 g, 0.84 mmol) in tetrahydrofuran (20 mL) were added acetyl chloride (0.13 mL, 1.8 mmol) and triethylamine (0.50 mL, 3.6 mmol) sequentially, and the resulting mixture was stirred at room temperature for 30 minutes. Aqueous sodium hydrogen carbonate was added to the reaction mixture and extracted with ethyl acetate. The extracts were washed with water, dried, and concentrated. The residue was recrystallized from ethyl acetate-hexane to give a title compound (0.24 g, yield 62%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.Cl.[NH2:12][C:13]1[CH:29]=[CH:28][C:27]2[C:18]3[NH:19][C:20](=[O:26])[C:21]4[N:22]([CH:23]=[CH:24][N:25]=4)[C:17]=3[CH2:16][C:15]=2[CH:14]=1.C(N(CC)CC)C>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[NH:12][C:13]2[CH:29]=[CH:28][C:27]3[C:18]4[NH:19][C:20](=[O:26])[C:21]5[N:22]([CH:23]=[CH:24][N:25]=5)[C:17]=4[CH2:16][C:15]=3[CH:14]=2)=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: Nc1ccc2c(c1)Cc1c-2[nH]c(=O)c2nccn12
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(F)cc1)Nc1ccc2c(c1)Cc1c-2[nH]c(=O)c2nccn12
Reaction time: 12 h
Yield: 54.9 %

Procedure:
A solution of 1.76 g of 4-fluorophenyl isocyanate in 20 ml of dimethylformamide is added over 30 minutes to a solution of 2 g of 8-amino-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazine-4-one hydrochloride, 20 ml of dimethylformamide and 1.3 g of triethylamine and stirring is carried out for 12 hours at a temperature in the region of 20° C. The reaction mixture is filtered and the insoluble material is washed with dimethylformamide (2×10 ml) and then with water (3×15 ml) and dried in the air. The crude product is then triturated in 30 ml of dimethylformamide, filtered, washed with water and then with isopropyl ether and dried at 60° C. under vacuum (1 mm Hg, 0.13 kPa). There are obtained 1.5 g of 8-[3-(4-fluoro-phenyl)ureido]-5H,10H-imidazo[1,2-a]indeno[1,2-e]-pyrazine-4-one in the form of a beige solid melting above 260° C. (Analysis, % calculated C: 64.00, H: 3.76, F: 5.06, N: 18.66, O: 8.52, % found C: 64.0, H: 3.8, N: 19.0).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1[CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:47]=[CH:46][C:18]([CH2:19][CH:20]2[S:24][C:23](=[O:25])[N:22](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:21]2=[O:45])=[CH:17][CH:16]=1.C(O)(=O)C>O>[CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1[CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:47]=[CH:46][C:18]([CH2:19][CH:20]2[S:24][C:23](=[O:25])[NH:22][C:21]2=[O:45])=[CH:17][CH:16]=1
Reactant: Cn1c(CCCOc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)nc2cccnc21
Solvent: O
Solvent: CC(=O)O
Product: Cn1c(CCCOc2ccc(CC3SC(=O)NC3=O)cc2)nc2cccnc21

Procedure:
A procedure similar to that described in Example 12 was repeated, except that 240 mg of 5-[4-{3-(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)propoxy}benzyl]-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 35) and 10 ml of a 3:1 by volume mixture of acetic acid and water were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of hexane and ethyl acetate in ratios ranging from 1:3 to 0:1 by volume as the eluent, to give 93 mg of the title compound, melting at 185-186° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:15])[CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:15])[CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:4][CH:3]=2)=[CH:20][CH:19]=1
Reactant: CC(CNS(C)(=O)=O)c1ccc(Br)cc1
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2ccc(C(C)CNS(C)(=O)=O)cc2)cc1

Procedure:
The title compound was prepared from the product of Example 1 as described in Example 6 with the exception that 4-methoxybenzeneboronic acid was used instead of 2-methoxybenzeneboronic acid.
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:13][CH2:14][C@H:15]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:16](=[O:32])[NH:17][C@@H:18]1[CH2:24][CH2:23][CH2:22][CH2:21][N:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]1=[O:31])[C:9]([O:11]C)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-].O.Cl>CO>[CH2:1]([C@@H:8]([CH2:13][CH2:14][C@H:15]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:16](=[O:32])[NH:17][C@@H:18]1[CH2:24][CH2:23][CH2:22][CH2:21][N:20]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:19]1=[O:31])[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H](CC[C@H](Cc1ccccc1)C(=O)N[C@@H]1CCCCN(c2ccccc2)C1=O)Cc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)[C@H](CC[C@H](Cc1ccccc1)C(=O)N[C@@H]1CCCCN(c2ccccc2)C1=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 95.8 %

