Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[NH:17][C:16](=[O:18])[NH:15][C:11]3=[N:12][C:13]=2[CH3:14])=[CH:4][CH:3]=1.[CH:19](O)=O>>[CH3:19][NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[NH:17][C:16](=[O:18])[NH:15][C:11]3=[N:12][C:13]=2[CH3:14])=[CH:4][CH:3]=1
Reactant: Cc1nc2[nH]c(=O)[nH]c2cc1-c1ccc(N)cc1
Reactant: O=CO
Product: CNc1ccc(-c2cc3[nH]c(=O)[nH]c3nc2C)cc1

Procedure:
It is contemplated that 6-(4-aminophenyl)-1,3-dihydro-5-methyl-2H-imidazo[4,5-b]pyridin-2-one can be alkylated by reacting it with formic acid followed by reduction of the intermediate formylamino derivative to obtain 6-[4-(methylamino)phenyl]-1,3-dihydro-5-methyl-2H-imidazo[4,5-b]pyridin-2-one [I; Ar=4-CH3NHC6H4, R1 and R3 =H, R5 =CH3 ]; or by reacting it with formaldehyde under reducing conditions to obtain 6-[4-(dimethylamino)phenyl]-1,3-dihydro-5-methyl-2H-imidazo[4,5-b]pyridin-2-one [I; Ar=4-(CH3)2NC6H4, R1 and R3 =H, R5 =CH3 ].
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([CH:11]([CH3:13])[CH3:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[CH:14]([NH2:16])=O>>[CH:11]([C:9]1[CH:10]=[C:2]2[C:3]([C:4](=[O:5])[NH:16][CH:14]=[N:1]2)=[CH:7][CH:8]=1)([CH3:13])[CH3:12]
Reactant: CC(C)c1ccc(C(=O)O)c(N)c1
Reactant: NC=O
Product: CC(C)c1ccc2c(=O)[nH]cnc2c1
Yield: 34 %

Procedure:
The product of Example 431D (0.579 g, 3.231 mmol) was reacted with formamide (1.3 mL) under a nitrogen atmosphere in a microwave (Personal Chemistry Emrys Creator, 300 W) at 150°C for 30 minutes. The cooled reaction gave a solid mass which was recrystallized from absolute ethanol (2 mL) to afford the title compound as an off-white solid (0.208 g, 1.105 mmol, 34%). 1H NMR (300 MHz, DMSO-D6) δ ppm 1.26 (d, J=6.99 Hz, 6 H) 2.91-3.21 (m, 1 H) 7.44 (dd, J=8.27, 1.65 Hz, 1 H) 7.50 (d, J=1.84 Hz, 1 H) 8.02-8.07 (m, 2 H) 12.15 (s, 1 H); MS (APCI) m/z 189 (M+H)+, 211 (M+Na)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]3[N:22]=[CH:23][C:24]([C:25](O)=[O:26])=[C:14]3[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([S:35]([C:38]2[CH:39]=[C:40]([NH2:44])[CH:41]=[CH:42][CH:43]=2)(=[O:37])=[O:36])[CH2:31][CH2:30]1>>[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([S:35]([C:38]2[CH:39]=[C:40]([NH:44][C:25]([C:24]3[CH:23]=[N:22][N:15]4[C:16]([C:18]([F:21])([F:20])[F:19])=[CH:17][C:12]([C:4]5[CH:5]=[CH:6][C:7]([C:8]([F:11])([F:9])[F:10])=[C:2]([CH3:1])[CH:3]=5)=[N:13][C:14]=34)=[O:26])[CH:41]=[CH:42][CH:43]=2)(=[O:37])=[O:36])[CH2:31][CH2:30]1
Reactant: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)O)c3n2)ccc1C(F)(F)F
Reactant: CN1CCN(S(=O)(=O)c2cccc(N)c2)CC1
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)Nc4cccc(S(=O)(=O)N5CCN(C)CC5)c4)c3n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 5-(3-methyl-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.8) and 3-(4-methyl-piperazine-1-sulfonyl)-phenylamine [CAS 436095-35-1] according to general procedure II. Yellow solid. MS (ISP) 627.4 [(M+H)+]; mp 199° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[N:5]=[C:4](O)[CH:3]=1.O=P(Cl)(Cl)[Cl:20]>>[Cl:20][C:4]1[CH:3]=[C:2]([CH3:1])[N:7]=[C:6](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[N:5]=1
Reactant: Cc1cc(O)nc(/C=C/c2cccc(F)c2)n1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc(Cl)nc(/C=C/c2cccc(F)c2)n1
Yield: 82.7 %

