Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([CH2:13][CH2:14][CH2:15][NH2:16])[C:5]2[S:10](=[O:12])(=[O:11])[CH2:9][CH2:8][C:6]=2[N:7]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1>O1CCOCC1>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:2]3[N:3]=[C:4]([CH2:13][CH2:14][CH2:15][NH2:16])[C:5]4[S:10](=[O:12])(=[O:11])[CH2:9][CH2:8][C:6]=4[N:7]=3)[CH2:26][CH2:25]2)=[CH:22][CH:23]=1
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: NCCCc1nc(Cl)nc2c1S(=O)(=O)CC2
Solvent: C1COCCO1
Product: NCCCc1nc(N2CCN(c3ccc(Cl)cc3)CC2)nc2c1S(=O)(=O)CC2
Temperature: 150 °C
Yield: 69.9 %

Procedure:
0.262 g (1.00 mmol) of (2-chloro-5,5-dioxo-6,7-dihydro-5H-5λ6-thieno[3,2-d]pyrimidin-4-yl)propylamine (II) and 0.433 g (2.20 mmol) of 1-(4-chlorophenyl)piperazine are placed in 4.50 mL of dioxane, then heated to 150° C. in the microwave for 0.75 hours. Then the reaction mixture is concentrated by evaporation, the residue is treated with water. It is suction filtered, washed with water, and dried. The product which is not yet clean is purified by chromatography (column: 10 g Chromabond SiOH cartridge, solvent: petroleum ether/ether 1:1). Corresponding fractions are combined and concentrated by evaporation. 0.295 g of product III (70%) is obtained as a powder (m.p. 243° C.-245° C.).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C@@H:12]2[CH2:16][CH2:15][NH:14][CH2:13]2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:17][C:18]1[C:28]([O:29][CH3:30])=[C:27](F)[CH:26]=[CH:25][C:19]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CS(C)=O>[C:1]([O:5][C:6]([NH:8][C:9]1([C@@H:12]2[CH2:16][CH2:15][N:14]([C:27]3[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:18]([F:17])[C:28]=3[O:29][CH3:30])[CH2:13]2)[CH2:10][CH2:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1ccc(F)c(OC)c1F
Reactant: CC(C)(C)OC(=O)NC1([C@@H]2CCNC2)CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(N2CC[C@@H](C3(NC(=O)OC(C)(C)C)CC3)C2)c(OC)c1F
Reaction time: 18 h
Yield: 76 %

Procedure:
(3R)-3-(1-Tert-butoxycarbonylaminocyclopropyl)-pyrrolidine (4.75 g, 85% content) was dissolved in dimethylsulfoxide (30 mL). After adding thereto ethyl 2,4-difluoro-3-methoxybenzoate (3.2 g) and triethylamine (3.1 mL), the mixture was stirred at 75° C. After 18 hours, the mixture was allowed to cool, incorporated with 10% aqueous citric acid solution, and extracted with AcOEt. An organic layer was dried with anhydrous sodium sulfate and filtered, and then the solvent was distilled away. The resulting residual crystals (6.22 g) (2-position:4-position=17:83) were subjected to chromatography on silica gel (hexane:ethyl acetate=4:1) to give the title compound as white crystals (4.75 g).
Reaction SMILES: [CH3:1][CH:2]([CH:9]=[CH2:10])[CH2:3][CH2:4][CH:5]=[C:6]([CH3:8])[CH3:7].[C:11]([OH:14])(=[O:13])[CH3:12]>>[CH3:1][CH:2]([CH:9]=[CH2:10])[CH2:3][CH2:4][CH2:5][C:6]([O:14][C:11]([CH3:12])=[O:13])([CH3:8])[CH3:7]
Reactant: C=CC(C)CCC=C(C)C
Reactant: CC(=O)O
Product: C=CC(C)CCCC(C)(C)OC(C)=O

