Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[CH2:12](Br)[C:13]#[CH:14].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH2:14][C:13]#[CH:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: C#CCBr
Reactant: CC(C)(C)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: C#CCOc1ccccc1C(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 89.9 %

Procedure:
To a solution of 2-(tert-butyl)phenol (21.0 g, 140 mmol) and propargyl bromide (18.8 mL, 168 mmol) in acetonitrile (250 mL) was added potassium carbonate (23.3 g, 168 mmol). The reaction was stirred at ambient temperature for two days. The reaction mixture was diluted with water (50 mL) and extracted diethyl ether (2×150 mL). The combined organic extracts were concentrated to provide 23.7 g (90%) of the title compound which was used without further purification. 1H NMR (300 MHz, DMSO-d6) δ 7.26-7.14 (m, 2H), 7.02 (d, J=8.0 Hz, 1H), 6.94-6.86 (m, 1H), 4.83 (d, J=2.4 Hz, 2H), 3.55 (t, J=2.4 Hz, 1H), 1.34 (s, 9H).
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:21]=[CH:20][CH:19]=[CH:18][C:7]=1[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][N:12]=1)=[O:9])=[O:4].C(=O)([O-])[O-].[K+].[K+].[N:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[CH:30][CH:29]=1.O>ClCCl>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:8](=[O:9])[C:7]2[CH:18]=[CH:19][CH:20]=[CH:21][C:6]=2[NH:5][C:3]([CH2:2][N:37]2[CH2:38][CH2:39][N:34]([C:31]3[CH:32]=[CH:33][N:28]=[CH:29][CH:30]=3)[CH2:35][CH2:36]2)=[O:4])=[N:12][CH:13]=1
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: O=C(CBr)Nc1ccccc1C(=O)Nc1ccc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: O=C(CN1CCN(c2ccncc2)CC1)Nc1ccccc1C(=O)Nc1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.7 %

Procedure:
To a solution of 2-(bromoacetyl)amino-N-(5-chloropyridin-2-yl)benzamide (0.369 g, 1 mmol) in dichloromethane (10 ml) was added potassium carbonate (0.169 g, 1.22 mmol) and 1-(4-pyridyl)piperazine (0.171 mg, 1.05 mmol). The reaction was stirred overnight at room temperature. Water (2 mL) was added and the mixture was passed through a column of flux-calcined, high purity, inert diatomaceous earth packed into a polypropylene tube (article number CE 1103 from Varian) to remove water. The solvent was removed and the residue was purified by RPHPLC (CH2Cl2/5% 2 N ammonia in methanol) to give 0.08 g of pure title product.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:12]=[C:13]4[C:19]([C:20]([NH:22][CH:23]([CH3:25])[CH3:24])=[O:21])=[CH:18][N:17]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:14]4=[N:15][CH:16]=3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH2:36](I)[CH3:37]>CN(C=O)C.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:12]=[C:13]4[C:19]([C:20]([NH:22][CH:23]([CH3:25])[CH3:24])=[O:21])=[CH:18][N:17]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:31])([CH3:33])[CH3:32])[C:14]4=[N:15][CH:16]=3)=[N:7][N:8]2[CH2:36][CH3:37])=[CH:4][CH:3]=1
Reactant: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4cc(Cl)ccc34)nc12
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1nc(-c2cnc3c(n2)c(C(=O)NC(C)C)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61.5 %

