Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.C(N(CC)CC)C.[NH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:21][CH2:20]1>CN(C=O)C.C(OCC)(=O)C>[CH2:28]([O:27][C:25]([N:22]1[CH2:23][CH2:24][CH:19]([CH2:18][NH:17][C:6]2[CH:5]=[C:4]([CH3:9])[N:3]=[C:2]([Cl:1])[N:7]=2)[CH2:20][CH2:21]1)=[O:26])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: NCC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: Cc1cc(Cl)nc(Cl)n1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(NCC2CCN(C(=O)OCc3ccccc3)CC2)nc(Cl)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 2,4-dichloro-6-methyl-pyrimidine (3.61 g, 22.15 mmol), triethylamine (7.02 mL, 50.34 mmol) in DMF (15 mL) was slowly added benzyl-4-(aminomethyl)piperidine-1-carboxylate (EXAMPLE 13, Step 1, 5.00 g, 20.13 mmol). The resulting reaction solution was stirred at rt for 2 h, then diluted with ethyl acetate (400 mL), washed with water (3×30 mL), brine (30 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (20–80% ethyl acetate in hexane) to give 4-[(2-chloro-6-methyl-pyrimidin-4-ylamino)-methyl]-piperidine-1-carboxylic acid benzyl ester. M.S.(M+1):375.36
Reaction SMILES: C([O:3][CH:4]1[CH:9]([CH:10](OCC)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[CH2:8][CH2:7][CH:6](OCC)[O:5]1)C.C(OC1C(C(OCC)C2C=CC(OC)=CC=2)CCC(OCC)O1)C>>[Cl:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH:10]=[C:9]([CH2:8][CH2:7][CH:6]=[O:5])[CH:4]=[O:3]
Reactant: CCOC1CCC(C(OCC)c2ccccc2Cl)C(OCC)O1
Agent: CCOC1CCC(C(OCC)c2ccc(OC)cc2)C(OCC)O1
Product: O=CCCC(C=O)=Cc1ccccc1Cl
Yield: 57 %

Procedure:
Following a procedure analagous to that of Example 1(b) but using respectively 2,6-diethoxy-3-(α-ethoxy-2-chlorobenzyl)tetrahydropyran and 2,6-diethoxy-3-(α-ethoxy-4-methoxybenzyl)tetrahydropyran there was obtained respectively 2-(2-chlorobenzylidene)glutaraldehyde, b.p. 155° C. (0.8 mm), yield: 57%; and 2-(4-methoxybenzylidene)glutaraldehyde, b.p. 175° C. (1.0 mm), yield 61%.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]2([CH2:22][CH2:23][N:24]3[CH:29]4[CH2:30][CH2:31][CH:25]3[CH2:26][CH:27]([N:32]3[C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=5[N:34]=[C:33]3[CH3:41])[CH2:28]4)[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[BrH:42]>>[BrH:42].[CH3:41][C:33]1[N:32]([CH:27]2[CH2:28][CH:29]3[N:24]([CH2:23][CH2:22][C:9]4([C:5]5[CH:4]=[C:3]([OH:2])[CH:8]=[CH:7][CH:6]=5)[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]4)[CH:25]([CH2:31][CH2:30]3)[CH2:26]2)[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[N:34]=1
Reactant: COc1cccc(C2(CCN3C4CCC3CC(n3c(C)nc5ccccc53)C4)CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: Br
Product: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2cccc(O)c2)CCNCC1
Temperature: 100 °C