Procedure:
A process according to claim 8, wherein dihydromyrcene is reacted with acetic acid to produce dihydromyrcenyl acetate, which is then reacted with 4-tertiarybutylcyclohexanol to produce dihydromyrcenol and 4-tertiarybutylcyclohexyl acetate.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.Cl[C:29]1[CH:34]=[CH:33][N:32]=[CH:31][N:30]=1>>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C@:13]2([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11](=[O:27])[N:10]([C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([C:29]4[CH:34]=[CH:33][N:32]=[CH:31][N:30]=4)=[CH:3][CH:4]=3)[CH3:9])[CH2:15][CH2:14]2)=[CH:21][CH:22]=1
Reactant: Clc1ccncn1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccncn2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one following procedures analogous to those described in Example 313 Steps 3 and 4 using 4-chloropyrimidine in Step 4. LC-MS Method 2 tR=1.172, m/z=392.1; 1H NMR (CDCl3) 1.28-1.40 (m, 1H), 1.52 (m, 3H), 1.64 (m, 2H), 1.81-1.99 (m, 2H), 2.09-2.37 (m, 3H), 2.90 (m, 1H), 3.51 (t, 2H), 5.68 (m, 1H), 6.88-7.07 (m, 3H), 7.16-7.28 (m, 3H), 7.58 (m, 1H), 7.79 (d, 2H), 8.61-8.80 (d, 1H), 9.18 (s, 1H).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])(=O)C.[Na+]>CN(C)C=O>[C:14]1([NH:13][CH2:2][C:3]([O:5][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(CBr)OCc1ccccc1
Reactant: Nc1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(CNc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of benzyl bromoacetate (4.0 ml) and aniline (2.28 ml) in 25 ml of dry dimethylformamide was added sodium acetate (2.05 g). The reaction was stirred at room temperature overnight and extracted from water with three portions of ethyl acetate. The combined organic layers were washed with water and dried over sodium sulfate. The volatiles were removed, and the residue was purified by flash column chromatography on silica gel (eluting with 10% ethyl acetate/hexane) to yield 4.54 g of benzyl N-phenylglycinate.
Reaction SMILES: [CH2:1]([C:4]1[C:13]([O:14][CH3:15])=[C:12]([O:16][CH3:17])[CH:11]=[C:10]2[C:5]=1[C:6]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)=[N:7][CH:8]=[N:9]2)[CH:2]=[CH2:3].[I:26]I>ClCCl.C(Cl)(Cl)Cl>[Cl:25][C:22]1[CH:21]=[CH:20][C:19]([N:18]2[CH:2]([CH2:3][I:26])[CH2:1][C:4]3[C:5]4[C:6]2=[N:7][CH:8]=[N:9][C:10]=4[CH:11]=[C:12]([O:16][CH3:17])[C:13]=3[O:14][CH3:15])=[CH:24][CH:23]=1
Reactant: C=CCc1c(OC)c(OC)cc2ncnc(Nc3ccc(Cl)cc3)c12
Reactant: II
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COc1cc2ncnc3c2c(c1OC)CC(CI)N3c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (5-allyl-6,7-dimethoxy-quinazolin-4-yl)-(4-chloro-phenyl)-amine (0.3 g, 0.85 mmol) (from Example 16, Step E, supra) in dichloromethane (50 mL) was added I2 (0.53 g, 4.2 mmol). The reaction mixture was stirred at room temperature for 3 hours. The mixture was diluted with chloroform (100 mL), and washed with a saturated aqueous Na2SO3 solution. The organic layer was separated, dried over Na2SO4, and concentrated. The residue was purified by chromatography using EtOAc/CH2Cl2/Et3N (2:1:0.01) as eluent to give the desired 4-(4-chloro-phenyl)-5-iodomethyl-7,8-dimethoxy-5,6-dihydro-4H-1,3,4-triaza-phenalene as a white solid. (Yield 0.15 g, 37%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[NH:9][CH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:25]([CH:27]3[CH2:29][CH2:28]3)=[O:26])[CH2:21][CH2:20]2)=[O:18])[CH2:13][CH2:12]1.C(N(CC)CC)C.Cl[C:38](Cl)([O:40]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:38](=[O:40])[N:9]([CH2:10][C@H:11]3[CH2:12][CH2:13][C@H:14]([C:17]([N:19]4[CH2:24][CH2:23][N:22]([C:25]([CH:27]5[CH2:29][CH2:28]5)=[O:26])[CH2:21][CH2:20]4)=[O:18])[CH2:15][CH2:16]3)[C:3]=2[CH:4]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccc(Cl)cc1NC[C@H]1CC[C@H](C(=O)N2CCN(C(=O)C3CC3)CC2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(C1CC1)N1CCN(C(=O)[C@H]2CC[C@H](Cn3c(=O)[nH]c4ccc(Cl)cc43)CC2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of {trans-4-[(2-Amino-5-chloro-phenylamino)-methyl]-cyclohexyl}-(4-cyclopropane carbonyl-piperazin-1-yl)-methanone (448 mg, 1.07 mmol), triethylamine (0.45 mL, 3.22 mmol) in DCM (10 mL) was cooled at 0° C. Triphosgene (104 mg, 0.35 mmol) was added and the reaction was allowed to warm up to room temperature and left stirring for 18 hours. The reaction was diluted with 0.4 M Na2CO3 solution, the organic phase collected and the solvent removed under reduced pressure. The crude product was purified by SiO2 column eluting with ethylacectate-methanol (9:1), affording 230 mg of the pure product (49% yield).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1.[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[O:26][CH2:27][CH2:28][CH2:29]Cl>CS(C)=O.O>[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH2:29][CH2:28][CH2:27][O:26][C:17]2[CH:18]=[CH:19][C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:16]=2)=[CH:11][CH:10]=1
Reactant: ClCCCOc1ccc2ccccc2c1
Reactant: COc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(NCCCOc2ccc3ccccc3c2)cc1
Temperature: 135 °C