Procedure:
To a round bottom flask was added (2R,5R)-methyl 2,5-dibenzyl-6-oxo-6-((R)-2-oxo-1-phenylazepan-3-ylamino)hexanoate (300 mg, 0.570 mmol), 2 M LiOH in water (5.0 mL, 10 mmol) and MeOH (5 mL). The reaction was stirred at rt for 2 days. The reaction mixture was then cooled in an ice-bath and aqueous 1 M HCl was added slowly to adjust the pH to 4. A white precipitant was formed. The product was collected by filtration and washed with water (2×5 mL) to give (2R,5R)-2,5-dibenzyl-6-oxo-6-((R)-2-oxo-1-phenylazepan-3-ylamino)hexanoic acid (280 mg, 0.546 mmol, 96% yield) as a white solid. Anal. Calcd. for C32H36N2O4 m/z 512.4. found: 513.3 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].Br[CH:19]([CH3:24])[C:20]([O:22][CH3:23])=[O:21]>C(#N)C>[CH3:23][O:22][C:20]([CH:19]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:9])=[O:10])[CH3:24])=[O:21]
Reactant: NS(=O)(=O)c1ccccc1O
Reactant: COC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)C(C)Oc1ccccc1S(N)(=O)=O

Procedure:
34.6 g of 2-hydroxybenzenesulfonamide and 55.3 g of potassium carbonate are added to 800 ml of acetonitrile. With efficient stirring, 33.4 g of methyl 2-bromopropionate are added dropwise over 10 minutes and the suspension is then heated for 5 hours to 45° C. After the reaction mixture has cooled, the precipitated salts are isolated and the filtrate is concentrated in vacuo. The residue is recrystallised from ethanol, affording 41.8 of 2-(1-methoxycarbonylethoxy)benzenesulfonamide with a melting point of 140°-142° C.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([O:12][C:13]1[CH:14]=[CH:15][C:16]2[O:21][CH2:20][C:19](=[O:22])[NH:18][C:17]=2[CH:23]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(O)(=O)C>[N+:1]([C:14]1[C:13]([O:12][CH2:5][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)=[CH:23][C:17]2[NH:18][C:19](=[O:22])[CH2:20][O:21][C:16]=2[CH:15]=1)([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: O=C1COc2ccc(OCc3ccccc3)cc2N1
Solvent: CC(=O)O
Product: O=C1COc2cc([N+](=O)[O-])c(OCc3ccccc3)cc2N1
Reaction time: 1 h

Procedure:
Aqueous 65% nitric acid (5.04 g, 0.052 mole) was added under stirring at room temperature to the oxazinone ((d), 12 g, 0.047 mole) in acetic acid (ml 30). After 1 hour, the separated solid was filtered and washed with acetic acid to give the nitroxazinone ((e), 9 g, 64%) as yellow prisms. The product structure was confirmed by NMR analysis.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[S:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6].[H-].[Na+].[CH:16]1(Br)[CH2:20][CH2:19][CH2:18][CH2:17]1>CN(C)C=O>[CH:16]1([O:1][C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=2[S:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COC(=O)c1ccc(SC)c(O)c1
Reactant: BrC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(SC)c(OC2CCCC2)c1
Reaction time: 0.42 h

Procedure:
A stirred solution of methyl 3-hydroxy-4-(methylthio)benzoate (1.98 g; that is prepared as described in Reference Example 53) in dry dimethyl-formamide (40 mL) is treated with sodium hydride (0.44 g of a 60% dispersion in mineral oil; 11 mmol) and the solution is stirred for a further 25 minutes. The reaction mixture is treated with cyclopentyl bromide (1.64 g), stirred at 60° C. for 3 hours and then concentrated. The resulting residue is partitioned between dichloromethane (50 mL) and water (50 mL), the aqueous layer is extracted with dichloromethane (50 mL), and the combined organic layers are dried and concentrated, to give a red oil. The oil is subjected to flash chromatography, eluting with a mixture of diethyl ether and pentane (1:9 v/v), to give methyl 3-cyclopentyloxy-4-(methylthio)benzoate (1.9 g), m.p. 53-55° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][C:26]=4[O:28][C@@H:29]([CH3:33])[C:30]([OH:32])=O)[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>>[CH3:33][C@H:29]([O:28][C:26]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:27]=1[C:18]([NH:17][C:13]1[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[N:9]=[CH:10]3)=[N:19][CH:20]=[N:21]2)[C:30]([N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)=[O:32]
Reactant: C1COCCN1
Reactant: C[C@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12)C(=O)O
Product: C[C@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12)C(=O)N1CCOCC1
Yield: 34 %

