Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[CH3:9][C:10]([OH:14])([C:12]#[CH:13])[CH3:11].C(N(CC)CC)C>CN(C=O)C.[Cu]I>[Cl:1][C:2]1[N:3]=[N:4][C:5]([C:13]#[C:12][C:10]([CH3:11])([OH:14])[CH3:9])=[CH:6][CH:7]=1
Reactant: C#CC(C)(C)O
Reactant: Clc1ccc(Cl)nn1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(O)C#Cc1ccc(Cl)nn1
Temperature: 80 °C

Procedure:
To a solution of 3,6-dichloropyridazine (250 mg, 1.68 mmol) and 2-methylbut-3-yn-2-ol (282 mg, 3.36 mmol) in DMF (4 mL) were added CuI (64 mg, 0.33 mmol), triethylamine (0.47 mL, 3.36 mmol), and palladium tetrakis triphenylphosphine (194, 0.168 mmol). The solution was degassed and heated to 80° C. overnight. The residue was worked up with EtOAc and water, dried with MgSO4, filtered, and concentrated. Column chromatography on silica gel 100% Hex to 100% EtOAc provided the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][C@H:12]1[C:20](O)=[O:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1CCOCC1)C.ClC(OCC(C)C)=O.[CH2:39]([NH2:43])[CH2:40][CH2:41][CH3:42]>O1CCCC1.C(Cl)Cl>[CH2:39]([NH:43][C:20]([C@@H:12]1[CH2:13][C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])=[O:21])[CH2:40][CH2:41][CH3:42]
Reactant: O=C(O)[C@@H]1Cc2ccccc2N1C(=O)OCc1ccccc1
Reactant: CCCCN
Agent: CC(C)COC(=O)Cl
Agent: CCN1CCOCC1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCCNC(=O)[C@@H]1Cc2ccccc2N1C(=O)OCc1ccccc1
Reaction time: 0.75 h

Procedure:
7.699 g (25.9 mmol) of N-benzyloxycarbonyl-2(S)-indolinecarboxylic acid prepared as in Example 16 a) are dissolved in tetrahydrofuran (150 ml), under nitrogen. 2.986 g (25.9 mmol) of N-ethylmorpholine are added, at 0° C., followed by 3.54 g (25.9 mmol) of isobutyl chloroformate. After 45 minutes, 1.903 g (25.9 mmol) of n-butylamine are added and the suspension is stirred overnight. Methylene chloride (300 ml) is added and the organic phase is washed with 10% citric acid (3×100 ml) and then NaHCO3 (3×100 ml). After drying and evaporation, a white solid is obtained which is recrystallized from methanol.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=2)[C:18]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[O:19])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:40](O)=[O:41].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=2)[C:18]([CH:20]2[CH2:21][CH2:22][N:23]([C:40]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][N:34]=3)=[O:41])[CH2:24][CH2:25]2)=[O:19])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(C1CCNCC1)N(CCCN1CCC(Cc2ccccc2)CC1)c1ccc(Cl)c(Cl)c1
Reactant: O=C(O)c1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(c1ccccn1)N1CCC(C(=O)N(CCCN2CCC(Cc3ccccc3)CC2)c2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 91.2 %

Procedure:
To the solution of the compound obtained in Example 66 (391 mg, 0.80 mmol), picolinic acid (108 mg, 88 mmol) and 1-hydroxybenzotriazole (119 mg, 0.88 mmol) in DMF (8 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (307 mg, 1.60 mmol), and the mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure, and to the concentrate were added a saturated aqueous solution of sodium hydrogen carbonate (15 mL) and water (5 mL). The mixture was extracted with ethyl acetate (15 mL×5). The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate (5 mL×3), saturated sodium chloride solution (5 mL), successively, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was subjected to column chromatography (silica gel 10 g, ethyl acetate/methanol=1/0 to 9/1), and the desired fraction was concentrated under reduced pressure to give the titled compound (433 mg, 0.73 mmol, Yield 91%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[NH2:32][CH2:33][CH2:34][OH:35]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:32][CH2:33][CH2:34][OH:35])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: NCCO
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(C)cccc1C
Product: Cc1cc(F)ccc1-c1nc(NCCO)nc2c1ccc(=O)n2-c1c(C)cccc1C