Procedure:
A mixture of anhydrous potassium carbonate (10 gm, in excess) and p-anisidine (0.42 gm, 0.003 mole) was taken in dry DMSO (40 ml). Now 3-(2-naphthyloxy)-1-chloropropane (0.5 gm, 0.002 mole) was added in it. Reaction mixture was refluxed at 135° C. for 7 hrs and the reaction was completed as checked by TLC. Reaction mixture was poured in distilled water (60 ml) and extracted with ethyl acetate thrice. The organic layer was separated and concentrated to get oily compound which was later crystallized by benzene hexane to get N-(4-methoxyphenyl)-[3-(naphthalen-2-yloxy)propyl]amine yellow solid, m.p. 110° C., (yield 0.66 gm, 95.6%).
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8](O)=[O:9])=[CH:4][CH:3]=1.Cl.[CH3:14][NH:15][O:16][CH3:17].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C>ClCCl>[Br:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([N:15]([O:16][CH3:17])[CH3:14])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)C=Cc1ccc(Br)cc1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)C=Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.6 %

Procedure:
4-Bromocinnamic acid (28.3 g, 124.6 mmol), N,O-dimethylhydroxylamine hydrochloride (14.6 g, 149.6 mmol), HOBT (33.7 g, 249.3 mmol), EDAC (47.8 g, 249.3 mmol) and triethylamine (34.7 mL, 249.3 mmol) were added to dichloromethane (800.0 mL). The reaction mixture was stirred at room temperature for 16 hours, quenched with a saturated solution of ammonium chloride, and then extracted with dichloromethane three times. The combined extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/2) to give 26.8 g of the titled compound as a white solid.
Reaction SMILES: [CH:1]1([C:6]([C:8]2[S:12][C:11]([NH:13][C:14](=[O:20])OC(C)(C)C)=[N:10][C:9]=2[C:21]2[O:22][CH:23]=[CH:24][CH:25]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>O1CCOCC1>[CH:1]1([C:6]([C:8]2[S:12][C:11]([NH:13][C:14]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:20])=[N:10][C:9]=2[C:21]2[O:22][CH:23]=[CH:24][CH:25]=2)=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)Nc1nc(-c2ccco2)c(C(=O)C2CCCC2)s1
Reactant: C1COCCN1
Solvent: C1COCCO1
Product: O=C(c1sc(NC(=O)N2CCOCC2)nc1-c1ccco1)C1CCCC1
Reaction time: 8 h
Yield: 64.6 %

Procedure:
Compound 432 (251 mg, 0.693 mmol) was dissolved in 1,4-dioxane (5 mL), and morpholine (6.19 mL, 70.9 mmol) was added thereto, followed by stirring overnight under heating and reflux. The reaction mixture was concentrated under reduced pressure, and water was added to the resulting residue, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (hexane:ethyl acetate=3:1) to afford the entitled Compound 435 (168 mg, 64%) as a pale brown solid.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[Cl:11][C:12]1[N:17]2[N:18]=[CH:19][C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:16]2[N:15]=[C:14]([CH3:27])[C:13]=1[CH2:28][C:29]([O:31][CH3:32])=[O:30].C1(C2[O:41]N2S(C2C=CC=CC=2)(=O)=O)C=CC=CC=1>C1COCC1>[Cl:11][C:12]1[N:17]2[N:18]=[CH:19][C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:16]2[N:15]=[C:14]([CH3:27])[C:13]=1[CH:28]([OH:41])[C:29]([O:31][CH3:32])=[O:30]
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Reactant: COC(=O)Cc1c(C)nc2c(-c3ccccc3)cnn2c1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)C(O)c1c(C)nc2c(-c3ccccc3)cnn2c1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 50.2 %

