Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1.[N:34]1[CH:39]=[C:38]([CH3:40])[CH:37]=[C:36]([CH3:41])[CH:35]=1>C(#N)C>[Br-:1].[CH3:41][C:36]1[CH:35]=[N+:34]([CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[C:5]([NH:9][C:10](=[O:33])[CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:14][CH:13]=3)[CH:4]=2)[CH:39]=[C:38]([CH3:40])[CH:37]=1
Reactant: CCCCCCCCCCCCCCOc1ccc(CC(=O)Nc2cccc(CBr)c2)cc1
Reactant: Cc1cncc(C)c1
Solvent: CC#N
Product: CCCCCCCCCCCCCCOc1ccc(CC(=O)Nc2cccc(C[n+]3cc(C)cc(C)c3)c2)cc1
Product: [Br-]
Yield: 88.3 %

Procedure:
A mixture of 1.5 g of N-[3-(bromomethyl)phenyl]-4-(tetradecyloxy)benzeneacetamide and 933.5 mg of 3,5-lutidine is refluxed in 25 ml of acetonitrile for 4 hours under argon. The solvent is evaporated and the residue stirred with ether and collected by centrifugation. The solid is washed several times with ether and vacuum dried to give 1.6 g of the desired product as a white powder, m.p. 122°-125° C.
Reaction SMILES: Br.Br.[OH:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.Cl[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[N:19][N:18]=1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>C(Cl)Cl>[OH:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=[N:19][N:18]=3)[CH2:12][CH2:11]2)=[CH:8][CH:9]=1
Reactant: Oc1ccc(N2CCNCC2)cc1
Reactant: Clc1nncc2ccccc12
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Oc1ccc(N2CCN(c3nncc4ccccc34)CC2)cc1
Temperature: 85 °C
Reaction time: 3 h
Yield: 15.9 %

Procedure:
A mixture of 5.11 g (15 mmol) of 1-(4-hydroxyphenyl)piperazine dihydrobromide, 2.48 g (15 mmol) of 1-chlorophthalazine, 2.08 g (15 mmol) of powdered K2CO3 and 55 ml of absolute DMF was warmed to 85° C., and 346 mg of powdered K2CO3 were added at 85° C. with stirring in each case after 10 minutes, after a further 25 minutes and after a further 60 minutes (a total of 1.038 g, 7.51 mmol of K2CO3), and the mixture was stirred for a further 2 hours at 90° C. and 3 hours at 105° C. The DMF was then removed by distillation in vacuo, the residue was taken up in CH2Cl2 /water, the phases were separated after through mixing, and the aqueous solution was extracted three times with CH2Cl2. The combined CH2Cl2 extracts were dried, filtered and evaporated in vacuo. The residue remaining (4.75 g) was chromatographed on a silica gel S/CH2Cl2 column (diameter 2.6 cm, height 43 cm) by elution with CH2Cl2 /C2H5OH mixtures with increasing C2H5OH content (1-10% by volume). The fractions in which, according to TLC, the required compound was concentrated were combined and evaporated. The crystalline residue produced (2.04 g) was boiled briefly with 15 ml of CH2Cl2, cooled in an ice bath, and filtered off under suction. 0.73 g of pure 1-(4-hydroxyphenyl)-4-(1-phthalazinyl)piperazine, melting point 244°-45° C., were thus obtained. The mother liquor was again purified by chromatography in analogous fashion to the first column chromatography on a silica gel/CH2Cl2 column (diameter 2.0 cm, height 22 cm). The concentrated product produced from this procedure was, like the first part, boiled briefly with 7 ml of CH2Cl2 and filtered off under suction when cool. A further 0.28 g of pure compound, melting point 244°-45° C., was obtained from this procedure. The total yield was 1.01 g=22% of theory;
Reaction SMILES: COC(=O)C=CC1C2N(C3C=CC=CC=3)C=NC=2C=C(C(F)(F)F)C=1.CN1[CH2:32][CH2:31][N:30]([C:33](=[O:55])[CH:34]=[CH:35][C:36]2[C:44]3[N:43]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[CH:42]=[N:41][C:40]=3[CH:39]=[C:38]([C:51]([F:54])([F:53])[F:52])[CH:37]=2)[CH2:29][CH2:28]1>>[N:30]1([C:33](=[O:55])[CH:34]=[CH:35][C:36]2[C:44]3[N:43]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[CH:42]=[N:41][C:40]=3[CH:39]=[C:38]([C:51]([F:52])([F:54])[F:53])[CH:37]=2)[CH2:29][CH:28]=[CH:32][CH2:31]1
Reactant: CN1CCN(C(=O)C=Cc2cc(C(F)(F)F)cc3ncn(-c4ccccc4)c23)CC1
Agent: COC(=O)C=Cc1cc(C(F)(F)F)cc2ncn(-c3ccccc3)c12
Product: O=C(C=Cc1cc(C(F)(F)F)cc2ncn(-c3ccccc3)c12)N1CC=CC1
Yield: 6 %