Procedure:
Using the same procedure as in Example 44, (2S)-2-[(4-{[1-(pyridin-2-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoic acid (300 mg, 0.68 mmol) was reacted with morpholine to give the title compound as a white solid (120 mg, 34%); NMR spectrum 1.58 (d, 3H), 3.67-3.58 (m, 8H), 5.77 (s, 2H), 5.88 (q, 1H), 6.95 (d, 1H), 7.29 (m, 2H), 7.35 (d, 1H), 7.75-7.67 (m, 3H), 7.83 (m, 1H), 8.15 (s, 1H), 8.52 (m, 3H), 11.12 (s, 1H); Mass spectrum MH+ 510.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][N:3]=1.[C:16]([NH:24][NH2:25])(=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C=O)C>[C:17]1([C:16]2[N:3]3[CH:4]=[C:5]([C:12]([O:14][CH3:15])=[O:13])[C:6]4[C:11]([C:2]3=[N:25][N:24]=2)=[CH:10][CH:9]=[CH:8][CH:7]=4)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1cnc(Cl)c2ccccc12
Reactant: NNC(=O)c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cn2c(-c3ccccc3)nnc2c2ccccc12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 1-Chloroisoquinoline-4-carboxylate, prepared essentially according to procedures described in Example 1, part 4, (293 mg) and benzoic hydrazide (192 mg) in 8 ml of DMF is stirred at 100° C. overnight. The mixture is cooled and poured into water. The solid is then collected by filtration and dried to give the title compound as a solid (258 mg). LC-MS data for the title compound: HPLC: 2.34 min. MS (ES+) m/e 304 [M+H]+. (The HPLC retention time is obtained by the method of Example 1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([S:16][CH2:17][C:18]([N:20]2[CH2:25][CH2:24]O[CH2:22][CH2:21]2)=[O:19])[CH3:15])=[CH:10][CH:9]=1.[CH2:26]1CCCCC1.C(OCC)(=O)C>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([S:16][CH2:17][C:18]([N:20]2[CH2:25][CH2:24][CH2:26][CH2:22][CH2:21]2)=[O:19])[CH3:15])=[CH:10][CH:9]=1
Reactant: C1CCCCC1
Reactant: CC(SCC(=O)N1CCOCC1)c1ccc(-c2ccccc2Cl)cc1
Solvent: CCOC(C)=O
Product: CC(SCC(=O)N1CCCCC1)c1ccc(-c2ccccc2Cl)cc1

Procedure:
[1-(2'-Chloro-4-biphenylyl)-ethylthio]-acetic acid morpholide, oil, Rf -value: 0.4 on carrier 1 with cyclohexane/ethyl acetate = 1:1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2(Br)[CH2:11][C:10]2(Br)Br)=[CH:4][CH:3]=1.C[Li].O>C(OCC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH2:10][CH:11]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(CC2(Br)CC2(Br)Br)cc1
Agent: [Li]C
Solvent: CCOCC
Solvent: O
Product: Clc1ccc(CC2=CC2)cc1
Reaction time: 0.25 h
Yield: 87.6 %

Procedure:
A solution of 1.20 g (0.00298 mol) of 2-(4-chlorophenylmethyl)-1,1,2-tribromocyclopropane in 6 ml of diethyl ether was placed under a nitrogen atmosphere via use of a Firestone valve. While cooling in an ice water bath, 6.38 ml (0.00893 mol) of 1.4M methyl lithium in diethyl ether was added slowly by syringe. After 15 minutes, 2 ml of water was added via syringe. The resulting mixture was transferred to a separatory funnel and the phases were separated. The organic layer was dried over MgSO4 and filtered. The solvent was removed from the filtrate in vacuo with a bath temperature under 20° C. to yield 0.430 g of 1-(4-chlorophenylmethyl)-cyclopropene as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11](=O)[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])([O-])=O>[Pd].C(O)C>[NH:1]1[C:4]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:10]=[C:11]1[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)CC(=O)Cc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)Cc1cc2ccccc2[nH]1

Procedure:
A mixture of ethyl 4-(2-nitrophenyl)-3-oxobutanoate (17.04 g, 67.8 mmol), 10% palladium on carbon (3.6 g), and ethanol (280 mL) was placed under hydrogen pressure (50 psi, 3.4×105 Pa) on a Parr apparatus for 96 hours. The reaction mixture was filtered through a layer of CELITE filter aid. The filtrate was concentrated under reduced pressure to provide crude ethyl 1H-indol-2-ylacetate.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:6]=[C:5]([CH3:18])[C:3]=1[NH2:4].CCN(C(C)C)C(C)C.[Cl:28][CH2:29][C:30](Cl)=[O:31]>ClCCl>[Cl:28][CH2:29][C:30]([NH:4][C:3]1[C:2]([CH3:1])=[CH:8][C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:6][C:5]=1[CH3:18])=[O:31]
Reactant: CCCCCCCCOc1cc(C)c(N)c(C)c1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCOc1cc(C)c(NC(=O)CCl)c(C)c1