Procedure:
A mixture of tert-butyl 4-(3-methoxy phenyl)-4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidine-1-carboxylate (235 mg, 0.42 mmol) and 48% hydrobromic acid was heated at 100° C. for 6 h. The mixture was concentrated and used without further purification.
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:30])[CH2:15][NH:16][C:17]([C:19]2[CH:28]=[C:27]([OH:29])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=2)=[O:18])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:37]([O:44][C:45](=[O:48])[CH2:46]Br)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>CN(C=O)C.O>[CH2:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:30])[CH2:15][NH:16][C:17]([C:19]2[CH:28]=[C:27]([O:29][CH2:46][C:45]([O:44][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:48])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=2)=[O:18])[CH2:12][CH2:13]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)N1CCN(C(=O)CNC(=O)c2cc(O)c3ccccc3n2)CC1
Reactant: O=C(CBr)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOC(=O)N1CCN(C(=O)CNC(=O)c2cc(OCC(=O)OCc3ccccc3)c3ccccc3n2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 10 g 4-{2-[(4-Hydroxy-quinoline-2-carbonyl)-amino]acetyl}-piperazine-1-carboxylic acid butyl ester in 41 ml of DMF, 8.6 g of cesium carbonate and 6.1 g of Bromo-acetic acid benzyl ester were added and the reaction mixture was stirred for 16 h at RT. Then, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 5.2 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([N:8]=[C:9]=[S:10])[CH:7]=1.[CH2:12]([NH:14][C:15]1[C:16]([CH3:22])=[N:17][N:18]([CH3:21])[C:19]=1[CH3:20])[CH3:13]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([NH:8][C:9](=[S:10])[N:14]([CH2:12][CH3:13])[C:15]2[C:16]([CH3:22])=[N:17][N:18]([CH3:21])[C:19]=2[CH3:20])[CH:7]=1
Reactant: Cc1ccc(Cl)cc1N=C=S
Reactant: CCNc1c(C)nn(C)c1C
Product: CCN(C(=S)Nc1cc(Cl)ccc1C)c1c(C)nn(C)c1C
Yield: 34.1 %

Procedure:
Prepared using Method A from 9.33 g (51 mmol) of 5-chloro-2-methyl-phenyl isothiocyanate and 4-ethylamino-1,3,5-trimethylpyrazole (7.2 g, 47 mmol) of step B to give 5.4 g of title compound as a white solid (70% yield, m.p. 144-145° C.).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]([O:17][NH:18][CH2:19][CH:20]([CH3:22])[CH3:21])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(Cl)Cl>[CH2:10]([O:17][N:18]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:8]([NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:9])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)CNOCc1ccccc1
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Product: CC(C)CN(OCc1ccccc1)C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 77 %

Procedure:
Phenyl isocyanate (3.2 g, 27 mmol) was added via pipette to a solution of N-benyloxy-N-(2-methylpropyl)amine (4.8 g, 27 mmol) in methylene chloride (30 mL). The reaction mixture was allowed to stir at ambient temperature for 3 days. The solvent was removed under vacuum. The residue was purified by column chromatography (silica gel; 1:9 ethyl acetate:hexanes) to provide 6.2 g of 1-benzyloxy-1-(2-methylpropyl)-3-phenylurea as a white crystalline solid, m.p. 85°-87° C. Analysis: Calculated for C18H22N2 : %C, 72.46; %H, 7.43; %N, 9.39; Found: %C, 72.53; %H, 7.51; %N, 9.44.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([S:18][C:19]([F:24])([F:23])[CH:20]([F:22])[F:21])[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:26][O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:28]([O:27][CH2:26][N:10]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=[C:9]1[S:18][C:19]([F:23])([F:24])[CH:20]([F:22])[F:21])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: FC(F)C(F)(F)Sc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Reactant: ClCOCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)C(F)(F)Sc1nc(-c2ccccc2)c(-c2ccccc2)n1COCc1ccccc1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
A mixture of 3.5 g (0.01 mole) of 4,5-diphenyl-2-(1,1,2,2-tetrafluoroethylthio)imidazole, 2.1 g (0.013 mole) benzyl chloromethyl ether, 3.6 g (0.026 mole) potassium carbonate in 25 ml DMF was stirred for 24 hours. TLC showed some starting material, so an additional 0.5 g (0.003 mole) of benzyl chloromethyl ether was added and stirring continued for another 24 hours. The mixture was poured into ice water, extracted three times with ether and the ether layers backwashed three times with water. The ether solution was dried and concentrated on a rotary evaporator. The residue was chromatographed on 200 g SilicAR CC-7, eluting with toluene to give, after recrystallization from hexane, 3.6 g (76.6%) of white product, mp 70°-70.5°.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[C@H:20]([CH3:25])[CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH3:26]I.[H-].[Na+]>>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[C@H:20]([CH3:25])[CH2:21][N:22]([CH3:26])[C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CI
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](C)CNC2=O)CC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](C)CN(C)C2=O)CC1
Yield: 19 %