Procedure:
2-(6-Chloro-1H-indazol-3-yl)-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (120 mg, 247 μmol) was dissolved in DMF (1 mL) and cooled to 0° C. Sodium hydride (12.9 mg, 322 μmol) was added and the mixture was allowed to stir for 30 min at 0° C. Ethyl iodide (57.9 mg, 30.0 μL, 371 μmol) was added and the mixture was warmed to 20° C. After 15 h the mixture was diluted with water and extracted with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by chromatography (silica, 40 g Analogix pre-packed column, 20-50% ethyl acetate in hexanes, 15 minute gradient) to give 2-(6-chloro-1-ethyl-1H-indazol-3-yl)-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (78 mg, 152 μmol, 61%) as a yellow powder. MS (M+Na)+=535; 1H NMR (CDCl3) δ: 9.26 (s, 1H), 8.44-8.49 (m, 1H), 8.39-8.42 (m, 1H), 8.20-8.28 (m, 1H), 7.47-7.56 (m, 1H), 7.23 (d, J=1.5 Hz, 1H), 5.67-5.77 (m, 2H), 4.43-4.59 (m, 1H), 4.13 (q, J=7.2 Hz, 1H), 3.52-3.67 (m, 1H), 1.57-1.65 (m, 4H), 1.42 (d, J=6.4 Hz, 4H), 0.88-1.01 (m, 2H)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH2:22][O:23][CH3:24])=[CH:18][CH:19]=2)[O:14][CH2:13][C:12]1([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][O:34][CH3:35])=[CH:28][CH:27]=1)[CH3:25].[F:36][C:37]([F:49])([C:45]([F:48])([F:47])[F:46])[CH2:38][CH2:39][CH2:40]S(Cl)(=O)=O.C(N(CC)CC)C>C(Cl)Cl>[CH3:24][O:23][CH2:22][O:21][C:17]1[CH:16]=[C:15]2[C:20]([CH:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][CH2:40][CH2:39][CH2:38][C:37]([F:49])([F:36])[C:45]([F:48])([F:47])[F:46])[C:12]([C:26]3[CH:27]=[CH:28][C:29]([O:32][CH2:33][O:34][CH3:35])=[CH:30][CH:31]=3)([CH3:25])[CH2:13][O:14]2)=[CH:19][CH:18]=1
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2CCCCCCCCCN)cc1
Reactant: O=S(=O)(Cl)CCCC(F)(F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2CCCCCCCCCNCCCC(F)(F)C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.8 %

Procedure:
4-(9-aminononyl)-7-methoxymethoxy-3-(4-methoxymethoxyphenyl)-3-methylchroman (82.3 mg, 0.17 mmol) was dissolved in 5 ml of methylenechloride under argon atmosphere, which was then cooled down to 0° C. 4,4,5,5,5-pentafluoropentylsulfonyl chloride (110.4 mg, 0.42 mmol) in 1 ml of methylene chloride and triethylamine (0.07 ml, 0.5 mmol) was added thereto, and the mixture was stirred at the same temperature for 30 minutes. The reaction was quenched with water, and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and concentrated. The residue was subject to flash chromatography in silica gel (n-hexane:ethyl acetate=5:1) to give the title compound (81 mg, yield: 67%) as a colorless oil.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@@:18]([CH3:26])([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].Cl[C:28]([O:30][CH:31]([CH3:33])[CH3:32])=[O:29].C(N(CC)CC)C>ClCCl>[CH:31]([O:30][C:28]([N:23]1[CH2:24][CH2:25][CH:20]([C@@:18]2([CH3:26])[O:17][C:14]3=[CH:15][N:16]=[C:11]([C:8]4[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH2:6][CH:7]=4)[CH:12]=[C:13]3[CH2:19]2)[CH2:21][CH2:22]1)=[O:29])([CH3:33])[CH3:32]
Reactant: CC(C)OC(=O)Cl
Reactant: C[C@@]1(C2CCNCC2)Cc2cc(C3=CCN(S(C)(=O)=O)CC3)ncc2O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)N1CCC([C@]2(C)Cc3cc(C4=CCN(S(C)(=O)=O)CC4)ncc3O2)CC1

Procedure:
The title compound is prepared from (S)-5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine by treatment with isopropyl chloroformate in the presence of triethylamine using dichloromethane as a solvent. LC (method 6): tR=0.96 min; Mass spectrum (ESI+): m/z=464 [M+H]+.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])CCC.CCCCCC.[C:25]([C:29]1[CH:30]=[C:31]([CH3:49])[C:32](=[C:34]([C:42]2[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=2)[C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)[CH:33]=1)([CH3:28])([CH3:27])[CH3:26].Cl>C(OCC)C>[C:25]([C:29]1[CH:30]=[C:31]([CH3:49])[CH:32]([C:34]([C:1]2[C:13]3[CH2:12][C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:5]=3[CH:4]=[CH:3][CH:2]=2)([C:35]2[CH:36]=[CH:37][C:38]([Cl:41])=[CH:39][CH:40]=2)[C:42]2[CH:43]=[CH:44][C:45]([Cl:48])=[CH:46][CH:47]=2)[CH:33]=1)([CH3:26])([CH3:27])[CH3:28]
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: CC1=CC(C(C)(C)C)=CC1=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CC1=CC(C(C)(C)C)=CC1C(c1ccc(Cl)cc1)(c1ccc(Cl)cc1)c1cccc2c1Cc1ccccc1-2
Temperature: 25 °C