Procedure:
Prepared as described above in Example 60 starting from 8-(2,6-dimethyl-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-methanesulfonyl-8H-pyrido[2,3-d]pyrimidin-7-one and 2-aminoethanol to give the title compound 8-(2,6-dimethyl-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-(2-hydroxy-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one. 1H-NMR (CDCl3): δ 1.92 (s, 6H), 2.12 (s, 3H), 2.95 (br s, 2H), 3.30 (br s, 2H), 3.45 (br s, 1H), 6.31 (d, 1H, J=9.7 Hz), 6.92 (m, 2H), 7.17 (m, 5H). LC MS (m/e)=419.4 (MH+). Rt=1.84 min
Reaction SMILES: [Si]([O:8][CH:9]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([C:31]3[NH:35][C:34](=[O:36])[O:33][N:32]=3)[CH:29]=2)[O:24][C:11]2([CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[CH2:10]1)(C(C)(C)C)(C)C.C([O-])(O)=O.[Na+]>CCO.C1COCC1>[OH:8][CH:9]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([C:31]3[NH:35][C:34](=[O:36])[O:33][N:32]=3)[CH:29]=2)[O:24][C:11]2([CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(O[Si](C)(C)C(C)(C)C)c1cc(-c3noc(=O)[nH]3)ccc1O2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(O)c1cc(-c3noc(=O)[nH]3)ccc1O2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 13.4 g of tert-butyl 4-([tert-butyl(dimethyl)silyl]oxy)-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-spiro[chroman-2,4′-piperidine]-1′-carboxylate in 200 mL of EtOH-THF (5.5:1) at 0° C. was added 67 ml of 1M HClaq dropwise, and the reaction mixture was stirred at rt for 18 h. The reaction mixture was cooled to 0° C., and the mixture was basified with NaHCO3. The mixture was concentrated in reduced pressure, and the residue was acidified with 1M HClaq. The aqueous mixture was extracted with a mixture of CHCl3-MeOH (9:1) three times, and the combined organic layers was washed with brine, dried over Na2SO4, and concentrated in reduces pressure to give the product as a pale brown solid.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([CH2:7][CH2:8][C:9]([OH:11])=O)[O:4][N:3]=1.[NH2:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1>>[OH:1][C:2]1[CH:6]=[C:5]([CH2:7][CH2:8][C:9]([NH:12][CH2:13][CH2:14][CH:15]2[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20]2)=[O:11])[O:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCN)CC1
Reactant: O=C(O)CCc1cc(O)no1
Product: CC(C)(C)OC(=O)N1CCC(CCNC(=O)CCc2cc(O)no2)CC1

Procedure:
The title compound was prepared from commercially available 3-(3-hydroxyisoxazol-5-yl)propanoic acid and tert-butyl 4-(2-aminoethyl)piperidine-1-carboxylate analogously to Example 21 (step 2);
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]2[N:15]=[C:14]([C:16]([OH:18])=O)[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]=2)[N:3]=[CH:2]1.Cl.[OH:20][C:21]1[C:30]([N:31]([CH3:33])[CH3:32])=[CH:29][CH:28]=[C:27]2[C:22]=1[CH2:23][CH2:24][NH:25][CH2:26]2>>[S:1]1[CH:5]=[C:4]([C:6]2[N:15]=[C:14]([C:16]([N:25]3[CH2:24][CH2:23][C:22]4[C:27](=[CH:28][CH:29]=[C:30]([N:31]([CH3:33])[CH3:32])[C:21]=4[OH:20])[CH2:26]3)=[O:18])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]=2)[N:3]=[CH:2]1
Reactant: O=C(O)c1nc(-c2cscn2)nc2ccccc12
Reactant: CN(C)c1ccc2c(c1O)CCNC2
Agent: Cl
Product: CN(C)c1ccc2c(c1O)CCN(C(=O)c1nc(-c3cscn3)nc3ccccc13)C2
Yield: 39 %

