Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH:22]4O[CH:25]=[N:24][CH:23]4S(C4C=CC(C)=CC=4)(=O)=O)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH3:37]>CCO>[N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3([C:22]4[N:37]=[CH:25][NH:24][CH:23]=4)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:14][CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: N
Reactant: Cc1ccc(S(=O)(=O)C2N=COC2C2(c3ccc(OCCCN4CCCC4)cc3)CCOCC2)cc1
Solvent: CCO
Product: c1nc(C2(c3ccc(OCCCN4CCCC4)cc3)CCOCC2)c[nH]1
Temperature: 110 °C
Yield: 12 %

Procedure:
The 5-{4-[4-(3-Pyrrolidin-1-yl-propoxy)-phenyl]-tetrahydro-pyran-4-yl}-4-(toluene-4-sulfonyl)-4,5-dihydro-oxazole (500 mg) was dissolved in EtOH saturated with ammonia (7 ml) before heating in a bomb at 110° C. for 18 hours. The solvent was removed in vacuo and the residue was taken up in DCM (10 ml) and washed with saturated sodium bicarbonate solution (15 ml), followed by brine (15 ml). The organic layer was dried over Na2SO4 and concentrated in vacuo, before purifying by column chromatography, eluting with a gradient of DCM:MeOH:NH3 (from 99:1:0.1 to 90:10:1), but this failed to separate the product from a close running impurity. The residue was therefore purified using column chromatography a second time, eluting with an isocratic solution of cyclohexane:DCM:Et2O:MeOH:NH3 (10:5:3:2:0.2) to afford the title compound as a colourless solid (70 mg, 12%). 1H NMR (400 MHz, CDCl3) δ 1.8 (m, 4H), 1.93-2.05 (m, 2H), 2.24-2.39 (m, 4H), 2.57 (m, 4H), 2.63 (t, 2H), 3.67 (m, 2H), 3.79 (m, 2H), 4.00 (t, 2H), 6.77 (s, 1H), 6.81 (d, 2H), 7.18 (d, 2H), 7.38 (s, 1H). LRMS ESI+ m/z 356 [MH]+, 354 [M−H+]−.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH2:13])[C:8]=2[C:14]#[CH:15])=[CH:4][CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1.O1CCCC1>O>[NH2:13][C:9]1[C:8]([C:14]#[CH:15])=[C:7]([O:6][C:5]2[CH:16]=[CH:17][C:2]([NH:1][C:26]([NH:25][C:22]3[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=3)=[O:27])=[CH:3][CH:4]=2)[CH:12]=[CH:11][N:10]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: C#Cc1c(Oc2ccc(N)cc2)ccnc1N
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1c(Oc2ccc(NC(=O)Nc3ccc(F)cc3)cc2)ccnc1N

Procedure:
4-(4-Aminophenoxy)-3-(1-ethynyl)-2-pyridinamine (260 mg), para-fluorophenyl isocyanate (0.13 ml) and tetrahydrofuran (5 ml) were stirred at room temperature for 20 hours. Water was added to the reaction solution, the tetrahydrofuran was distilled off, and then a small amount of ethyl acetate was added and the precipitated solid was filtered off to obtain 20 mg of a light brown solid.
Reaction SMILES: [Br:1][C:2]1[C:14](=[O:15])[N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:5]2[N:6]=[C:7](S(C)=O)[N:8]=[CH:9][C:4]=2[C:3]=1[CH3:21].[CH3:22][O:23][CH2:24][CH2:25][N:26]([CH2:34][CH2:35][O:36][CH3:37])[C:27]1[CH:28]=[CH:29][C:30]([NH2:33])=[N:31][CH:32]=1>C1(C)C=CC=CC=1>[CH3:37][O:36][CH2:35][CH2:34][N:26]([CH2:25][CH2:24][O:23][CH3:22])[C:27]1[CH:28]=[CH:29][C:30]([NH:33][C:7]2[N:8]=[CH:9][C:4]3[C:3]([CH3:21])=[C:2]([Br:1])[C:14](=[O:15])[N:13]([CH:16]4[CH2:20][CH2:19][CH2:18][CH2:17]4)[C:5]=3[N:6]=2)=[N:31][CH:32]=1
Reactant: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(S(C)=O)ncc12
Reactant: COCCN(CCOC)c1ccc(N)nc1
Solvent: Cc1ccccc1
Product: COCCN(CCOC)c1ccc(Nc2ncc3c(C)c(Br)c(=O)n(C4CCCC4)c3n2)nc1
Temperature: 110 °C
Reaction time: 5 h
Yield: 85.4 %