Procedure:
This was prepared from 3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)acrylic acid methyl ester in a similar manner to 1-(4-methylpiperazin-1-yl)-3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)prop-2-en-1-one. The oily residue was purified by preparative LCMS to afford the title compound as a white solid (6.2 mg, 6%), m/z 384.0 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([C:6](=O)[CH2:7][CH:8]2[C:13](=O)[CH2:12][CH2:11][S:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:18][N:19]([CH3:24])[CH2:20][CH2:21][CH2:22][NH2:23]>Cl.C(O)C>[CH3:18][N:19]([CH3:24])[CH2:20][CH2:21][CH2:22][N:23]1[C:6]([C:5]2[CH:16]=[CH:17][C:2]([Br:1])=[CH:3][CH:4]=2)=[CH:7][C:8]2[CH2:9][S:10][CH2:11][CH2:12][C:13]1=2
Reactant: CN(C)CCCN
Reactant: O=C(CC1CSCCC1=O)c1ccc(Br)cc1
Agent: Cl
Solvent: CCO
Product: CN(C)CCCn1c(-c2ccc(Br)cc2)cc2c1CCSC2
Reaction time: 8 h

Procedure:
A solution of 60 g (0.019 mole) of 3-(4-bromophenacyl)-2,3,5,6-tetrahydrothiopyran-4-one, 1.97 g of 3-dimethylaminopropylamine, 20 ml. of ethanol, and one drop of concentrated hydrochloric acid is heated under reflux under nitrogen for 2.5 hours and allowed to stand overnight during which time crystals precipitated. Recrystallization from ethanol gives colorless crystals of 1-(3-dimethylaminopropyl)-2-(4-bromophenyl)-1,4,6,7-tetrahydrothiopyrano[4,3-b]-pyrrole, m.p. 88° to 90°C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19](C3ON=CC=3)=[CH:18][CH:17]=2)[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=1.NC1C=C([N:37]2[CH2:41][CH2:40][CH2:39][C:38]2=[O:42])C=CC=1>>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N:37]3[CH2:41][CH2:40][CH2:39][C:38]3=[O:42])[CH:17]=2)[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=1
Reactant: NC(=O)c1cnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1ccc(-c2ccno2)cc1
Reactant: Nc1cccc(N2CCCC2=O)c1
Product: NC(=O)c1cnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1cccc(N2CCCC2=O)c1

Procedure:
This compound was synthesised using the synthetic scheme described for the synthesis of compound 122, and using 1-(3-aminophenyl)pyrrolidin-2-one in step 1. MS: 410.5 (M+H).
Reaction SMILES: [C:1]([Si:5]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)Cl)([CH3:4])([CH3:3])[CH3:2].C1CCN2C(=NCCC2)CC1.[CH2:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][C:31]1=[O:39]>C1C=CC=CC=1.CCOCC>[O:39]([C:31]1[CH2:32][C:33]2[C:38]([CH:30]=1)=[CH:37][CH:36]=[CH:35][CH:34]=2)[Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O=C1Cc2ccccc2C1
Solvent: CCOCC
Solvent: c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)[Si](OC1=Cc2ccccc2C1)(c1ccccc1)c1ccccc1
Reaction time: 8 h
Yield: 74.1 %