Procedure:
To a stirred solution of KHMDS (0.5 M in toluene, 4.6 mL, 4.75 mmol) in THF (12 mL) at −78° C. was added a solution of methyl 2-(7-chloro-5-methyl-3-phenylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (0.48 g, 1.5 mmol) in THF (12 mL) over 20 mins. The reaction mixture was stirred at −78° C. for 30 min. A solution of 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine (0.6 g, 2.3 mmol) in THF (12 mL) was added over 10 min and the resulted reaction mixture was stirred for an additional 30 min at −78° C. The reaction mixture was quenched with saturated NH4Cl aqueous solution (2 mL). The mixture was allowed to warm up to room temperature and diluted with EtOAc (100 mL). The organic phase was washed with water and brine and dried with sodium sulfate. The solvent was evaporated. Purification by silica gel chromatography provided the title compound (250 mg, 51%). 1H-NMR (500 MHz, DMSO-d6) δ ppm 2.65 (3H, s), 3.7 (3H, s), 5.79 (1H, s), 6.62 (1H, s), 7.35-7.59 (3H, m), 8.95 (1H, s).
Reaction SMILES: C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Br:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:21][CH3:22])=[C:18]([Pb+3])[CH:19]=1.[CH:23]12[CH2:30][CH:27]([CH2:28][CH2:29]1)[C:26](=[O:31])[CH2:25][C:24]2=[O:32].C1(C)C=CC=CC=1>C(Cl)(Cl)Cl.CN(C)C1C=CN=CC=1>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:21][CH3:22])=[C:18]([CH:25]2[C:26](=[O:31])[CH:27]3[CH2:30][CH:23]([CH2:29][CH2:28]3)[C:24]2=[O:32])[CH:19]=1
Reactant: O=C1CC(=O)C2CCC1C2
Reactant: CCc1ccc(Br)cc1[Pb+3]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CCc1ccc(Br)cc1C1C(=O)C2CCC(C2)C1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 55.1 %

Procedure:
To a solution of 5-bromo-2-ethylphenyllead triacetate (16.34 g, 28.80 mmol) in chloroform (160 ml) is added bicyclo[3.2.1]octane-2,4-dione (3.61 g, 26.10 mmol) and 4-dimethylaminopyridine (16.63 g, 131 mmol), and the reaction mixture is stirred at room temperature for 5 minutes. Next toluene (40 ml) is added, and the mixture is stirred at 80° C. for 1 hour (pre-heated oil bath). The reaction mixture is allowed to cool to room temperature, quenched with 1M hydrochloric acid, and the organic phase separated. The aqueous phase is further washed with dichloromethane (×2), and again the phases are separated. All organics are combined then evaporated under reduced pressure to give a crude oil, which is purified by flash column chromatography on silica gel (30% to 50% ethyl acetate/iso-hexane eluant ratio, then 10% methanol/dichloromethane eluant ratio). The resulting gum is then recrystalised from dichloromethane/hexane to afford 3-(5-bromo-2-ethylphenyl)bicyclo[3.2.1]octane-2,4-dione (4.62 g, 55%) as a cream coloured solid.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([C:16]1[CH:28]=[CH:27][C:19]([C:20]([O:22]C(C)(C)C)=[O:21])=[C:18]([NH:29][C:30]([C:32]2[CH:33]=[N:34][C:35]([N:38]3[CH:42]=[CH:41][CH:40]=[CH:39]3)=[CH:36][CH:37]=2)=[O:31])[CH:17]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)Cl>[CH2:8]([C:16]1[CH:28]=[CH:27][C:19]([C:20]([OH:22])=[O:21])=[C:18]([NH:29][C:30]([C:32]2[CH:33]=[N:34][C:35]([N:38]3[CH:42]=[CH:41][CH:40]=[CH:39]3)=[CH:36][CH:37]=2)=[O:31])[CH:17]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1NC(=O)c1ccc(-n2cccc2)nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(CCc2ccccc2)ccc1C(=O)O)c1ccc(-n2cccc2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.6 %