Procedure:
In a 200 ml three-necked flask equipped with a magnetic stirrer chip and three-way cock thoroughly purged with nitrogen, 1.42 g of fluorene (8.52 mmol) was dissolved in 60 ml of dehydrated diethyl ether in a nitrogen atmosphere. To the solution, 5.6 ml of n-butyl lithium/hexane solution (1.58M: 8.85 mmol) was gradually added dropwise in an ice bath and stirred at room temperature over night. To the reaction solution, 2.99 g of 3-tert-butyl-1-methyl-6,6-di(4-chloro-phenyl)fulvene (8.08 mmol) was added and stirred under reflux for several days. The reaction mixture was gradually added dropwise to 30 ml of a hydrochloric acid aqueous solution (1N) set in an ice bath, and stirred briefly. Therein, diethyl ether was added to separate an organic phase. The organic phase was washed with a saturated sodium bicarbonate aqueous solution, water and saturated brine. The organic phase was dried with anhydrous magnesium sulfate, thereafter the drying agent was filtered off and the solvent was distilled off from the filtrate under reduced pressure to give a red solid. The solid was purified with a column chromatography using 180 g of silica gel (developing solvent: n-hexane) and the developing solvent was distilled off under reduced pressure. Thereafter, the remaining product was re-crystallized using hexane and dried under reduced pressure, and thereby the aimed compound was obtained in an amount of 1.69 g (3.16 mmol) as a pale yellow solid (yield: 39%).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[NH:4][C:3]=1[C:18]([O:20][CH3:21])=[O:19].Br[CH2:23][CH2:24][CH2:25][O:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[N:4]([CH2:23][CH2:24][CH2:25][O:26][C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=[CH:29][CH:28]=2)[C:3]=1[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)c1[nH]c2cccc(-c3ccccc3C)c2c1Br
Reactant: BrCCCOc1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1c(Br)c2c(-c3ccccc3C)cccc2n1CCCOc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 126B (1.14 g) and 1-(3-bromopropoxy)naphthalene (0.922 g) in N,N-dimethylformamide (20 ml) was added cesium carbonate (2.158 g). The reaction was stirred at room temperature overnight and diluted with ethyl acetate and washed with water. The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography, eluting with 0-50% dichloromethane in hexane to provide the title product.
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:11](=[O:20])[C:10]2[C:5](=[CH:6][C:7]([O:23][CH3:24])=[C:8]([O:21][CH3:22])[CH:9]=2)[N:4]=1.[N:25]1[C:33]([NH2:34])=[C:32]2[C:28]([N:29]=[CH:30][NH:31]2)=[N:27][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:34][C:33]1[N:25]=[CH:26][N:27]=[C:28]2[C:32]=1[N:31]=[CH:30][N:29]2[CH2:2][C:3]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:11](=[O:20])[C:10]2[C:5](=[CH:6][C:7]([O:23][CH3:24])=[C:8]([O:21][CH3:22])[CH:9]=2)[N:4]=1
Reactant: COc1cc2nc(CCl)n(-c3ccccc3Cl)c(=O)c2cc1OC
Reactant: Nc1ncnc2nc[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2nc(Cn3cnc4c(N)ncnc43)n(-c3ccccc3Cl)c(=O)c2cc1OC
Yield: 64.8 %