Procedure:
Reaction of 2-(4-thiazolyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-dimethylamino-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 82 (39% yield) as a light yellow solid. 1H NMR (300 MHz, CD3OD) δ 2.63 and 2.67 (2s, 6H), 2.82 and 3.06 (2m, 2H), 3.58 and 4.17 (2t, 2H), 4.46 and 5.03 (2s, 2H), 6.31 and 6.81 (2d, 1H), 6.91 and 7.12 (2d, 1H), 7.69-7.95 (m, 2H), 8.04-8.12 (m, 2H), 8.22-8.28 (m, 1H), 8.63-8.73 (2s, 1H), 9.21-9.23 (m, 1H); MS (ESI) m/z 432 ([M+H]+).
Reaction SMILES: [OH:1][C:2]1[CH:19]=[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:11](=[O:18])[C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=4[C:4](=[C:5]23)[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:26]([CH:28]([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:29]Br)[CH3:27].CN(C)C=O>O>[CH2:26]([CH:28]([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:29][O:1][C:2]1[CH:19]=[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:11](=[O:18])[C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=4[C:4](=[C:5]23)[CH:3]=1)[CH3:27]
Reactant: O=C1c2ccccc2-c2cc(O)cc3cccc1c23
Reactant: CCCCC(CC)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCC(CC)COc1cc2c3c(cccc3c1)C(=O)c1ccccc1-2
Temperature: 25 °C
Reaction time: 7 h

Procedure:
A 500 ml three neck flask was equipped with a mechanical stirrer, heating mantle and condenser. To the flask was added 25 g 2-hydroxy-7H-benzo[de]anthracene-7-one, 18 g powdered potassium carbonate, 25 g 2-ethylhexyl bromide and 250 g dimethylformamide (DMF). The mixture was heated to reflux. After seven hours, 4.5 g 2-ethylhexyl bromide was added and the mixture heated at reflux for an additional three hours. The mixture was then cooled to room temperature and 500 g deionized water was added. The solution was extracted twice with 200 g chloroform. The organic layers were combined and washed twice with 250 g water. The solvent was removed on a rotary evaporator, then the crude product was passed through a flash silica gel column using methylene chloride as the elutant. The product fractions were collected and the solvent removed using a rotary evaporator. The yield of 2-[(2-ethylhexyl)oxy]-7H-benzo[de]anthracene-7-one was 28.5 g.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:20])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17]Br)=[CH:13][C:12]=1[F:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]([O:24][C:25]([CH:27]1[C:32](=[O:33])[CH:31]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:30][S:29][CH2:28]1)=[O:26])[CH:22]=[CH2:23]>C1CCCCC1.CCOC(C)=O>[CH2:21]([O:24][C:25]([C@@:27]1([CH2:17][C:14]2[CH:15]=[CH:16][C:11]([NH:10][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:20])=[C:12]([F:19])[CH:13]=2)[C:32](=[O:33])[CH:31]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:30][S:29][CH2:28]1)=[O:26])[CH:22]=[CH2:23]
Reactant: C=CCOC(=O)C1CSCC(NC(=O)OC(C)(C)C)C1=O
Reactant: O=C(Nc1ccc(CBr)cc1F)OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: C=CCOC(=O)[C@]1(Cc2ccc(NC(=O)OCc3ccccc3)c(F)c2)CSCC(NC(=O)OC(C)(C)C)C1=O

Procedure:
The title compound was prepared in analogous manner as described for example 1c from (4-bromomethyl-2-fluoro-phenyl)-carbamic acid benzyl ester (37 g, 109 mmol) and 5-tert-butoxycarbonylamino-4-oxo-tetrahydro-thiopyran-3-carboxylic acid allyl ester (33 g, 105 mmol, example 1b) to yield a diastereomeric mixture of a yellow solid: TLC (cyclohexane-EtOAc 1:1) Rf=0.77; ESIMS [M+NH4]+=590; LCMS [M+NH4]+=590, RtI=1.60 min.
Reaction SMILES: [CH:1](=[O:5])[CH2:2][CH2:3][CH3:4].[CH2:6](O)[CH2:7][CH2:8][OH:9]>P(=O)(O)(O)O>[CH2:2]([CH:1]1[O:9][CH2:8][CH2:7][CH2:6][O:5]1)[CH2:3][CH3:4]
Reactant: OCCCO
Reactant: CCCC=O
Agent: O=P(O)(O)O
Product: CCCC1OCCCO1
Yield: 56 %