Procedure:
To a solution of tert-butyldiphenylchlorosilane (42.43 g, 154.4 mmol) and DBU (25.64 g, 168.4 mmol) in benzene (200 mL) was added 2-indanone (18.38 g, 139.1 mmol) in one portion. The reaction mixture was stirred overnight, diluted with Et2O (200 mL), washed with 10% HCl (2×200 mL) and water (2×200 mL) and dried over sodium sulfate. The solvents were evaporated to leave a dark brown oil. Distillation under reduced pressure gave 38.22 g (74.1%) of the title compound as a yellow oil (bp. 172-175° C./0.05 mbar). 1H NMR (CDCl3, δ): 7.77-7.74 (m, 4H); 7.46-7.36 (m, 6H) 7.18-7.16 (m, 1H); 7.11-7.07 (m, 1H); 6.98-6.94 (m, 2H); 5.48 (d, 4J=0.7 Hz, 1H); 3.29 (s, 2H); 1.09 (s, 9H). 13C NMR (CDCl3, δ): 162.13; 145.17; 136.75; 135.53; 132.43; 130.20; 127.99; 126.51; 123.15; 122.49; 119.24; 107.91; 39.43; 26.60; 19.46.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]=1[NH2:15].CCN(CC)CC.[CH3:23][Si:24]([C:27]#[CH:28])([CH3:26])[CH3:25]>C1(C)C=CC=CC=1.O.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.[Cu]I>[C:8]([C:6]1[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]([NH:15][C:28]#[C:27][Si:24]([CH3:26])([CH3:25])[CH3:23])=[CH:2][CH:7]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)(C)c1cc(Br)c(N)cc1[N+](=O)[O-]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(NC#C[Si](C)(C)C)cc1[N+](=O)[O-]
Temperature: 70 °C
Yield: 86.1 %

Procedure:
To a mixture of 2-bromo-4-tert-butyl-5-nitro-phenylamine (27.3 g, 100 mmol) in toluene (200 mL) and water (100 mL) was added Et3N (27.9 mL, 200 mmol), Pd(PPh3)2Cl2 (2.11 g, 3.00 mmol), CuI (950 mg, 0.500 mmol) and trimethylsilyl acetylene (21.2 mL, 150 mmol) under a nitrogen atmosphere. The reaction mixture was heated at 70° C. in a sealed pressure flask for 2.5 h., cooled down to room temperature and filtered through a short plug of Celite. The filter cake was washed with EtOAc. The combined filtrate was washed with 5% NH4OH solution and water, dried over Na2SO4 and concentrated. The crude product was purified by column chromatography (0-10% ethyl acetate/petroleum ether) to provide 4-tert-butyl-5-nitro-2-trimethylsilanylethynyl-phenylamine as a brown viscous liquid (25 g, 81%).
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[Cl:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][C:27]=1[C:35]#[N:36]>>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:5]2[C:4]([C:3]([OH:2])=[O:24])=[CH:9][C:8]([C:10]3[S:11][CH:12]=[C:13]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=4)[N:14]=3)=[CH:7][CH:6]=2)=[CH:28][C:27]=1[C:35]#[N:36]
Reactant: N#Cc1cc(B(O)O)ccc1Cl
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Product: N#Cc1cc(-c2ccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cs3)cc2C(=O)O)ccc1Cl
Yield: 18.5 %

Procedure:
Using the conditions of General Procedure B for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 89 mg, 0.2 mmol) was reacted with 4-chloro-3-cyanophenylboronic acid (available from Combi-Blocks Inc.; 73 mg, 0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 4′-chloro-3′-cyano-4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2-carboxylic acid (18 mg, 19%). 1H NMR (400 MHz, DMSO-d6) δ 13.35 (br s, 1H), 8.44-8.51 (m, 2H), 8.34 (d, J=2.0 Hz, 1H), 8.28 (dd, J=8.0, 1.8 Hz, 1H), 8.09 (dd, J=8.5, 2.0 Hz, 1H), 8.06 (d, J=2.3 Hz, 1H), 7.82 (d, J=8.5 Hz, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.74 (dd, J=8.5, 2.3 Hz, 1H), 7.61 (d, J=8.0 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[C:6]([O:12][CH3:13])[CH:5]=1)=O.C[O:15][C:16](=[O:30])/[C:17](=[CH:23]/[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)/[CH2:18][C:19]([O:21][CH3:22])=[O:20].CC(C)([O-])C.[K+].C(OC(C)C)(C)C>C(O)(C)(C)C.O>[CH3:1][C:2]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[C:6]([O:12][CH3:13])[CH:5]=1)=[C:18]([C:19]([O:21][CH3:22])=[O:20])[C:17]([C:16]([OH:30])=[O:15])=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COc1cc(OC)cc(C(C)=O)c1
Reactant: COC(=O)C/C(=C\c1ccccc1)C(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)OC(C)C
Solvent: O
Solvent: CC(C)(C)O
Product: COC(=O)C(C(=Cc1ccccc1)C(=O)O)=C(C)c1cc(OC)cc(OC)c1
Temperature: 25 °C
Yield: 111.1 %