Procedure:
Prepared according to Procedure C using Intermediate 2a (200 mg, 0.546 mmol), adenine (81 mg, 0.601 mmol), K2CO3 (83 mg, 0.601 mmol), and DMF (4 mL). The crude product was recrystallized from ethanol (EtOH) to provide 164 mg of a beige solid (65%), mp 281.5-282.7° C. (decomposes). 1H NMR (DMSOd6) δ: 8.06 (s, 1H); 8.04 (s, 1H); 7.76-7.81 (m, 1H); 7.70-7.76 (m, 1H); 7.60-7.67 (m, 2H); 7.45 (s, 1H); 7.22 (s, 2H); 6.90 (s, 1H); 5.08 (d, J=17 Hz, 1H); 4.91 (d, J=17 Hz, 1H); 3.87 (s, 3H); 3.87 (s, 3H). 13C NMR (DMSO-d6) ppm: 159.9, 156.2, 155.4, 152.9, 150.0, 149.7, 149.4, 143.0, 141.9, 133.7, 132.1, 131.9, 131.2, 130.8, 129.3, 118.4, 113.6, 108.4, 105.8, 56.5, 56.1, 44.7. MS (ES): m/z 464.1 (M+). Anal. calcd. for C22H18ClN7O3.0.1C2H6O.0.05KCl: C, 56.47; H, 3.97; Cl, 7.88; N, 20.76. Found: C, 56.54; H, 4.05; Cl, 7.77; N, 20.55.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[N:3]=1.[CH2:12]([N:14]1[C:22]2[C:17](=[N:18][CH:19]=[CH:20][CH:21]=2)[N:16]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)[C:15]1=[O:30])[CH3:13].[H-].[Na+]>CN(C=O)C.CO>[CH2:12]([N:14]1[C:22]2[C:17](=[N:18][CH:19]=[CH:20][CH:21]=2)[N:16]([C:23]2[CH:24]=[CH:25][C:26]([O:29][C:2]3[N:6]([CH3:7])[C:5]4[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=4[N:3]=3)=[CH:27][CH:28]=2)[C:15]1=[O:30])[CH3:13]
Reactant: CCn1c(=O)n(-c2ccc(O)cc2)c2ncccc21
Reactant: Cn1c(Cl)nc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CCn1c(=O)n(-c2ccc(Oc3nc4ccccc4n3C)cc2)c2ncccc21
Temperature: 150 °C
Yield: 82.1 %

Procedure:
2-Chloro-1-methyl-1H-benzimidazole (500 mg) was added to a solution of 1-ethyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (789 mg) and NaH (132 mg) in DMF (10 ml) at room temperature. The mixture was heated at 150° C. for 1 h under microwave irradiation. The reaction mixture was diluted with MeOH and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 0%-50% EtOAc in hexane) to give 1-ethyl-3-{4-[(1-methyl-1H-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (950 mg) as white crystals.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH2:10][OH:11])[CH:7]=[CH:8][CH:9]=1.Cl[C:13]1[CH:18]=[CH:17][N+:16]([O-:19])=[CH:15][CH:14]=1>C1COCC1>[Cl:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[CH2:10][O:11][C:13]1[CH:18]=[CH:17][N+:16]([O-:19])=[CH:15][CH:14]=1
Reactant: [O-][n+]1ccc(Cl)cc1
Reactant: OCc1cccc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: [O-][n+]1ccc(OCc2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.4 %

Procedure:
To an ice-cold suspension of NaH (40% oil dispersion, 1.51 g) in THF (60 ml) was added (3-chlorophenyl)methanol (3.0 g) at 0° C. The reaction mixture was stirred at the same temperature for 30 min followed by the portionwise addition of 4-chloropyridine 1-oxide (2.73 g) at 0° C. The resulting reaction mixture was stirred for 1 h at 0° C. and then warmed to room temperature. After 2 h, the reaction mixture was poured into ice-water (100 g) and extracted with DCM. The DCM layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was triturated with Et2O to give the title compound (2.2 g) as a brown solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[CH:5]=[C:4]([C:15]([F:18])([F:17])[F:16])[N:3]=1.[Br:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1>>[Br:19][C:20]1[CH:25]=[C:24]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=3)[CH:5]=[C:4]([C:15]([F:18])([F:17])[F:16])[N:3]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: OB(O)c1cccc(Br)c1
Reactant: Fc1ccc(-c2cc(C(F)(F)F)nc(Cl)n2)cc1
Product: Fc1ccc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)c3)n2)cc1