Procedure:
In analogy to example 12c), by heating (E)-6-methyl-2-[2-(3-fluoro-phenyl)-vinyl]-pyrimidin-4-ol 1 (1.12 g, 4.86 mmol) in POCl3 (9 ml, 0.1 mol) at 130° C. for 4.5 h there was obtained (E)-4-chloro-6-methyl-2-[2-(3-fluoro-phenyl)-vinyl]-pyrimidine (1 g, 86%) as a white solid. EI mass spectrum, m/e: 248 (M calculated for C14H13ClFN2: 248).
Reaction SMILES: [CH2:1]([C:3]1([CH2:15][CH3:16])[O:8][C:7](=[O:9])[NH:6][C:5]2[CH:10]=[CH:11][C:12](I)=[CH:13][C:4]1=2)[CH3:2].[N+:17]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1)([O-:19])=[O:18]>O>[CH2:1]([C:3]1([CH2:15][CH3:16])[O:8][C:7](=[O:9])[NH:6][C:5]2[CH:10]=[CH:11][C:12]([C:24]3[CH:23]=[CH:22][CH:21]=[C:20]([N+:17]([O-:19])=[O:18])[CH:25]=3)=[CH:13][C:4]1=2)[CH3:2]
Reactant: CCC1(CC)OC(=O)Nc2ccc(I)cc21
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Solvent: O
Product: CCC1(CC)OC(=O)Nc2ccc(-c3cccc([N+](=O)[O-])c3)cc21

Procedure:
Prepared from 4,4-diethyl-6-iodo-1,4-dihydrobenzo[d][1,3]oxazin-2-one and 3-nitrophenyl boronic acid according to Procedure A. Off-white solid: mp 193-194° C. 1H-NMR (CDCl3) δ9.19 (s, 1H, D2O exchangeable), 8.38 (t, 1H, J=1.9 Hz), 8.20 (m, 1H), 7.83 (m, 1H), 7.61 (t, 1H, J=8.0 Hz), 7.50 (dd, 1H, J=8.2, 2.0 Hz), 7.23 (d, 1H, J=1.7 Hz), 6.99 (d, 1H, J=8.3 Hz), 2.09 (q, 4H, J=7.4 Hz), 0.96 (t, 6H, J=8.3 Hz); MS (EI) m/z 325 ([M−H]−, 100%). Anal. Calc. For C18H18N2O4.0.3 H2O: C, 65.17; H, 5.65; N, 8.44. Found: C, 65.31; H, 5.60; N, 8.10.
Reaction SMILES: [C:1]1([C:7]([OH:9])=O)[CH2:6][CH:5]=[CH:4][CH2:3][CH:2]=1.[NH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[N:14][C:15]([Cl:21])=[CH:16][CH:17]=2)[N:12]=1.C(O)C>O>[Cl:21][C:15]1[N:14]=[C:13]2[C:18]([CH:19]=[CH:20][C:11]([NH:10][C:7]([C:1]3[CH2:6][CH:5]=[CH:4][CH2:3][CH:2]=3)=[O:9])=[N:12]2)=[CH:17][CH:16]=1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Reactant: O=C(O)C1=CCC=CC1
Solvent: CCO
Solvent: O
Product: O=C(Nc1ccc2ccc(Cl)nc2n1)C1=CCC=CC1
Temperature: 4 °C
Yield: 33 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 1,4-cyclohexadiene-1-carboxylic acid (6.2 g), N,N'-carbonyldiimidazole (8 g) and 2-amino-7-chloro-1,8-naphthyridine (8 g). The product produced by precipitation in water (11 g; m.p. 205° C.) is dissolved in boiling ethanol (250 cc). After 2 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with ethanol (3×15 cc) and dried at 40° C. under reduced pressure (0.067 kPa). N-(7Chloro-1,8-naphthyridin-2-yl)-1,4-cyclohexadiene-1-carboxamide (4.2 g) is produced, m.p. 210° C.
Reaction SMILES: [NH2:1][CH:2]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1)[CH:3]([C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)[OH:4].[F:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([C:33](O)=[O:34])=[CH:25][CH:24]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([C:33]([NH:1][C@@H:2]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:14][CH:13]=2)[C@H:3]([OH:4])[C:5]2[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=2)=[O:34])=[CH:25][CH:24]=1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccncc1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: O=C(N[C@@H](Cc1ccc(C(F)(F)F)cc1)[C@H](O)c1ccncc1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.9 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-pyridyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (70 mg, 0.24 mmol) in acetonitrile (5 ml) were added 4-fluoronaphthalenecarboxylic acid (45 mg, 0.24 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (68 mg, 0.35 mmol) and 1-hydroxy-1H-benzotriazole (36 mg, 0.24 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from ethyl acetate-diisopropyl ether to give the title compound (55 mg, 50%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][C:9]([OH:11])=O)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:12]([NH:19][CH2:20][CH2:21][OH:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.O>[CH2:12]([N:19]([CH2:20][CH2:21][OH:22])[C:9](=[O:11])[CH2:8][C:7]1[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][CH:6]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OCCNCc1ccccc1
Reactant: O=C(O)Cc1cccnc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Cc1cccnc1Cl)N(CCO)Cc1ccccc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 102.7 %