Procedure:
3,5-Dimethoxyacetophenone (246 g) and (E)-benzylidenesuccinic acid dimethyl ester (320 g) are dissolved in tert-butyl alcohol (1300 ml), and thereto is added potassium tert-butoxide (168.6 g) at room temperature, and the mixture is stirred. The mixture is allowed to cool to room temperature, and the mixture is further stirred at the same temperature for two hours. To the reaction mixture are added water (3 L) and diisopropyl ether (700 ml), and the aqueous layer is separated. To the remaining organic layer is added water, and the aqueous layer is separated. The aqueous layers are combined, and the pH value thereof is adjusted to pH 2-3 with conc. hydrochloric acid. The resulting oily product is extracted with ethyl acetate, and the extract is dried, and concentrated to give oily 1-methyl-1-(3,5-dimethoxyphenyl)-2-methoxycarbonyl-3-carboxy-4-phenylbutadiene (580 g) which is a mixture of (1Z,3E)-isomer and (1E,3E)-isomer. The oily product thus obtained is dissolved in diisopropyl ether-hexane, and the mixture is stirred at room temperature, and the precipitated crystals are collected. To the crystals is added ethyl acetate (1 L), and the mixture is heated at about 80° C., and the remaining crystals are collected by filtration to give (1E,3E)-1-methyl-1-(3,5-dimethoxyphenyl)-2-methoxycarbonyl-3-carboxy-4-phenylbutadiene (the same compound as the compound of Example 135) (117 g). The mother liquor (the filtrate) is concentrated, and ethyl acetate (700 ml) is added to the residue, and the (1Z,3E)-isomer is inoculated thereto. The mixture is stirred, and the precipitated crystals are collected to give (1Z,3E)-1-methyl-1-(3,5-dimethoxyphenyl)-2-methoxycarbonyl-3-carboxy-4-phenylbutadiene (the same compound as the compound of Example 121) (192 g).
Reaction SMILES: C(OC(=O)[NH:5][C:6]1[C:7]([C:12]#[C:13][Si](C)(C)C)=[N:8][CH:9]=[CH:10][CH:11]=1)C.[O-]CC.[Na+]>C(O)C.[Cl-].[Na+].O>[NH:5]1[C:6]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[CH:12]=[CH:13]1
Reactant: CCOC(=O)Nc1cccnc1C#C[Si](C)(C)C
Agent: CC[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: c1cnc2cc[nH]c2c1
Reaction time: 1 h
Yield: 63.5 %

Procedure:
(2-Trimethylsilanylethynyl-pyridin-3-yl)carbamic acid ethyl ester described in Preparation Example S-3 (0.42 g, 1.6 mmol) was dissolved in ethanol (8 mL), sodium ethoxide (204 mg, 3 mmol) was added thereto, followed by stirring for 1 hour under reflux. After the reaction was completed, the reaction mixture was poured into brine, and the solution was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, then evaporated, the resulting solid was washed with solvent (diethylether:hexane=1:2), and the title compound (0.12 g, 1 mmol, 63.5%) was obtained.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[OH:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>CCOC(C)=O.O>[N+:12]([C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[O:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Reactant: CC(C)(C)OC(=O)N1CCN(CCO)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(CCOc2ccc(C(F)(F)F)cc2[N+](=O)[O-])CC1
Temperature: 60 °C
Yield: 48.5 %