Procedure:
6-Bromo-8-cyclopentyl-2-methanesulfinyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (0.4 g, 1.08 mmol) and N5,N5-Bis-(2-methoxy-ethyl)-pyridine-2,5-diamine (0.5 g, 2.2 mmol) were combined in toluene (3.5 mL) and heated to 110° C. After 5 h the reaction mixture was allowed to cool and the crude product was directly chromatographed on silica gel eluting with a gradient of 25% to 100% ethyl acetate in hexanes to provide 2-{5-[bis-(2-methoxy-ethyl)-amino]-pyridin-2-ylamino}-6-bromo-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (0.49 g, 85%) as an orange gum. mp 94-95° C. MS (APCI); M++1: Calc'd, 530.2. Found 530.1. Anal. Calc'd for C24H32N6O3Br10.13H2O: C, 54.00; H, 5.90; N, 15.74. Found; C, 53.61; H, 5.68; N, 15.60.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:15]3[O:14][CH:13]([CH2:16][NH:17]C(=O)OCC4C=CC=CC=4)[CH2:12][C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH:2]=1.C[Si](I)(C)C>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:15]3[O:14][CH:13]([CH2:16][NH2:17])[CH2:12][C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH:2]=1
Reactant: O=C(NCC1Cc2cccc(-c3cccnc3)c2O1)OCc1ccccc1
Agent: C[Si](C)(C)I
Solvent: CO
Product: NCC1Cc2cccc(-c3cccnc3)c2O1

Procedure:
The title compound was prepared (0.172 g, 78%) following the general procedure of Example 129 as a light yellow solid, hydrochloride salt from (+)-benzyl {[7-pyridin-3-yl-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate (0.33 g, 0.91 mmol) and trimethylsilyl iodide (0.73 g, 3.64 mmol). [α]D25=−20.4 (c 10.0 in methanol); mp 168-171° C.
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH:10]=[C:9]([NH2:13])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14](Cl)(=[O:18])[C:15]([CH3:17])=[CH2:16]>N1C=CC=CC=1>[C:1]1([N:7]2[C:11](=[O:12])[CH:10]=[C:9]([NH:13][C:14](=[O:18])[C:15]([CH3:17])=[CH2:16])[NH:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=C(C)C(=O)Cl
Reactant: Nc1cc(=O)n(-c2ccccc2)[nH]1
Solvent: c1ccncc1
Product: C=C(C)C(=O)Nc1cc(=O)n(-c2ccccc2)[nH]1
Reaction time: 8 h