Procedure:
To a solution of the compound (3.40 g) obtained in step 4, N-benzylethanolamine (4.53 g) and HOBt.H2O (4.60 g) in DMF (50 mL) was added WSC.HCl (5.80 g), and the mixture was stirred at room temperature for 4 days. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and brine, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient; 80% ethyl acetate/hexane→2% methanol/ethyl acetate) to give N-benzyl-2-(2-chloropyridin-3-yl)-N-(2-hydroxyethyl)acetamide (6.20 g, 100%) as a pale-yellow oil.
Reaction SMILES: S(O[CH2:6][CH2:7][O:8][S:9](=[O:12])(=[O:11])[NH2:10])(=O)(=O)N.[CH2:13]([OH:18])[CH2:14]CCO>>[S:9]([O:18][CH2:13][CH2:14][CH2:6][CH2:7][O:8][S:9](=[O:11])(=[O:12])[NH2:10])(=[O:11])(=[O:8])[NH2:10]
Reactant: OCCCCO
Reactant: NS(=O)(=O)OCCOS(N)(=O)=O
Product: NS(=O)(=O)OCCCCOS(N)(=O)=O

Procedure:
1,4-Bis-O-sulfamyl-1,4-butanediol is prepared in the same manner as 1,2-bis-O-sulfamyl-1,2-ethanediol in Example 1 except that 1,4-butanediol (34.6 g., 0.385 mol.) is employed as the alkanediol.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:26])[C:10]([CH3:25])([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]2[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]2)[CH:14]=1)[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:27]([C:30]1[CH:40]=[CH:39][C:33]([O:34][CH2:35][C:36](O)=[O:37])=[CH:32][CH:31]=1)([CH3:29])[CH3:28].Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:26])[C:10]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]2[CH2:24][CH2:23][CH2:22][N:21]([C:36](=[O:37])[CH2:35][O:34][C:33]3[CH:39]=[CH:40][C:30]([CH:27]([CH3:28])[CH3:29])=[CH:31][CH:32]=3)[CH2:20]2)[CH:14]=1)([CH3:11])[CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(Oc1cccc(C2CCCNC2)c1)C(=O)OCc1ccccc1
Reactant: CC(C)c1ccc(OCC(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)c1ccc(OCC(=O)N2CCCC(c3cccc(OC(C)(C)C(=O)OCc4ccccc4)c3)C2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.7 %

Procedure:
To a solution of 2-methyl-2-(3-piperidin-3-yl-phenoxy)-propionic acid benzyl ester (Preparation 2, Method C; 30 mg, 0.085 mmol) in 1 mL methylene chloride was added 4-isopropylphenoxyacetic acid (33 mg, 0.17 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (33 mg, 0.17 mmol) and allowed to stir 18 h at ambient temperature. The reaction was concentrated under reduced pressure and the resultant oil flash chromatographed with 30% ethyl acetate/hexanes to yield 35 mg (78%) of 2-(3-{1-[(4-Isopropyl-phenoxy)-acetyl]-piperidin-3-yl}-phenoxy)-2-methyl-propionic acid benzyl ester as a clear oil.
Reaction SMILES: [C:1]1([C:11](=[O:13])[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Br:14]Br>O1CCOCC1>[Br:14][CH2:12][C:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)=[O:13]
Reactant: BrBr
Reactant: CC(=O)c1cccc2ccccc12
Solvent: C1COCCO1
Product: O=C(CBr)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 93.2 %