Procedure:
The title compound was prepared from 2-chloro-4-(4-fluoro-phenyl)-6-trifluoromethyl-pyrimidine (example A.45) (1.50 g, 5.42 mmol) and commercially available 3-bromo-benzene-boronic acid (1.31 g, 6.52 mmol) according to the general procedure IVb. Obtained as a white solid (1.17 g, 54%). MS (EI) 395.9, 397.9 [(M)+]; mp 111° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH:9]([F:11])[F:10])[CH:5]=[C:4]([CH3:12])[N:3]=1.[C:13]1([O:19][C:20](Cl)=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O1CCCC1.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[O:19]([C:20]([NH:1][C:2]1[N:7]=[C:6]([O:8][CH:9]([F:11])[F:10])[CH:5]=[C:4]([CH3:12])[N:3]=1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cc1cc(OC(F)F)nc(N)n1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(OC(F)F)nc(NC(=O)Oc2ccccc2)n1
Reaction time: 24 h
Yield: 54.4 %

Procedure:
To a solution of 9.0 g of 2-amino-4-difluoromethoxy-6-methyl-pyrimidine in 30 ml of absolute tetrahydrofuran are added successively 3.9 g of chloroformic acid-phenyl ester and 0.05 g of 4-dimethylamino-pyridine. After the solution has been stirred at 20° to 25° C. for 24 hours, the reaction mixture is diluted with 250 ml of ethyl acetate, and the occurring precipitate is separated. There are thus obtained 3.1 g of 2-amino-4-difluoromethoxy-6-methyl-pyrimidine hydrochloride, m.p. 204° to 205° C. (decomposition). In order to remove the residual starting material, the filtrate is eluted through an acid with ion-exchanger I®(MERCK), dried over sodium sulfate and concentrated by evaporation to thus obtain as crude product, in the form of a viscous oil, 4.0 g of 2-phenoxycarbonylamino-4-difluoromethoxy-6-methyl-pyrimidine (compound No. 2.28), which melts at 56° to 58° C. after crystallisation;
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[CH3:17][CH:18]([N:21]1[C:29]2[C:24](=[CH:25][C:26](/[C:30](/[CH3:35])=[CH:31]/[C:32](O)=[O:33])=[CH:27][CH:28]=2)[CH:23]=[CH:22]1)[CH2:19][CH3:20]>>[CH3:17][CH:18]([N:21]1[C:29]2[C:24](=[CH:25][C:26](/[C:30](/[CH3:35])=[CH:31]/[C:32]([NH:1][C:2]3[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=3[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:33])=[CH:27][CH:28]=2)[CH:23]=[CH:22]1)[CH2:19][CH3:20]
Reactant: CCC(C)n1ccc2cc(/C(C)=C/C(=O)O)ccc21
Reactant: CCOC(=O)CCCOc1ccccc1N
Product: CCC(C)n1ccc2cc(/C(C)=C/C(=O)Nc3ccccc3OCCCC(=O)O)ccc21

Procedure:
1.21 g compound 15 was obtained in a similar manner to those described in the Examples 1 and 2 using 1.80 g of ethyl 4-(2-aminophenoxy)butyrate and 1.04 g of 3-[1-(1-methylpropyl)indol-5-yl]isocrotonic acid obtained according to the procedures described in the Reference Examples 1-4.
Reaction SMILES: [F:1][C:2]1([CH:8]([OH:11])C#N)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[BH4-].[Na+]>CC(O)C.O>[F:1][C:2]1([CH2:8][OH:11])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1
Reactant: N#CC(O)C1(F)CCOCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: OCC1(F)CCOCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 18.5 %

Procedure:
Dissolve (4-fluorotetrahydropyran-4-yl)-hydroxyacetonitrile (4.4 g, 29.8 mmol) in 2-propanol (48 mL) and water (12 mL). Cool to 0° C. under a nitrogen atmosphere. Add sodium borohydride (1.2 g, 31.7 mmol) and allow the resulting mixture to slowly warm to room temperature over 5.5 hours. Quench with acetone and stir for 1 h. Concentrate the mixture to ⅓ volume and dilute with ethyl acetate. Wash the resulting organic solution with saturated aqueous sodium bicarbonate solution and saturated aqueous ammonium chloride solution (twice). Combine the aqueous washes and dilute with saturated aqueous sodium chloride solution and extract with ethyl acetate (twice). Add these extracts to the crude reaction mixture and wash the resulting solution with saturated aqueous sodium chloride solution, dry (magnesium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 0:100 to 1:1 ethyl acetate:hexanes) to give the desired compound as a yellow oil (740 mg, 18%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]2[C:3]=1[C:4]([CH2:12]N(C)C)=[CH:5][NH:6]2.[C-:16]#[N:17].[K+]>CN(C=O)C.O>[CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]2[C:3]=1[C:4]([CH2:12][C:16]#[N:17])=[CH:5][NH:6]2
Reactant: Cc1cc(C)c2c(CN(C)C)c[nH]c2c1
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C)c2c(CC#N)c[nH]c2c1