Procedure:
The 1-phenyl-3-methacrylamido-5-pyrazolone was prepared by acylation of 1-phenyl-3-amino-5-pyrazolone with an excess of methacrylyl chloride at 40° in pyridine by the following procedure. To a 500 mL three-necked flask fitted with a stirrer and thermometer there were added 35 g (0.2 mol) of 1-phenyl-3-amino-5-pyrazolone and 200 ml of dry pyridine. The mixture was stirred and the temperature held at 40° to 42°, and 42 g (0.4 mol) of methacrylyl chloride was added dropwise. After completion of the addition, the mixture was warmed to 75°. It was then poured onto cracked ice and allowed to stand overnight. The product was filtered on a suction filter, washed with water and then recrystallized from methanol.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][OH:20])=[CH:13][CH:12]=2)[CH2:9][CH2:8][N:7]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:6]1)=[O:4].[Cl:28][C:29]1[C:34](O)=[C:33]([Cl:36])[CH:32]=[C:31]([CH3:37])[CH:30]=1.P(CCCC)(CCCC)CCCC>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([CH:5]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][O:20][C:34]3[C:29]([Cl:28])=[CH:30][C:31]([CH3:37])=[CH:32][C:33]=3[Cl:36])=[CH:13][CH:12]=2)[CH2:9][CH2:8][N:7]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:6]1)=[O:4]
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1c1ccc(OCCO)cc1
Reactant: Cc1cc(Cl)c(O)c(Cl)c1
Agent: CCCCP(CCCC)CCCC
Solvent: Cc1ccccc1
Product: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1c1ccc(OCCOc2c(Cl)cc(C)cc2Cl)cc1
Temperature: 50 °C
Yield: 90.4 %

Procedure:
A mixture of compound 4-[4-(2-Hydroxyethoxy)phenyl]piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (5.50 g, 15 mmol), 2,6-dichloro-p-cresol (3.08 g, 18 mmol), azodicarboxylic dipiperidine (7.31 g, 29 mmol) and PBu3 (14 mL, 58 mmol) in toluene (150 mL) was heated to 50° C. for 16 h. The mixture was allowed to cool to rt, filtered, and the precipitate was washed with toluene. The filtrate was diluted with EtOAc, and washed with water (2×) and brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc/heptane 0:1→1:9→2:8) yielded the compound as a colorless oil (7.3 g, 90%). LC-MS: tR=1.18 min, ES+=538.34.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.O>CC(C)=O>[F:8][C:4]1[CH:3]=[C:2]([C:20]2[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: Fc1cccc(Br)c1
Reactant: COc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(-c2cccc(F)c2)cc1
Temperature: 40 °C
Yield: 86.6 %

Procedure:
1-Bromo-3-fluorobenzene (28.8 g, 0.165 mol), potassium carbonate (50 g, 0.362 mol), 4-methoxybenzene boronic acid (27.6 g, 0.182 mol), water (100 ml) and acetone (300 ml) were placed in 1 L round-bottom three necked flask equipped with condenser, thermometer, mechanical stirrer and nitrogen inlet and outlet. The reaction flask was flushed with nitrogen and minor flow was held during whole reaction time. The mixture was heated up to the boiling point to 40° C. to degas the reaction system and then cooled down and the catalyst palladium acetate (0.1 g) was added. The temperature has increased of few degrees and the solution turned brown. The mixture was refluxed for 6 hours, then was cooled down, poured on cold water and the precipitated gray solid was filtered off. The raw product was recrystallized from ethanol (500 ml). The product (28.9 g) in a form of white crystals was obtained, 88% of theor. yield. The melting point 63-64° C.
Reaction SMILES: [OH-].[NH4+].[CH2:3]([N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[N:7]=[C:6]1S)[CH3:4]>[Ni].C(O)C>[CH2:3]([N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[N:7]=[CH:6]1)[CH3:4]
Reactant: CCn1cc(-c2ccc(O)cc2)nc1S
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: CCn1cnc(-c2ccc(O)cc2)c1
Reaction time: 2 h

Procedure:
To a stirred mixture of 10 parts of Raney-nickel catalyst and 96 parts of ethanol are added successively 9 parts of ammonium hydroxide and 9 parts of 4-(1-ethyl-2-mercapto-1H-imidazol-4-yl)phenol. Stirring is continued for 2 hours at reflux temperature. The reaction mixture is filtered and the filtrate is evaporated. The precipitated product is filtered off, washed with a small amount of a mixture of 2,2'-oxybispropane and ethanol, and dried, yielding 6.7 parts of 4-(1-ethyl-1H-imidazol-4-yl)phenol.
Reaction SMILES: [Cl:1][C:2]([Cl:13])=[CH:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH2:8]Br.C1N2CN3CN(C2)CN1C3.C(O)(=[O:26])C>O>[Cl:1][C:2]([Cl:13])=[CH:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:26]
Reactant: CC(=O)O
Reactant: ClC(Cl)=COc1cccc(CBr)c1
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O
Product: O=Cc1cccc(OC=C(Cl)Cl)c1