Procedure:
To a solution of 1-(naphthalen-1-yl)ethanone (500 mg, 2.9 mmol) in dioxane (5 mL) was added to a solution of bromine (510 mg, 3.19 mmol) in dioxane (10 mL), at room temperature, over a period of 30 minutes. The reaction mixture was then stirred at room temperature for 20 minutes and concentrated. The resulting residue was diluted with ether and washed with saturated sodium bicarbonate, water, dried over sodium sulfate and concentrated. Purification by preparative thin layer chromatography (70% DCM/30% hexanes) afforded 2-bromo-1-(naphthalen-1-yl)ethanone (673 mg, 93%).
Reaction SMILES: C[Li].[CH3:3]C1(C)CCCC(C)(C)N1.[CH2:13]([O:15][C:16]1[C:17]([F:27])=[C:18]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][CH3:26])[C:19]#[N:20])[CH3:14].CI.Cl>O1CCCC1>[CH2:13]([O:15][C:16]1[C:17]([F:27])=[C:18]([C:21]([CH3:3])=[CH:22][C:23]=1[O:24][CH2:25][CH3:26])[C:19]#[N:20])[CH3:14]
Reactant: CC1(C)CCCC(C)(C)N1
Reactant: CCOc1ccc(C#N)c(F)c1OCC
Agent: Cl
Agent: [Li]C
Solvent: CI
Solvent: C1CCOC1
Product: CCOc1cc(C)c(C#N)c(F)c1OCC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 81.9 %

Procedure:
Under a stream of nitrogen gas, methyl lithium (1.03 M diethyl ether solution, 18.2 mL, 18.8 mmol) was added to an ice-cooled solution of 2,2,6,6-tetramethylpiperidine (3.16 mL, 18.7 mmol) in tetrahydrofuran (30 mL), followed by 30 minutes of stirring. After cooling the reaction system to −78° C., a solution of 3,4-diethoxy-2-fluorobenzonitrile (3.90 g, 18.6 mmol) in tetrahydrofuran (20 mL) was added dropwise, and 30 minutes later, methyl iodide (1.4 mL, 22.4 mmol) was added dropwise, followed by 2 hours of stirring. The reaction system was gradually warmed to room temperature, and 1N hydrochloric acid was added to the reaction solution, after which ethyl acetate extraction was performed. The extract was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off, and the residue was purified by silica gel column chromatography (n-hexane, ethyl acetate) to give 3.40 g of the subject compound (yield: 81.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6]([CH2:13][CH2:14]Cl)[CH:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[O:30])=[CH:25][CH:24]=1>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6]([CH2:13][CH2:14][N:34]1[CH2:35][CH2:36][CH:31]([C:29](=[O:30])[C:26]3[CH:25]=[CH:24][C:23]([F:22])=[CH:28][CH:27]=3)[CH2:32][CH2:33]1)[CH:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: O=C1Nc2ccc(Cl)cc2C(c2ccccc2)N1CCCl
Solvent: CCO
Product: O=C(c1ccc(F)cc1)C1CCN(CCN2C(=O)Nc3ccc(Cl)cc3C2c2ccccc2)CC1
Yield: 57 %

Procedure:
A mixture of 5.8 parts of 6-chloro-3-(2-chloroethyl)-3,4-dihydro-4-phenyl-2(1H)-quinazolinone, 7.4 parts of (4-fluorophenyl) (4-piperidinyl)methanone and 56 parts of ethanol is stirred and refluxed overnight. The reaction mixture is evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The oily residue solidifies on triturating in 2,2'-oxybispropane. The product is filtered off and dried, yielding 5 parts (57%) of 6-chloro-3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-3,4-dihydro-4-phenyl-2(1H)-quinazolinone; mp. 196° C.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8](Br)=[CH:9][CH:10]=3)[C:5]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:4]=2[CH:3]=1.C([Sn](CCCC)(CCCC)[C:33]1[S:34][CH:35]=[CH:36][CH:37]=1)CCC.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:12]([C:11]3[CH:10]=[CH:9][C:8]([C:33]4[S:34][CH:35]=[CH:36][CH:37]=4)=[CH:7][C:6]=3[C:5]2([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:13][CH:14]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: CCCCCCC1(CCCCCC)c2cc(Br)ccc2-c2ccc(Br)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCCCCC1(CCCCCC)c2cc(Br)ccc2-c2ccc(-c3cccs3)cc21
Reaction time: 1 h