Procedure:
The title compound was synthesized in analogy to example 17, from (R)-8-(1-isopropyl-piperidin-4-yloxy)-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 8), methyl iodide and sodium hydride, to give the desired product as a light yellow oil (19%).
Reaction SMILES: [NH3:1].C([O:4][C:5](=O)[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:17]=[C:16]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:15]=[CH:14][N:13]=2)=[CH:8][CH:7]=1)C>CO.ClCCl>[CH2:18]([C:16]1[CH:15]=[CH:14][N:13]=[C:12]([C:9]2[CH:10]=[CH:11][C:6]([C:5]([NH2:1])=[O:4])=[CH:7][CH:8]=2)[N:17]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: N
Reactant: CCCCCCCc1ccnc(-c2ccc(C(=O)OCC)cc2)n1
Solvent: CO
Solvent: ClCCl
Product: CCCCCCCc1ccnc(-c2ccc(C(N)=O)cc2)n1

Procedure:
30 ml. of liquid ammonia are added to 4.4 g. of 4-(4-n-heptylpyrimid-2-yl)-benzoic acid ethyl ester, dissolved in 50 ml. of a methanol-dichloromethane (1:1) mixture, in an autoclave and the mixture is then warmed to 90° for 5 hours (pressure: 16 atmospheres absolute). The reaction mixture is evaporated to dryness and the more sparingly soluble amide is separated from unreacted educt, whereby 4-(4-n-heptylpyrimid-2-yl)-benzoic acid amide is obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[N:15]1([CH2:21][CH2:22][CH2:23][OH:24])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[N:15]1([CH2:21][CH2:22][CH2:23][O:24][C:2]2[N:7]=[CH:6][C:5]([C:8]3[CH:9]=[CH:10][C:11](=[O:14])[NH:12][N:13]=3)=[CH:4][CH:3]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: OCCCN1CCCCC1
Reactant: O=C1CCC(c2ccc(Cl)nc2)=NN1
Product: O=c1ccc(-c2ccc(OCCCN3CCCCC3)nc2)n[nH]1

Procedure:
This compound was prepared using the intermediate from step 1 example 139 and 3-piperidin-1-yl-propanol using methods described for example 146; Mp 155-158° C. MS m/z 315 (M+H).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:15][OH:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23].C(N(CC)CC)C.Cl>C1C=CC=CC=1>[CH3:21][S:22]([O:16][CH2:15][CH:14]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[O:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:17][CH2:18][CH2:19][CH3:20])(=[O:24])=[O:23]
Reactant: CCCCC(CO)c1ccccc1Oc1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCCCC(COS(C)(=O)=O)c1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.7 %

Procedure:
Into a 500 ml round bottom flask are placed 15.6 g (0.06 mole) of 2-(o-phenoxyphenyl)hexan-1-ol, in 100 ml of benzene and 7.9 g. (0.07 mole) of methane sulfonyl chloride. To this mixture is added 8.2 g (0.08 mole) of triethyl amine dropwise at 10°. The reaction mixture is stirred overnight at room temperature and poured into 150 ml 10% hydrochloric acid. It is then extracted with benzene and the combined benzene extracts are washed with water and dried over Na2SO4. Solvent is evaporated to give 20 g of product.
Reaction SMILES: [I:1][C:2]1[CH:14]=[N:13][C:5]2[N:6]([CH3:12])[C:7](=[O:11])O[C:9](=[O:10])[C:4]=2[CH:3]=1.IC1C=NC(NC)=[C:20](C=1)[C:21]([O:23][CH3:24])=[O:22].IC1C=NC(NC)=C(C=1)C(OCC)=O.ClC(OC(Cl)(Cl)Cl)=O>ClCCCl.O1CCOCC1>[OH:10][C:9]1[C:4]2[C:5](=[N:13][CH:14]=[C:2]([I:1])[CH:3]=2)[N:6]([CH3:12])[C:7](=[O:11])[C:20]=1[C:21]([O:23][CH3:24])=[O:22]
Reactant: CNc1ncc(I)cc1C(=O)OC
Reactant: Cn1c(=O)oc(=O)c2cc(I)cnc21
Agent: CCOC(=O)c1cc(I)cnc1NC
Agent: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Solvent: ClCCCl
Product: COC(=O)c1c(O)c2cc(I)cnc2n(C)c1=O
Temperature: 80 °C