Procedure:
To a solution of 8.5 g of 3-(2,2-dichlorovinyloxy)-benzyl bromide in 12.6 ml of acetic acid and 12.6 ml of water are added 8.4 g of hexamethylene tetramine. The resultant solution is refluxed for two hours. Subsequently 10 ml of HC1 are added and the reaction mixture is stirred for half an hour at 100°-110° C. The solution is washed with 100 ml of water and extracted cold (3 times) with 100 ml of ethyl acetate. The extract is washed with sodium carbonate solution and evaporated, to yield 5.8 g of 3-(2,2-dichlorovinyloxy)-benzaldehyde as a yellowish-brown oil, which can be used without further purification.
Reaction SMILES: [C:1]([O:4][C:5]([C:7]([F:10])([F:9])[F:8])=[CH2:6])(=[O:3])[CH3:2].[Cl:11][SiH:12]([Cl:14])[Cl:13].CCCCCCC>C1(C)C(C)=CC=CC=1>[C:1]([O:4][CH:5]([C:7]([F:10])([F:9])[F:8])[CH2:6][Si:12]([Cl:14])([Cl:13])[Cl:11])(=[O:3])[CH3:2]
Reactant: Cl[SiH](Cl)Cl
Reactant: C=C(OC(C)=O)C(F)(F)F
Solvent: CCCCCCC
Solvent: Cc1ccccc1C
Product: CC(=O)OC(C[Si](Cl)(Cl)Cl)C(F)(F)F
Temperature: 25 °C

Procedure:
1-(Trifluoromethyl)ethenyl acetate (Aldrich, 188.0 grams, 1.22 mole), trichlorosilane (80.6 grams, 0.60 mole), and 200 ml heptane were placed in a round bottom flask equipped with a water condenser and nitrogen inlet. Platinum(O)-1,3-divinyl-1,1,3,3-tetramethyldisiloxane complex in xylene (10 ml) was added to this solution and heated to reflux for 18 hours. Afterwards, the solution was cooled to room temperature and additional portions of trichlorosilane (80.6 grams, 0.60 mole) and platinum complex (5 ml) were added and heated to reflux for 48 hours. Proton NMR of the solution indicated about 75% conversion. A third portion of trichlorosilane (67.7 grams, 0.50 mole) and platinum complex (5 ml) were then added and the solution heated to reflux for 48 hours. Solvents were distilled off at atmospheric pressure and the residue was fractionally distilled under reduced pressure. 2-Acetoxy-3,3,3-trifluoropropyltrichlorosilane (251.7 grams) (1.A) was collected between 100-125° C. at 20 mm pressure as a clear liquid.
Reaction SMILES: [CH:1]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl>[CH:1]1([CH2:7][O:8][S:19]([CH3:18])(=[O:21])=[O:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCC1CCCCC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)OCC1CCCCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Cyclohexylmethanol (1.25 mL, 10.0 mmol) was dissolved in CH2Cl2 (50 mL), treated with diisopropylethylamine (7.0 mL, 40.0 mmol), cooled to 0° C., treated with methanesulfonyl chloride (0.85 mL, 11.0 mmol), and stirred for 1 hour at room temperature. The reaction was diluted with CH2Cl2 (200 mL), washed with saturated bicarbonate solution and brine, dried over Na2SO4, and concentrated to give 2.42 g (125% crude yield) of the desired product which was used immediately without purification.
Reaction SMILES: [CH2:1]1[C:6]2([C:15](=[S:16])[NH:14][C:8]3([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:17]1([CH3:26])[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[O:25])=[CH:19][CH:18]=1.[C-]#N.[K+].N12CCN(CC1)CC2>C1C=CC=CC=1>[C:17]1([CH3:26])[CH:22]=[CH:21][C:20]([NH:23][C:24]([N:14]2[C:15](=[S:16])[C:6]3([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5]3)[NH:7][C:8]32[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)=[O:25])=[CH:19][CH:18]=1
Reactant: S=C1NC2(CCCCC2)NC12CCCCC2
Reactant: Cc1ccc(N=C=O)cc1
Agent: C1CN2CCN1CC2
Agent: [C-]#N
Agent: [K+]
Solvent: c1ccccc1
Product: Cc1ccc(NC(=O)N2C(=S)C3(CCCCC3)NC23CCCCC3)cc1
Reaction time: 24 h