Procedure:
Into a 1-neck round-bottom flask was added 4-fluoro-3-nitrobenzotrifluoride (1.62 mL, 0.012 mol), tert-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (4.00 g, 0.017 mol), cesium carbonate (11.3 g, 0.035 mol), and DMF (100 mL). The reaction was allowed to stir and heat at 60° C. overnight. The reaction mixture was allowed to cool to rt and diluted with EtOAc and water. The organic solution was separated, washed with water and brine, and concentrated to yellow oil. The residue was purified by column chromatography to give tert-butyl 4-{2-[2-nitro-4-(trifluoromethyl)phenoxy]ethyl}piperazine-1-carboxylate (2.44 g, 48%) as a brown oil. LCMS: (AA) ES+420.1.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=C1)([N:3]1[CH:7]=[CH:6]N=C1)=[O:2].[C:13]1([O:19][C:20]([N:22]2[C:30]3[C:25](=[CH:26][CH:27]=C(N)C=3)[C:24]([CH3:33])([CH3:32])[CH2:23]2)=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.NC1C=[CH:51][C:38]([O:39][C:40]2[CH:45]=[CH:44][N:43]=[C:42]([NH:46][CH2:47][CH2:48][CH2:49][OH:50])[N:41]=2)=[CH:37][CH:36]=1>C1COCC1>[C:13]1([O:19][C:20]([N:22]2[C:30]3[C:25](=[CH:26][CH:27]=[C:12]([NH:8][C:1]([NH:3][C:7]4[CH:6]=[CH:51][C:38]([O:39][C:40]5[CH:45]=[CH:44][N:43]=[C:42]([NH:46][CH2:47][CH2:48][CH2:49][OH:50])[N:41]=5)=[CH:37][CH:36]=4)=[O:2])[CH:11]=3)[C:24]([CH3:32])([CH3:33])[CH2:23]2)=[O:21])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc(Oc2ccnc(NCCCO)n2)cc1
Reactant: CC1(C)CN(C(=O)Oc2ccccc2)c2cc(N)ccc21
Solvent: C1CCOC1
Product: CC1(C)CN(C(=O)Oc2ccccc2)c2cc(NC(=O)Nc3ccc(Oc4ccnc(NCCCO)n4)cc3)ccc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
278 mg (1.71 mmol) 1,1′-Carbonyl-diimidazol (CDI) were given to a solution of 484 mg (1.63 mmol) 6-amino-3,3-dimethyl-2,3-dihydro-indole-1-carboxylic acid phenyl ester in 10 ml THF. A solution of 425 mg (1.63 mmol) 3-[4-(4-Amino-phenoxy)-pyrimidin-2-ylamino]-propan-1-ol in 10 ml THF was added within 15 min. and the mixture stirred for 12 h at r.t. The reaction mixture was evaporated and the residue was purified by chromatography on silica gel (dichloromethane/methanol 95:5). The obtained material was washed with dichloromethane/ether, the precipitate was isolated by filtration and dried. Yield: 540 mg (57%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[C:18](=[O:19])[N:17]([CH2:20][C@H:21]([OH:23])[CH3:22])[C:8]2[N:9]=[C:10](S(C)(=O)=O)[N:11]=[CH:12][C:7]=2[CH:6]=1.[NH2:29][C:30]([CH3:34])([CH3:33])[CH2:31][OH:32]>>[F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[C:18](=[O:19])[N:17]([CH2:20][C@H:21]([OH:23])[CH3:22])[C:8]2[N:9]=[C:10]([NH:29][C:30]([CH3:34])([CH3:33])[CH2:31][OH:32])[N:11]=[CH:12][C:7]=2[CH:6]=1
Reactant: C[C@@H](O)Cn1c(=O)c(Oc2ccc(F)cc2F)cc2cnc(S(C)(=O)=O)nc21
Reactant: CC(C)(N)CO
Product: C[C@@H](O)Cn1c(=O)c(Oc2ccc(F)cc2F)cc2cnc(NC(C)(C)CO)nc21
Temperature: 60 °C

Procedure:
A mixture of 6-(2,4-difluorophenoxy)-8-((R)-2-hydroxypropyl)-2-methanesulfonyl-8H-pyrido[2,3-d]pyrimidin-7-one (886 mg, 2.15 mmol) and 2-amino-2-methyl-1-propanol (5.15 g, 58 mmol) was heated at 60° C. under nitrogen for 2 hours. Cooled and chromatographed on silica gel eluding with 2% methanol in dichloromethane to give after converting to hydrochloride salt 385 mg 6-(2,4-Difluorophenoxy)-2-(2-hydroxy-1,1-dimethyl-ethylamino)-8-((R)-2-hydroxy-propyl)-8H-pyrido[2,3-d]pyrimidin-7-one (mass spec. M+1=421, MP=182.0-183.9° C.).
Reaction SMILES: C[Al](C)C.C1(C)C=CC=CC=1.[Cl-].[NH4+:13].[F:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[F:23])[C:18]#[N:19]>C(Cl)(Cl)Cl>[F:14][C:15]1[CH:16]=[C:17]([C:18](=[NH:13])[NH2:19])[CH:20]=[CH:21][C:22]=1[F:23]
Reactant: [NH4+]
Reactant: N#Cc1ccc(F)c(F)c1
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: N=C(N)c1ccc(F)c(F)c1
Temperature: 85 °C
Reaction time: 1.5 h
Yield: 33 %