Procedure:
This example illustrates the limitations of conventional synthesis methods. A 500 mL round bottom was charged with 191 g normal butyraldehyde, 101 g of 1,3-propanediol, and 4 drops 85% phosphoric acid. The round bottom was fitted with a Dean-Stark trap and condenser and the entire apparatus was placed into an electric heating mantle and brought to reflux. The aldehyde/water azeotrope condensed and separated into the trap. Heating was maintained until 24 mL of water had evolved (1 hr). The mixture was cooled and poured into a separatory funnel. The solution was washed twice with 50 mL of saturated sodium bicarbonate solution and once with 50 mL of distilled water. The organics were dried over MgSO4 and the residue distilled. A fraction collected at 150° C. was 99.6% acetal and had a mass of 95.7 g. This corresponds to a yield of 56%, lower than the yields reported in Table II.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[F:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][C:20]=1[F:21])[NH:17][C:16]([C:22]1[CH:23]=[CH:24][C:25]([O:29][CH3:30])=[C:26]([NH2:28])[CH:27]=1)=[CH:15]2.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][C:20]=1[F:21])[NH:17][C:16]([C:22]1[CH:23]=[CH:24][C:25]([O:29][CH3:30])=[C:26]([NH:28][CH2:7][C:6]3[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH:27]=1)=[CH:15]2
Reactant: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1N
Reactant: COc1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccc(CNc2cc(-c3cc4cc(F)c(F)cc4[nH]3)ccc2OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.3 %

Procedure:
4-Methoxybenzaldehyde (0.204 g, 1.5 mmol) was added to a stirred mixture of 5-(5,6-difluoro-1H-indol-2-yl)-2-methoxy-phenylamine (0.405 g, 1.48 mmol) in methylene chloride (125 mL), followed by acetic acid (0.3 g, 1.5 mmol). The resulting mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (0.31 g, 1.46 mmol) was added in one portion, and the resulting homogeneous solution stirred at room temperature for 3 days. Saturated aqueous sodium bicarbonate solution (100 mL) was added and the mixture stirred for 2 hours. The mixture was shaken, the organic layer separated and dried over Na2SO4. The solvent was evaporated to give a yellow oil. Recrystallization from methanol/water gave the product as off-white crystals (270 mg); mp 173-175° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([N:15]1[C:19]2([CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]2)[NH:18][CH:17]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:16]1=[O:39])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:8]([N:15]1[C:19]2([CH2:20][CH2:21][NH:22][CH2:23][CH2:24]2)[NH:18][CH:17]([CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:16]1=[O:39])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)NC(Cc1ccccc1)C(=O)N2Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1C(Cc2ccccc2)NC2(CCNCC2)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Trifluoroacetic acid (68.5 g, 601 mmol) was added dropwise at 0° C. to a solution of tert-butyl 1,3-dibenzyl-2-oxo-1,4,8-triazaspiro[4,5]decane-8-carboxylate (13.5 g, 31.0 mmol) in CH2Cl2 (93 ml), and the mixture was stirred at this temperature for 15 min. After warming to RT, the reaction solution was stirred for a further 2.5 h. Subsequently, the reaction solution was adjusted to pH 7 to 8 using NaHCO3 solution, the organic phase was separated off, and the aqueous phase was extracted with CH2Cl2 (2×30 ml). The combined organic phase was dried over Na2SO4, filtered and the solvent was removed by distillation. Workup was carried out by means of column chromatography to give 1,3-dibenzyl-1,4,8-triazaspiro[4,5]decan-2-one in a yield of 7.8 g (75% of theory).
Reaction SMILES: C[O:2][C:3]([CH:5]1[C:13]2[C:8](=[CH:9][C:10]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)=[O:16])=[C:11]([OH:14])[CH:12]=2)[CH2:7][CH2:6]1)=[O:4]>CCOCC>[C:20]1([CH3:23])[CH:21]=[CH:22][C:17]([C:15]([C:10]2[CH:9]=[C:8]3[C:13](=[CH:12][C:11]=2[OH:14])[CH:5]([C:3]([OH:4])=[O:2])[CH2:6][CH2:7]3)=[O:16])=[CH:18][CH:19]=1
Reactant: COC(=O)C1CCc2cc(C(=O)c3ccc(C)cc3)c(O)cc21
Solvent: CCOCC
Product: Cc1ccc(C(=O)c2cc3c(cc2O)C(C(=O)O)CC3)cc1