Procedure:
4.8 Parts of 7,14-diazadispiro[5.1.5.2]pentadecane-15-thione, 2.92 parts of p-tolyl isocyanate, 0.2 parts of potassium cyanide and a trace of 1,4-diazabicyclo[2.2.2]octane in 100 parts of dry benzene were heated at reflux for 24 hours. The solvent was then evaporated off in vacuo and the residue treated with excess water and allowed to stand for 24 hours. The solution was extracted with chloroform and the axtracts dried and evaporated in vacuo. The residue was crystallised from ethanol to yield 5.4 parts of 14-p-tolylcarbamoyl-7,14-diazadispiro[5.1.5.2]pentadecane-15-thione as a colourless solid of melting point 127° to 129°C. This material gave the following elemental analysis by weight:
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH:4]1[C:16]([O:18]C)=[O:17])=[O:2].[Li+:20].[OH-]>O1CCOCC1.O>[C:12]([O:11][C:9]([N:6]1[CH2:7][CH2:8][N:3]([CH:1]=[O:2])[CH:4]([C:16]([O-:18])=[O:17])[CH2:5]1)=[O:10])([CH3:15])([CH3:13])[CH3:14].[Li+:20]
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1C=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C=O)C(C(=O)[O-])C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 28 g of the compound obtained in Step A (103 mmol) in 515 mL of dioxane there are added 4.8 g of LiOH (113 mmol) in solution in 100 mL of H2O. The whole is stirred at ambient temperature for 4 hours. The reaction mixture is subsequently concentrated to dryness and then co-evaporated several times with ethyl acetate. The title product is obtained in the form of a solid and is used directly for the following cyclisation step.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:9][C:10]([CH3:13])([O-:12])[CH3:11].[K+]>O1CCCC1>[Br:1][C:2]1[C:3]([O:12][C:10]([CH3:13])([CH3:11])[CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[O-]
Reactant: Fc1ncccc1Br
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)Oc1ncccc1Br
Reaction time: 4 h

Procedure:
To a solution of 3-bromo-2-fluoropyridine (500 mg, 2.84 mmol) in anhydrous tetrahydrofuran (10 mL) under nitrogen was added potassium tert-butoxide (540 mg, 4.8 mmol) in portions over 30 minutes at 25° C., and stirring was continued for 4 hours at 25° C. The mixture was concentrated in vacuo and purified by silica gel flash chromatography eluting with dichloromethane/hexanes (50% to 100%) to give the title compound.
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7][CH:8]([CH3:10])[CH3:9])=[N:4][CH:3]=1.[C:11]1([CH3:29])[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[C:18]2[N:19]([CH:26]=[CH:27][N:28]=2)[CH:20]=[C:21](B(O)O)[CH:22]=1>>[CH:8]([S:7][C:5]1[S:6][C:2]([C:21]2[CH:22]=[C:17]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[CH3:29])[C:18]3[N:19]([CH:26]=[CH:27][N:28]=3)[CH:20]=2)=[CH:3][N:4]=1)([CH3:10])[CH3:9]
Reactant: Cc1ccccc1-c1cc(B(O)O)cn2ccnc12
Reactant: CC(C)Sc1ncc(Br)s1
Product: Cc1ccccc1-c1cc(-c2cnc(SC(C)C)s2)cn2ccnc12