Procedure:
3.6 mL (7.2 mmol) of trimethyl aluminum (2.0 M toluene solution) was dropwise added to a 10 mL of toluene containing 384 mg (7.17 mmol) of ammonium chloride at room temperature. After stirring for 1.5 hours, 1 g (7.1 mmol) of 3,4-difluorobenzonitrile was added thereto and the resulting mixture was heated to 85° C. for 9 hours. After completion of a reaction, the reaction solution was poured into 100 mL of chloroform containing 200 g of silicagel and filtered off. The residue was washed with 200 mL of methanol and distillation was conducted to give 370 mg (2.36 mmol) of the title compound in a yield of 33%.
Reaction SMILES: S(=O)(=O)(O)O.BrC(CC(O[C:13]1[CH:22]=[CH:21][CH:20]=[C:15]([C:16]([O:18][CH3:19])=[O:17])[C:14]=1[OH:23])=O)Br.[OH2:24].[CH3:25]O>>[CH:25]([C:13]1[C:14]([OH:23])=[C:15]([CH:20]=[CH:21][CH:22]=1)[C:16]([O:18][CH3:19])=[O:17])=[O:24]
Reactant: COC(=O)c1cccc(OC(=O)CC(Br)Br)c1O
Reactant: CO
Reactant: O
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(C=O)c1O
Temperature: 22.5 °C
Reaction time: 0.5 h

Procedure:
63 ml of concentrated sulfuric acid were added dropwise at approximately 20 to 25° C. to a solution of 64 g (0.17 mol) of the dibromide of Example 1 in 500 ml of anhydrous methanol. The temperature of the reaction solution was kept at 30° C. by cooling. After the mixture had been stirred for 30 minutes at 20 to 25° C., it was heated for 3 hours to 50° C. The reaction mixture was stirred into approximately 3.5 l of water. The precipitate was filtered off and washed with water and then with a pentane/MTBE mixture (5:1). After drying, 25 g of the title compound were obtained, which corresponds to 81% of theory. (m.p. 82° C.)
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH2:9][C:10](O)=[O:11])[CH:6]=[CH:7][CH:8]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[CH3:47][NH:48][O:49][CH3:50]>CN(C=O)C.C(OCC)(=O)C>[CH3:50][O:49][N:48]([CH3:47])[C:10](=[O:11])[CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:14])([F:13])[F:1])[CH:4]=1
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CON(C)C(=O)Cc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.7 %

Procedure:
A solution of 3-(trifluoromethyl)phenylacetic acid (1.00 g, TCI) in DMF (15 ml) was added with WSC HCl (1.28 g, KOKUSAN), HOBT (794 mg, KOKUSAN), and DIEA (1.02 ml, ALD), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was added with a solution of N,O-dimethylhydroxylamine hydrochloride (956 mg, WAKO) in DMF (5 ml) added with DIEA (1.74 ml) and stirred for 20 minutes at room temperature beforehand, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was added with ethyl acetate (150 ml), successively washed with 1 N aqueous hydrochloric acid, purified water, saturated aqueous sodium hydrogencarbonate, and saturated brine and dried, and then the solvent was evaporated under reduced pressure to obtain the title compound (Intermediate pa-01, 893 mg).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].C(N(CC)CC)C.[C:12]1([CH3:19])[C:17]([OH:18])=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[C:1]([O:18][C:17]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:19])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: Cc1ccccc1O
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccccc1C
Temperature: 65 °C

Procedure:
First 235.5 g (3.3 moles) acetyl chloride then 282.8 g (2.8 moles) triethylamine are added dropwise to a mixture of 324 g (3 moles) o-cresol and 36.6 g (0.3 mole) 4-dimethylaminopyridine in 1 liter of toluene. The mixture is then heated for 3 h at 65° C. The resulting solid hydrochloride is separated by filtration and the organic phase is washed twice with 1 N hydrochloric acid then with water. The solution is dried and then the solvent is recovered under vacuum. The remaining oil is distilled under vacuum. It has a boiling point of 87° C. at 12 Torr. The yield is 428.8 g.