Procedure:
Analogously to the method described in Example 2, 8.5 g of 5-(p-toluoyl)-6-hydroxy-indane-1-carboxylic acid methyl ester give 5-(p-toluoyl)-6-hydroxy-indane-1-carboxylic acid in the form of yellow crystals of melting point 186-8° C (from ether).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[NH:12][C@H:11]([C:13]([F:16])([F:15])[F:14])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1.[CH:17]12[O:24][CH:21]([CH2:22][CH2:23]1)[CH2:20][NH:19][CH2:18]2.C(N(CC)CC)C>>[CH:21]12[O:24][CH:17]([CH2:23][CH2:22]1)[CH2:18][N:19]([C:2]1[N:3]=[C:4]3[NH:12][C@H:11]([C:13]([F:16])([F:15])[F:14])[CH2:10][CH2:9][N:5]3[C:6](=[O:8])[CH:7]=1)[CH2:20]2
Reactant: O=c1cc(Cl)nc2n1CC[C@@H](C(F)(F)F)N2
Reactant: C1CC2CNCC1O2
Solvent: CCN(CC)CC
Product: O=c1cc(N2CC3CCC(C2)O3)nc2n1CC[C@@H](C(F)(F)F)N2
Yield: 92.2 %

Procedure:
500 mg (1.97 mmol) of (8S)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, 884 mg (5.91 mmol) of 8-oxa-3-azabicyclo[3.2.1]octane and 820 μl (5.91 mmol) of triethylamine are placed in a microwave tube. The mixture is irradiated for 10 minutes at 150° C. The reaction medium is purified directly by passing through an RP18 reverse-phase column (eluent: H2O: 100% to CH3CN: 100%) to give 600 mg of (8S)-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, the characteristics of which are as follows:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][SiH2:5][CH:6]=[C:7]([CH3:9])[CH3:8].[C:10]([O-:13])(=[O:12])[CH3:11].[Na+]>CN(C=O)C>[C:10]([O:13][CH2:2][CH2:3][CH2:4][SiH2:5][CH:6]=[C:7]([CH3:9])[CH3:8])(=[O:12])[CH3:11]
Reactant: CC(C)=C[SiH2]CCCCl
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCCC[SiH2]C=C(C)C
Temperature: 120 °C
Yield: 75 %

Procedure:
As shown in the Reaction Scheme 8, a mixture of 3-chloropropyldimethylvinylsilane (1.0 g, 6.15 mmol) and sodium acetate (1.01 g, 12.3 mmol) was dissolved in 17 mL of N,N′-dimethylformamide (DMF), and the resulting solution was heated at 120° C. for 12 hours. After the reaction, the organic layer was extracted with distilled water and ether. After evaporating the solvent, the resulting residue was purified by column chromatography (n-Hex:EA=10:1, Rf=0.36) to give 859 mg (75% yield) of pure 3-acetoxypropyldimethylvinylsilane.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]([Cl:10])=[C:6]([CH:9]=1)[C:7]#[N:8].[C:11](OC(=O)C)(=[O:13])[CH3:12].C([O-])([O-])=O.[Na+].[Na+]>O>[C:11]([NH:1][C:2]1[CH:3]=[N:4][C:5]([Cl:10])=[C:6]([CH:9]=1)[C:7]#[N:8])(=[O:13])[CH3:12]
Reactant: N#Cc1cc(N)cnc1Cl
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(=O)Nc1cnc(Cl)c(C#N)c1
Yield: 76 %