Procedure:
Under a nitrogen atmosphere, 2,6-dimethyl-4-(octyloxy)-aniline (7.2 mmols) was dissolved in 50 mL dichloromethane. To this was added DIPEA (9.4 mmols). The reaction mixture was cooled in an ice bath, and chloroacetyl chloride (7.95 mmoles) dissolved in 50 mL dichloromethane was added by dropping funnel. After the addition was complete, the reaction was stirred at room until reaction was complete by TLC (approximately 0.5 hours). The reaction mixture was concentrated, and partitioned between ethyl acetate and water. The organic layer was washed with saturated NaHCO3(×2), brine, dried over MgSO4, and filtered (rinsing with ethyl acetate). The filtrate was concentrated to yield 2-chloro-N-(2,6-dimethyl-4-octyloxyphenyl)-acetamide as a white solid (1.21 grams; 51%). The product was characterized by NMR (DMSO).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[Cl:11].[NH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15].O>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])=[O:7])=[CH:4][C:3]=1[Cl:11]
Reactant: C[Si](C)(C)CN
Reactant: O=C(O)c1ccc(Br)c(Cl)c1
Solvent: ClCCl
Solvent: O
Product: C[Si](C)(C)CNC(=O)c1ccc(Br)c(Cl)c1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
To a suspension of 4-bromo-3-chlorobenzoic acid (25.00 g, 106.2 mmol) in CH2Cl2 (320 mL) was added N,N-dimethyl aminopyridine (1.95 g), followed by N-ethyl-N-dimethylamine propylcarbodiimide hydrochloride (22.39 g) in small portions. After 30 min at room temperature, aminomethyl trimethylsilane (11.2 g, 7.87 mL, 108 mmol) was added while maintaining the temperature at 20° C. After stirring over night, water was added and the organic layer was separated. The aqueous layer was extracted twice with CH2Cl2 and the combined organic phases were dried and evaporated in vacuum. The residue was purified by flash chromatography on silica gel to give the title compound (34.00 g, 100%).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C@H:8]([NH:10]C(=O)OC(C)(C)C)[CH3:9])[CH2:4][CH2:3]1.CCOCC>ClCCl>[NH2:10][C@@H:8]([CH:5]1[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]1)[CH3:9]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C1CCC(O)CC1
Solvent: ClCCl
Solvent: CCOCC
Product: C[C@@H](N)C1CCC(O)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Tert-butyl (R)-1-(4-hydroxycyclohexyl)ethylcarbamate (4.49 g, 18.45 mmol) was dissolved in dichloromethane (25 mL) and cooled to 0° C. under nitrogen. HCl 2M in Ether (27.68 mL of 2 M, 55.35 mmol) was added and the reaction allowed to warm slowly to ambient temperature for 18 hours. The reaction mixture was concentrated in vacuo. The crude mixture was dissolved in MeOH (25 mL). MP-Carbonate was added (11.75 g, 36.90 mmol) and the reaction mixture was stirred for 3 hours. The resin was filtered and the mother liquors were concentrated to dryness to afford the title compound as an off white solid (2.39 g, 90% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:21]=[C:22]([O:25][CH2:26][CH3:27])[C:23]=1I)[CH2:12][C:13]1[C:14]([NH2:20])=[N:15][C:16]([NH2:19])=[N:17][CH:18]=1)[C:2]1C=CC=[CH:4][CH:3]=1.[N:28]1([CH2:34][C:35]2[S:39][C:38]([B])=[CH:37][CH:36]=2)[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[CH:2]1([CH2:1][O:8][C:9]2[CH:10]=[C:11]([CH:21]=[C:22]([O:25][CH2:26][CH3:27])[C:23]=2[C:38]2[S:39][C:35]([CH2:34][N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[CH:36][CH:37]=2)[CH2:12][C:13]2[C:14]([NH2:20])=[N:15][C:16]([NH2:19])=[N:17][CH:18]=2)[CH2:3][CH2:4]1
Reactant: CCOc1cc(Cc2cnc(N)nc2N)cc(OCc2ccccc2)c1I
Reactant: [B]c1ccc(CN2CCOCC2)s1
Product: CCOc1cc(Cc2cnc(N)nc2N)cc(OCC2CC2)c1-c1ccc(CN2CCOCC2)s1

Procedure:
Prepared analogously to example (2ac) starting from 5-(3-benzyloxy-5-ethoxy-4-iodo-benzyl)-pyrimidine-2,4-diamine (example 6) (1.429 g; 3 mmol) and (5-morpholin-4-ylmethyl-thiophen-2-yl)-boron acid (681 mg; 3 mmol).