Procedure:
A mixture of 2,7-dibromo-9,9-dihexylfluorene (7) (8.0 g, 16 mmol), 2-tributylstannylthiophene (2.98 g, 8.0 mmol), tetrakis(triphenylphosphine)palladium (0) (200 mg, 1.73×10′ mol) aqueous sodium carbonate (2M, 2 cm3), toluene (5 cm3) and ethanol (2 cm3) was heated under reflux for 24 h under argon. Toluene and ethanol were removed and hexane (10 cm3) and aqueous KI (2%, 10 cm3) added and the mixture stirred vigorously for 1 h. Diethyl ether (10 cm3) and dilute HCl(nq) (3M, 10 cm3) were added, the aqueous layer separated and washed with diethyl ether (2×10 cm3). The organic layers were combined, dried over anhydrous magnesium sulphate, filtered and concentrated to a dark brown oil which was purified by column chromatography [silica gel, hexane] to yield a pale jade coloured oil.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH3:10][S:11][CH2:12]Cl.C(N(CC)CC)C>>[C:1]([O:9][CH2:10][S:11][CH3:12])(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCC(=O)O
Reactant: CSCCl
Solvent: CCN(CC)CC
Product: CCCCCCC(=O)OCSC

Procedure:
This product was prepared according to the procedure described in Example 1, by reacting heptanoic acid with chloromethyl methyl sulfide in the presence of one equivalent of triethylamine; b.p. 80°-81° C./2 mm Hg, n20 1.4591.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:19](=[O:42])[CH2:20][CH2:21][NH:22][C:23]1[CH:28]=[CH:27][N:26]=[C:25]([C:29]2[O:33][N:32]=[C:31]([C:34]3[C:39]([Cl:40])=[CH:38][CH:37]=[CH:36][C:35]=3[Cl:41])[CH:30]=2)[CH:24]=1)[CH2:10][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:50][CH:51]([Cl:55])[C:52](Cl)=[O:53]>ClCCl>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C:19](=[O:42])[CH2:20][CH2:21][N:22]([C:23]1[CH:28]=[CH:27][N:26]=[C:25]([C:29]2[O:33][N:32]=[C:31]([C:34]3[C:39]([Cl:40])=[CH:38][CH:37]=[CH:36][C:35]=3[Cl:41])[CH:30]=2)[CH:24]=1)[C:52](=[O:53])[CH:51]([Cl:55])[Cl:50])[CH2:10][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: CC(C)(C)OC(=O)CC[C@@H](NC(=O)OC(C)(C)C)C(=O)CCNc1ccnc(-c2cc(-c3c(Cl)cccc3Cl)no2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CC[C@@H](NC(=O)OC(C)(C)C)C(=O)CCN(C(=O)C(Cl)Cl)c1ccnc(-c2cc(-c3c(Cl)cccc3Cl)no2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.2 %