Procedure:
6-Iodo-1-methyl-1H-pyrido[2,3-d][1,3]oxazine-2,4-dione. To a mixture of methyl 5-iodo-2-(methylamino)nicotinate and ethyl 5-iodo-2-(methylamino)nicotinate (10.5 g) and 1,4-dioxane (10 mL) in anhydrous 1,2-dichloroethane (1000 mL) was added trichloromethyl chloroformate (15.43 mL, 128.45 mmol) dropwise over 1 hour, with stirring and heating at 80° C. After addition, the reaction mixture was stirred at 80° C. for 4 hours, and was allowed to reach room temperature. The solvent was evaporated, and the residue was washed with a 1:1 mixture of EtOAc/hexanes (100 mL) and dried in vacuo to give the title compound.
Reaction SMILES: [CH2:1]([NH:7][C:8](=[S:10])[S-:9])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[CH2:11]([NH+](CC)CC)C.C(Br)Br.C(N(CC)CC)C.S1CCS1>CN(C)C=O>[CH2:1]([N:7]=[C:8]1[S:9][CH2:11][S:10]1)[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[NH+](CC)CC
Reactant: S=C([S-])NCc1ccco1
Agent: C1CSS1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: BrCBr
Product: c1coc(CN=C2SCS2)c1
Temperature: 0 °C

Procedure:
A mixture of 13.7 g. of triethylammonium furfuryldithiocarbamate, 10.5 ml. of methylene bromide, and 7.0 ml. of triethylamine in 100 ml. of dimethylformamide was stirred for several hours and then poured into ice-water. The oily product was partitioned into ether and the ether mixture was extracted with 3N hydrochloric acid. After extracting the acidic solution with methylene chloride, it was made basic with potassium hydroxide solution and re-extracted with methylene chloride. The methylene chloride mixture, after water washing, drying, and concentrating in vacuo afforded 4.9 g. of the desired dithietane as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:13]([O:15][CH3:16])=[O:14])=[N:6][C:7]=1[O:8][CH2:9][CH:10]([CH3:12])[CH3:11].[F:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=1B(O)O.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=1[C:2]1[CH:3]=[CH:4][C:5]([C:13]([O:15][CH3:16])=[O:14])=[N:6][C:7]=1[O:8][CH2:9][CH:10]([CH3:12])[CH3:11]
Reactant: COc1ccc(F)c(B(O)O)c1
Reactant: COC(=O)c1ccc(Br)c(OCC(C)C)n1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(OCC(C)C)n1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 73.6 %

Procedure:
Under an argon atmosphere, to a solution of methyl 5-bromo-6-isobutoxypicolinate (698 mg), 2-fluoro-5-methoxyphenylboronic acid (454 mg), tris(dibenzylideneacetone)dipalladium(0) (65 mg) and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (117 mg) in toluene (10 mL) was added 2.0 M aqueous sodium carbonate solution (2.67 mL), and the mixture was stirred at 100° C. for 30 min. The reaction mixture was filtered through celite, and water was added at room temperature. The reaction mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (594 mg) as a pale-yellow oil.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[C:2]#[CH:3].[Br:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11](I)[CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[Cu]I>[Br:8][C:9]1[CH:10]=[C:11]([C:3]#[C:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])[CH:12]=[CH:13][CH:14]=1
Reactant: C#CC(=O)OCC
Reactant: Brc1cccc(I)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C#Cc1cccc(Br)c1
Reaction time: 1 h
Yield: 24.1 %

Procedure:
Ethyl propiolate (2.15 mL, 21.2 mmol, 1.20 equiv) was added to a mixture of 1-bromo-3-iodobenzene (5.00 g, 17.7 mmol, 1 equiv), PdCl2(CH3CN)2 (367 mg, 1.41 mmol, 0.080 equiv), copper (1) iodide (135 mg, 0.707 mmol, 0.040 equiv) and potassium carbonate (2.93 g, 21.2 mmol, 1.20 equiv) in N,N-dimethylformamide (44 mL) at 22° C. The reaction mixture was stirred for 1 hour, then was partitioned between ethyl acetate and saturated aqueous ammonium chloride solution. The organic layer was washed sequentially with water and saturated aqueous sodium chloride solution. The washed solution was dried over sodium sulfate, and the dried solution was filtered. The filtrate was concentrated, and the residue was purified by flash-column chromatography on silica gel (hexanes, grading to 40% ethyl acetate-hexanes) to afford ethyl 3-(3-bromophenyl)prop-2-ynoate (1.08 g, 24%). Calc'd (M+1)+: 253.0. Found: 252.9.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.C(N(CC)CC)C.[F:17][C:18]([F:23])([F:22])[C:19](Cl)=[O:20]>O1CCCC1>[F:17][C:18]([F:23])([F:22])[C:19]([C:3]1[C:2]([Cl:1])=[CH:7][N:6]=[C:5]([NH2:8])[C:4]=1[NH2:9])=[O:20]
Reactant: Nc1cc(Cl)cnc1N
Reactant: O=C(Cl)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ncc(Cl)c(C(=O)C(F)(F)F)c1N
Reaction time: 2 h