Procedure:
Prepared using the procedure describe for Example 34, step 4 from 5-bromo-2-(isopropylthio)thiazole and 8-o-tolylimidazo[1,2-a]pyridin-6-ylboronic acid. LCMS (Conditions C): Tr 2.96 min.; (M+H)+: 366.3.
Reaction SMILES: [Br-:1].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.[CH:55]1([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=2[OH:65])[CH2:58][CH2:57][CH2:56]1.S([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>C(Cl)Cl>[Br:1][C:63]1[CH:62]=[CH:61][C:60]([OH:65])=[C:59]([CH:55]2[CH2:56][CH2:57][CH2:58]2)[CH:64]=1
Reactant: [Br-]
Reactant: Oc1ccccc1C1CCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Oc1ccc(Br)cc1C1CCC1
Reaction time: 8 h
Yield: 166.9 %

Procedure:
Tetra-n-butylammonium tribromide (4.72 g) was added to a solution of 2-cyclobutylphenol (1.21 g) in CH2Cl2 (24.2 mL) at room temperature, and the mixture was stirred at the same temperature overnight. After the reaction mixture was pour into a saturated aqueous sodium sulfite solution, extraction was performed on the mixture using EtOAc, and the extract was washed with water and saturated brine. The organic layer was dried over Na2SO4 and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex:EtOAc=100:0 to 84:16), whereby 4-bromo-2-cyclobutylphenol (1.85 g) was obtained as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[CH2:12]([NH:16][CH2:17][C:18]([OH:20])=[O:19])[CH2:13][CH2:14][CH3:15].O>C(O)C.[OH-].[Na+]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([N:16]([CH2:17][C:18]([OH:20])=[O:19])[CH2:12][CH2:13][CH2:14][CH3:15])[CH:3]=1
Reactant: CCCCNCC(=O)O
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCN(CC(=O)O)c1cc(Br)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 22.1 %

Procedure:
A mixture of 4-bromo-2-fluoro-nitro benzene (34 g, 0.15 mol), N-n-butyl glycine (20 g, 0.15 mol) in ethanol (600 ml), and water (150 ml) was heated to reflux for 6 hours. After cooling to room temperature, the mixture was diluted with 2N sodium hydroxide, extracted with CH2Cl2 and the pH was adjusted to 5 with 1N HCl. The mixture was extracted with CH2Cl2, the CH2Cl2 solution was dried (MgSO4) and evaporated to obtain the crude product (11 g, 22%) as a brown oil, which was used without further purification. 1H-NMR (DMSO-d6) δ0.84 (t, J=7.30 Hz, 3H), 1.23 (m, 2H), 1.45 (m, 2H), 3.18 (t, J=7.30 Hz, 2H), 3.91 (s, 2H), 7.16 (dd, J=8.68, 1.91 Hz, 1H), 7.40 (d, J=1.94 Hz, 1H), 7.69 (d, J=8.68 Hz, 1H); MS (EI) m/z331 (M+).
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][C:12]1[NH:13][C:14](=[O:22])[C:15]2[CH:21]=[CH:20][CH:19]=[N:18][C:16]=2[N:17]=1)C1C=CC=CC=1.CC(OC)(C)C>Br>[NH2:10][CH2:11][C:12]1[NH:13][C:14](=[O:22])[C:15]2[CH:21]=[CH:20][CH:19]=[N:18][C:16]=2[N:17]=1
Reactant: O=C(NCc1nc2ncccc2c(=O)[nH]1)OCc1ccccc1
Agent: Br
Solvent: COC(C)(C)C
Product: NCc1nc2ncccc2c(=O)[nH]1