Procedure:
(R)-tert-butyl 4-(tert-butoxycarbonylamino)-7-(2-(3-(2,6-dichlorophenyl)isoxazol-5-yl)pyridin-4-ylamino)-5-oxoheptanoate (280 mg, 0.45 mmol) was dissolved in anhydrous dichloromethane with triethylamine (126 μL, 0.90 mmol). The mixture was cooled in an ice-bath under nitrogen, then a solution of dichloroacetyl chloride (66 μL, 0.68 mmol) was added dropwise. After the addition was completed the ice-bath was removed and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and then washed successively with water, 10% hydrochloric acid and saturated sodium bicarbonate solution. The organic solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography, on silica gel, eluting with 99:1 dichloromethane:methanol to yield (R)-tert-butyl 4-(tert-butoxycarbonylamino)-7-(2,2-dichloro-N-(2-(3-(2,6-dichlorophenyl)isoxazol-5-yl)pyridin-4-yl)acetamido)-5-oxoheptanoate (165 mg) as a white foam. 1H NMR (CDCl3): 8.77 (m, 1H), 7.89 (m, 1H), 7.42 (m, 2H), 7.40-7.31 (m, 2H), 7.07 (s, 1H), 6.00 (s, 1H), 5.20 (m, 1H), 4.20 (m, 1H), 4.00 (m, 2H), 2.97 (m, 2H), 2.27 (m, 2H), 2.10 (m, 1H), 1.78 (m, 1H), 1.41 ppm (m, 18H). MW=730 confirmed by LC-MS, tr=13.34 min (Method A) MH+=728-732.
Reaction SMILES: [N:1]([CH:4]1[CH2:23][N:8]2[C:9]3[C:14]([C:15]([CH2:16][C:17]([O:19]CCC)=[O:18])=[C:7]2[CH2:6][CH2:5]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N+:2]=[N-:3].[C:24]([CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)#[CH:25]>>[CH:26]1([C:24]2[N:1]([CH:4]3[CH2:23][N:8]4[C:9]5[C:14]([C:15]([CH2:16][C:17]([OH:19])=[O:18])=[C:7]4[CH2:6][CH2:5]3)=[CH:13][CH:12]=[CH:11][CH:10]=5)[N:2]=[N:3][CH:25]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: C#CC1CCCCC1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)CC(N=[N+]=[N-])CC2
Product: O=C(O)Cc1c2n(c3ccccc13)CC(n1nncc1C1CCCCC1)CC2

Procedure:
The title compound was prepared using procedures described in EXAMPLE 3 from propyl (7-azido-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)acetate and ethynylcyclohexane. MS (+ESI) m/z: 379.2.
Reaction SMILES: Br[CH2:2][C:3]#[C:4][CH3:5].C(=O)([O-])[O-].[K+].[K+].[CH3:12][N:13]1[C:21]2[N:20]=[CH:19][NH:18][C:17]=2[C:16](=[O:22])[NH:15][C:14]1=[O:23].CN(C)C=O>O>[CH2:2]([N:18]1[C:17]2[C:16](=[O:22])[NH:15][C:14](=[O:23])[N:13]([CH3:12])[C:21]=2[N:20]=[CH:19]1)[C:3]#[C:4][CH3:5]
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]cnc21
Reactant: CC#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC#CCn1cnc2c1c(=O)[nH]c(=O)n2C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-Bromo-2-butyne (55.3 mL) and anhydrous potassium carbonate (84.9 g) were added to a mixture of 3-methylxanthine [CAS No. 1076-22-8] (100 g) and N,N-dimethylformamide (1000 mL), and this reaction solution was stirred at room temperature for 18 hours. After completion of the reaction, water (1000 mL) was added to the reaction solution, this was stirred at room temperature for one hour, and then the white precipitate was collected by filtration. The white solid obtained was washed with water and t-butyl methyl ether to give the title compound (112 g).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12](=[O:14])[CH3:13])[CH:8]=2)[CH:3]=1.[CH2:15](O)[CH2:16][OH:17].[OH-].[Na+]>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]3([CH3:13])[O:17][CH2:16][CH2:15][O:14]3)[CH:8]=2)[CH:3]=1
Reactant: OCCO
Reactant: CC(=O)c1ccc2cc(Br)ccc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: CC1(c2ccc3cc(Br)ccc3c2)OCCO1
Yield: 79.7 %

Procedure:
A mixture of 13.0 g of 2-bromo-6-acetylnaphthalene, 20 g of ethylene glycol, 200 ml of benzene, and 530 mg of p-toluenesulfonic acid was heated at reflux for 18 hours using a Dean-Stark trap to effect continuous removal of water. The cooled reaction mixture was added to 100 ml of 0.1N sodium hydroxide solution and the resulting mixture extracted with three 75 ml portions of diethyl ether. The combined organic extract was washed with 100 ml saturated sodium chloride solution and then dried over sodium sulfate. The solvent is removed under vacuum and the residue recrystallized from hexane to give 12.2 g of 2-bromo-6-(2-methyl-1,3-dioxolan-2-yl)naphthalene, m.p. 80°-82° C.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:10]2[C:15]([CH3:16])=[CH:14][S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:10]3[C:15]([CH3:16])=[CH:14][S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: Cc1csc2nc(Cl)nc(NCc3ccccc3)c12
Product: Cc1csc2nc(-n3cncn3)nc(NCc3ccccc3)c12

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-5-methyl-4-benzylamino-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-5-methyl-4-benzylamino-thieno-[2,3-d]-pyrimidine.