Procedure:
5-Chloro-2,3-pyridinediamine (2.8 grams) was dissolved in 50 milliliters of tetrahydrofuran and 2.02 milliliters of triethylamine and the solution treated with trifluoroacetyl chloride (2.6 grams) in 100 milliliters of tetrahydrofuran. The addition was carried out at room temperature over a period of 2 hours, and the reaction mixture was then held at room temperature for another hour with stirring. Solvent was removed by evaporation, and the residue recrystallized from a chloroform/acetone mixture to obtain the desired N3 -trifluoroacetyl-5-chloro-2,3-pyridinediamine product, m.p., 292°-93°C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@H]2N1CCC2.CSC.B.CO>C1COCC1.O.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([OH:10])[CH3:9]
Reactant: CC(=O)c1ccccc1Cl
Agent: B
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@@H]2CCCN12
Solvent: CSC
Solvent: ClCCl
Solvent: C1CCOC1
Product: C[C@@H](O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2′-Chloroacetophenone (8.4 mL, 65 mmol) and (S)-(−)-2-methyl-CBS-oxazaborolidine (0.90 g, 0.32 mmol) were combined in THF (75 mL). Borane methyl sulfide complex (2M in THF; 21.5 mL, 43 mmol) was added over 20 minutes, and the reaction was stirred at room temperature for 30 minutes. MeOH was added, and the mixture was worked-up with CH2Cl2 and H2O. The organic layer was concentrated to give the title compound.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[CH:3]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19](OB(O)O)=[CH:18][CH:17]=1>>[CH3:13][O:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:19]3[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[CH:17][CH:18]=3)[CH:3]=2)[CH:8]=1
Reactant: COc1ccc(OB(O)O)cc1
Reactant: COc1ccc2cc(Br)ccc2c1
Product: COc1ccc(-c2ccc3cc(OC)ccc3c2)cc1
Reaction time: 5 h
Yield: 56 %

Procedure:
The compound is prepared by the reaction of 2-bromo-6-methoxynaphthalene (500 mg, 2.11 mmol, 1 eq) with 4-methoxyphenylboric acid (313 mg, 2.12 mmol, 1 eq) according to method A in 5 h. The desired product was precipitated from hexane in a yield of 56% (311 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[C:9](O)(=[O:14])[CH2:10][C:11](O)=[O:12].P(Cl)(Cl)(Cl)=O.C>C(=O)([O-])O.[Na+].[Cl-].[Zn+2].[Cl-]>[F:1][C:2]1[CH:3]=[C:4]2[C:5]([C:9]([OH:14])=[CH:10][C:11](=[O:12])[O:8]2)=[CH:6][CH:7]=1
Reactant: Oc1cccc(F)c1
Reactant: O=C(O)CC(=O)O
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: O=c1cc(O)c2ccc(F)cc2o1
Temperature: 65 °C
Reaction time: 2 h

Procedure:
A mixture of 3-fluorophenol (31.5 g, 0.281 mol), malonic acid (29.24 g, 0.281 g) and zinc chloride (100.0 g, 0.734 mol) in phosphorus oxychloride (70 mL, 0.751 mol) is heated at 65° C. overnight and poured into an ice/water mixture. The resultant aqueous mixture is filtered to obtain a pale green solid. A mixture of the solid in 10% sodium hydrogen carbonate solution is stirred at room temperature for 2 hours, decolorized with charcoal and filtered through diatomaceous earth. The filtrate is acidified with concentrated hydrochloric acid and the resultant precipitate is collected and dried to give the title product as a brown solid, mp 229°-230° C.
Reaction SMILES: [NH2:1][C@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[CH3:19][O:20][C:21]1[S:25][C:24]([C:26](O)=[O:27])=[N:23][CH:22]=1>>[Cl:17][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@H:2]([NH:1][C:26]([C:24]3[S:25][C:21]([O:20][CH3:19])=[CH:22][N:23]=3)=[O:27])[CH3:18])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: C[C@@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: COc1cnc(C(=O)O)s1
Product: COc1cnc(C(=O)N[C@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)s1
Yield: 9 %