Procedure:
(4-Oxo-3,4-dihydro-pyrido[2,3-d]pyrimidin-2-ylmethyl)-carbamic acid benzyl ester (383 mg, 1.23 mmol) in HBr (33% in acetic acid, 4 ml) was stirred for 2 h at ambient temperature. TBME (15 ml) was added and the precipitated solid was filtrated and washed with TBME to yield a salt of 2-aminomethyl-3H-pyrido[2,3-d]pyrimidin-4-one (0.1 CH3CO2H, 2.03 HBr) as white solid, MS: 176 [M+], which was subjected to the next reaction without further purification.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([N:13]1[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][C:21]([OH:23])=O)[CH2:15][CH2:14]1)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:24][O:25][C:26]([N:28]1[CH2:34][CH2:33][C:32]2[CH:35]=[CH:36][CH:37]=[CH:38][C:31]=2[CH2:30][CH2:29]1)=[O:27].[Cl-].[Al+3].[Cl-].[Cl-]>>[CH3:24][O:25][C:26]([N:28]1[CH2:34][CH2:33][C:32]2[CH:35]=[CH:36][C:37]([C:21](=[O:23])[CH2:20][CH2:19][CH:16]3[CH2:15][CH2:14][N:13]([C:5](=[O:12])[C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=4)[CH2:18][CH2:17]3)=[CH:38][C:31]=2[CH2:30][CH2:29]1)=[O:27]
Reactant: O=C(O)CCC1CCN(C(=O)c2ccccc2)CC1
Reactant: COC(=O)N1CCc2ccccc2CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Product: COC(=O)N1CCc2ccc(C(=O)CCC3CCN(C(=O)c4ccccc4)CC3)cc2CC1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 83.5 %

Procedure:
Under ice-cooling, 1.5 ml of thionyl chloride was added dropwise to 1.08 g (4.1 mmol.) of 3-(1-benzoylpiperidin-4-yl)propionic acid obtained in Reference Example 9. The mixture was stirred for 40 minutes at 0° C., then thionyl chloride was distilled off. The residue was dissolved in 20 ml of 1,2-dichloroethane, to which was added 0.81 g (3.9 mmol.) of 3- methoxycarbonyl-2,3,4,5-tetrahydro-1H-3-benzazepine obtained in Reference Example 10. To the mixture was added 1.75 g (13.1 mmol.) of aluminum chloride in small portions. The mixture was stirred for one hour at room temperature, then the reaction mixture was poured into ice-water and extracted with dichloromethane. The organic layers were combined and washed with water once, then dried over anhydrous sodium sulfate, followed by distilling off the solvent. Purification by means of a silica gel column chromatography gave 1.46 g (83%) of 3-methoxycarbonyl-7-[3-(1- benzoylpiperidin-4-yl)-1-oxopropyl]-2,3,4,5-tetrahydro-1H-3-benzazepine. Recrystallization from ethyl acetate --n-hexane gave colorless needles, m.p. 120°-123° C.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Br:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=1.[CH:18](N1CCCCC1)=[O:19].Cl>O1CCCC1.O>[Br:9][C:10]1[CH:15]=[C:14]([F:16])[C:13]([CH:18]=[O:19])=[C:12]([F:17])[CH:11]=1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: O=CN1CCCCC1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1c(F)cc(Br)cc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
55 ml (0.11 mmol) of 2 M lithium diisopropylamide are added with stirring at −70° C. to a solution of 19.3 g (0.1 mmol) of 1-bromo-3,5-difluorobenzene in 120 ml of dried tetrahydrofuran. After 30 minutes, N-formylpiperidine is added dropwise at this temperature. The mixture is allowed to warm to 0° C. At about 0° C., the reaction mixture is poured into cold water, acidified using 10% HCl and extracted twice with methyl tert-butyl ether. The combined organic phases are washed with water, dried over Na2SO4 and filtered, and the solvent is removed under reduced pressure. The residue is filtered through SiO2 (heptane/dichloromethane 1:1), (yield: 17.6 g, 78%).