Procedure:
A solution of 5-amino-2-chloronicotinonitrile (2.6 g, 0.017 m) and acetic anhydride (50 ml) was heated at reflux for 30 minutes. After cooling to 25°, the reaction mixture was poured into water, neutralized with saturated Na2CO3 solution and extracted with CH2Cl2. The organic layer was dried over Na2SO4, filtered and concentrated to dryness. The residue was recrystallized from benzene/hexane to yield 2.5 g (76% yield) of 5-acetamido 2-chloronicotinonitrile.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[N:9][C:10]([Cl:23])=[CH:11][C:12]=1[C:13]1[NH:14][C:15]2[C:20]([CH:21]=1)=[C:19]([F:22])[CH:18]=[CH:17][CH:16]=2)(=O)=O.[CH2:26]([Sn](CCCC)(CCCC)/C=C\C)[CH2:27][CH2:28]C.[Li+].[Cl-]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:23][C:10]1[CH:11]=[C:12]([C:13]2[NH:14][C:15]3[C:20]([CH:21]=2)=[C:19]([F:22])[CH:18]=[CH:17][CH:16]=3)[C:7](/[CH:26]=[CH:27]\[CH3:28])=[CH:8][N:9]=1
Reactant: O=S(=O)(Oc1cnc(Cl)cc1-c1cc2c(F)cccc2[nH]1)C(F)(F)F
Reactant: C/C=C\[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: C/C=C\c1cnc(Cl)cc1-c1cc2c(F)cccc2[nH]1
Temperature: 100 °C
Reaction time: 10 h
Yield: 61.5 %

Procedure:
To a mixture of 6-chloro-4-(4-fluoro-1H-indol-2-yl)pyridin-3-yl trifluoromethanesulfonate (200 mg, 0.51 mmol), (Z)-tributyl (prop-1-en-1-yl) stannane (170 mg, 0.51 mmol) and anhydrous LiCl (70 mg, 1.65 mmol) in DMF (2 mL), Pd(PPh3)2Cl2 (30 mg, 0.04 mmol) was added under N2 protection. The reaction mixture was stirred at 100° C. for 10 h. Then it was filtered and concentrated in vacuo. The residue was purified by column chromatography (PE:EA=10:1) to give the product of (Z)-2-(2-chloro-5-(prop-1-en-1-yl)pyridin-4-yl)-4-fluoro-1H-indole (90 mg, yield: 61.9%). 1H-NMR (CDCl3, 400 MHz) δ 12.02 (br s, 1H), 8.33 (s, 1H), 7.87 (s, 1H), 7.31 (d, J=7.6 Hz, 1H), 7.16˜7.21 (m, 1H), 6.98 (d, J=1.2 Hz, 1H), 6.85 (dd, J=10.8, 7.6 Hz, 1H), 6.57 (dd, J=11.2, 1.6 Hz, 1H), 6.06˜6.16 (m, 1H), 1.78 (dd, J=6.8, 1.6 Hz, 3H). MS (M+H)+: 287.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[CH:12]=[C:11]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)[N:10]=1>>[CH3:22][O:21][C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][C:16]=1[O:19][CH3:20])[C:9]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[N:10][C:11]([NH:23][C:24]1[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=1)=[CH:12]2
Reactant: COc1cc2cc(Nc3cc(C)[nH]n3)nc(Cl)c2cc1OC
Reactant: Oc1ccccc1
Product: COc1cc2cc(Nc3cc(C)[nH]n3)nc(Oc3ccccc3)c2cc1OC

Procedure:
Similar procedure as described in example 10 was used, starting from phenol and (1-chloro-6,7-dimethoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give (6,7-dimethoxy-1-phenoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 367(MH+).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)[CH2:12][CH2:11]2)=[O:9])[CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[CH2:32](Br)[CH3:33]>CN(C)C=O>[CH2:32]([N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:23])[F:24])[CH:17]=3)[CH2:12][CH2:11]2)=[O:9])[CH2:3]1)[CH3:33]
Reactant: O=C(C1CCCNC1)N1CCN(c2cccc(C(F)(F)F)c2)CC1
Reactant: CCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN1CCCC(C(=O)N2CCN(c3cccc(C(F)(F)F)c3)CC2)C1
Temperature: 25 °C

Procedure:
A mixture of 1-(piperidin-3-ylcarbonyl)-4-[3-(trifluoromethyl)phenyl]piperazine hydrochloride (600 mg) in N,N-dimethylformamide (10 ml) was stirred at room temperature. Potassium carbonate (800 mg) was added followed by ethyl bromide (158 mg) and the mixture was stirred overnight. The mixture was filtered through a sinter and then through a SCX-2 column eluting with methanol and then a 7M solution NH3 in methanol. The basic fraction was concentrated at reduced pressure. This gave 1-[(1-ethylpiperidin-3-yl)carbonyl]-4-[3-(trifluoromethyl)phenyl]piperazine as a colourless oil (420 mg)