Procedure:
(R)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (86 mg, 0.33 mmol) was coupled with 5-methoxythiazole-2-carboxylic acid (90 mg, 0.40 mmol) using the method of Example 34(d). Crude product was purified by CombiFlash (column: silica, eluent: 0-10% MeOH in DCM) to yield 12 mg (9%) of the title compound. 1H-NMR (400 MHz; CDCl3): δ 1.23 (d, 3H), 3.99 (s, 3H), 4.26 (dd, 1H), 4.40-4.46 (m, 1H), 4.49-4.59 (m, 1H), 6.63 (d, 1H), 7.22 (s, 1H), 7.49 (d, 1H), 7.68 (d, 1H), 7.78 (dd, 1H), 8.10 (broad d, 1H) overlapping with 8.13 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:11]2[CH2:12][CH2:13][N:14]=[C:10]2[C:9]2[CH:8]=[CH:7][C:6]([O:15][CH2:16][CH2:17][CH2:18][S:19]([N:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[C:5]([O:25][CH3:26])[C:4]=2[N:3]=1.[NH2:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][N:29]=1>>[NH2:27][C:28]1[CH:36]=[CH:35][C:31]([C:32]([NH:1][C:2]2[N:11]3[CH2:12][CH2:13][N:14]=[C:10]3[C:9]3[CH:8]=[CH:7][C:6]([O:15][CH2:16][CH2:17][CH2:18][S:19]([N:22]([CH3:24])[CH3:23])(=[O:20])=[O:21])=[C:5]([O:25][CH3:26])[C:4]=3[N:3]=2)=[O:33])=[CH:30][N:29]=1
Reactant: Nc1ccc(C(=O)O)cn1
Reactant: COc1c(OCCCS(=O)(=O)N(C)C)ccc2c1N=C(N)N1CCN=C21
Product: COc1c(OCCCS(=O)(=O)N(C)C)ccc2c1N=C(NC(=O)c1ccc(N)nc1)N1CCN=C21

Procedure:
The procedure used for the preparation of Example 16, Step 2 was used to prepare the title compound from 3-[(5-amino-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-8-yl)oxy]-N,N-dimethylpropane-1-sulfonamide (Example 17 Step 1) and 6-aminonicotinic acid. High vacuum drying gave the title compound (117 mg, 59%): HPLC MS RT=1.60 min, MH+=502.2; 1H NMR (DMSO-d6+2 drops TFA-d) δ: 2.19-2.24 (2H, m), 2.78 (6H, s), 3.19-3.24 (2H, m), 3.99 (3H, s), 4.20-4.26 (2H, m), 4.37 (2H, t), 4.47-4.54 (2H, m), 7.04 (1H, d), 7.46 (1H, d), 8.03 (1H, d), 8.48 (1H, dd), 8.77 (1H, d).
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:7]=[CH:8][C:9]2[CH2:12][C:11](=[O:13])[C:10]=2[CH:14]=1.[I-:15].[K+]>O.S(=O)(=O)(O)O>[I:15][C:6]1[CH:7]=[CH:8][C:9]2[CH2:12][C:11](=[O:13])[C:10]=2[CH:14]=1
Reactant: Nc1ccc2c(c1)C(=O)C2
Reactant: [I-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: O=C1Cc2ccc(I)cc21
Reaction time: 0.25 h

Procedure:
At 0°-5° C., a solution of sodium nitrite (0.759 g) in water (5 mL) was added into a suspension of the amine 8 in 2.5 mL of concentrated sulfuric acid and 10 mL of water. After stirring for 15 minutes, a solution of potassium iodide (1.826 g) in 3 mL of water was added slowly. The cloudy, orange-purple solution was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (50 mL) and extracted with with ether (2×100 mL). The etheral extracts were washed with aqueous sodium carbonate solution and water. Removal of solvent and flash chromatography of the residue afforded the iodide 17. 1H NMR (200 MHz, CDCl3) 4.00 (s, 2H), 7.27 (d d, 1H), 7.48 (d d, 1H), 8.13 (s, 1H); MS (EI, m/e, relative intensity %) 244 (M+., 12), 216 (M+. -CO, 7.8), 89 (216 (M+. -CO -.I, 40).