Procedure:
A solution of [(4,6-dimethyl-1H-indol-3-yl)methyl]dimethylamine from Step A (98.0 mg, 0.484 mmol) and potassium cyanide (315 mg, 4.84 mmol) in DMF (2 mL) and H2O (2 mL) was heated at 100° C. for 2 h. The reaction mixture was partitioned between EtOAc (20 mL) and saturated NaCl (10 mL). The layers were separated and the organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the crude product by silica gel chromatography, eluting with a gradient of CH2Cl2:MeOH-100:0 to 98:2, gave the title compound. MS: m/z=185 (M+1).
Reaction SMILES: [CH2:1]([N:5]([CH2:26][CH3:27])[C:6]1[C:7]2[CH2:15][C:14](=[O:16])[N:13]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[CH3:25])[C:8]=2[N:9]=[C:10]([CH3:12])[N:11]=1)[CH2:2][CH2:3][CH3:4].[O:28]=P(Cl)(Cl)Cl.C(N(CC)CC)C.CNC>C(#N)C>[CH2:1]([N:5]([CH2:26][CH3:27])[C:6]1[C:7]2[C:15](=[O:28])[C:14](=[O:16])[N:13]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[CH3:25])[C:8]=2[N:9]=[C:10]([CH3:12])[N:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCN(CC)c1nc(C)nc2c1CC(=O)N2c1c(C)cc(C)cc1C
Agent: CNC
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCCN(CC)c1nc(C)nc2c1C(=O)C(=O)N2c1c(C)cc(C)cc1C

Procedure:
To a solution of 4-(butyl-ethyl-amino)-2-methyl-7-(2,4,6-trimethyphenyl)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (76 mg, 0.207 mmol), POCl3 (0.039 ml, 0.415 mmol), triethylamine (0.059 ml), and dimethylamine (1 ml) in 2 ml acetonitrile was heated at reflux for 1 hour. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried and concentrated to give a brown form (105 mg). After silica gel column chromatography, the title compound was isolated as a yellow glass (10 mg). 1H NMR (CDCl3) δ 7.00 (s, 2H), 3.95–4.15 (m, 2H), 3.65–3.85 (m, 2H), 2.38 (s, 3H), 2.32 (s, 3H), 2.10 (s, 6H), 1.55–1.75 (m, 2H), 1.35–1.55 (m, 2H), 1.25 (t, 3H), 1.00 (t, 3H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[C:15](Br)[CH:14]=[C:13]3[Br:21])=[O:9])=[CH:4][CH:3]=1.[OH2:22]>C1(C)C=CC=CC=1.CCOC(C)=O>[Br:21][C:13]1[C:12]2[C:17](=[CH:18][CH:19]=[C:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[O:9])[CH:11]=2)[N:16]=[C:15]([O:22][C:5]([CH3:8])([CH3:6])[CH3:4])[CH:14]=1
Reactant: O
Reactant: O=C(c1ccc(Cl)cc1)c1ccc2nc(Br)cc(Br)c2c1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)Oc1cc(Br)c2cc(C(=O)c3ccc(Cl)cc3)ccc2n1
Temperature: 70 °C

Procedure:
A mixture of (4-chlorophenyl)(2,4-dibromoquinolin-6-yl)methanone (5 g) and KOBut (1.1 eq. 12.93 mmol) in dry toluene (60 mL) was heated at 70° C. for 2 hr. and then cooled to room temperature. The reaction was diluted with EtOAc and water. The aqueous layer was extracted with ethyl acetate. The organics were combined and then washed with water, concentrated and subjected to chromatography (5-15% EtOAc/hexanes silica column) to yield (4-bromo-2-(tert-butoxy)quinolin-6-yl)(4-chlorophenyl)methanone.