Procedure:
1.0 mL of trifluoroacetic acid was added to 1.0 mL of methylene chloride solution containing 20 mg of tert-butyl 4-phenethyl-2-(6-(1H-pyrrol-1-yl)pyridine-3-carboxamido)benzoate and stirred at room temperature for 1 hour and 30 minutes. Tine solvent was evaporated under reduced pressure and diisopropyl ether was added to the obtained residue and a solid substance was separated by filtration to obtain 17 mg of 4-phenethyl-2-(6-(1H-pyrrol-1-yl)pyridine-3-carboxamido)benzoic acid as white solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH3:18])=[N:11][N:12]=2)=[C:4](OC)[CH:3]=1.[CH3:27][CH:28]1[O:33][CH:32]([CH3:34])[CH2:31][NH:30][CH2:29]1>CS(C)=O>[CH3:34][CH:32]1[O:33][CH:28]([CH3:27])[CH2:29][N:30]([C:2]2[CH:3]=[CH:4][C:5]([C:8]3[O:9][C:10]([C:13]4[C:14]([C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)=[N:15][O:16][C:17]=4[CH3:18])=[N:11][N:12]=3)=[CH:6][CH:7]=2)[CH2:31]1
Reactant: COc1cc(F)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Reactant: CC1CNCC(C)O1
Solvent: CS(C)=O
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(N3CC(C)OC(C)C3)cc2)o1
Temperature: 200 °C
Yield: 23.6 %

Procedure:
A suspension of 2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole (200 mg, 0.62 mmol) in 2,6-dimethylmorpholine (2.00 mL, 16.0 mmol) was heated for 30 min at 200° C. (microwave) followed by stirring under gently reflux for 18 h at 160° C. After addition of DMSO (2 mL) and 2,6-dimethylmorpholine (0.50 mL, 4.00 mmol) the solution was stirred for another 24 h at 160° C. After cooling to ambient temperature the reaction mixture was extracted with water (20 mL) and ethyl acetate (20 mL). The aqueous layer was extracted with ethyl acetate (20 mL) and the combined organic layers were washed with brine (20 mL) and aqueous sodium carbonate (saturated, 20 mL). Drying over sodium sulfate, concentration and purification by chromatography (SiO2, heptane:ethyl acetate:dichloromethane=70:10:20 to 40:40:20) afforded the title compound (61 mg, 24%) as a white solid. MS: m/e=417.3 [M+H]+.
Reaction SMILES: NC(C)C[C:4]1[C:9]([NH2:10])=[CH:8][CH:7]=[CH:6][N:5]=1.C([O-])([O-])=O.[K+].[K+].[CH:18]([Cl:21])(Cl)Cl>>[CH2:4]([N:5]1[C:4]2[N:5]=[CH:6][CH:7]=[CH:8][C:9]=2[N:10]=[C:6]1[CH2:18][Cl:21])[CH2:9][CH3:8]
Reactant: ClC(Cl)Cl
Reactant: CC(N)Cc1ncccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCn1c(CCl)nc2cccnc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-aminopropyl-3-aminopyridine (172) (5.3 g, 35 mmol) is dissolved in 100 mL CHCl3 at room temperature. Ethylchloromethylimidate hydrochloride (14 g, 89 mmol) is added followed by K2CO3 (25 g, 180 mmol). The suspension was stirred vigorously at room temperature for 3 hours. The reaction mixture is filtered through Celite and the, solvent removed in vacuo. The residue is passed through a short plug of silica gel eluting with ethyl acetate to afford 3.7 g of 1-propyl-2-chloromethyl-7-azabenzimidazole (183).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17](Cl)[N:16]=2)[C:10]=1[C:11]([F:14])([F:13])[F:12])=[O:5])[CH3:2].B1(O)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[CH2:24][O:23]1.C([O-])([O-])=O.[Na+].[Na+]>C(#N)C>[OH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:17]1[N:16]=[C:15]([N:9]2[C:10]([C:11]([F:14])([F:13])[F:12])=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:7]=[N:8]2)[CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1cnn(-c2cccc(Cl)n2)c1C(F)(F)F
Reactant: OB1OCc2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1cnn(-c2cccc(-c3ccccc3CO)n2)c1C(F)(F)F
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
A mixture of the title compound from Example 1 Step A (300 mg, 0.94 mmol), 2,1-benzoxaborol-1(3H)-ol (189 mg, 1.40 mmol), trans-dichlorobis(triphenylphosphine) palladium (II) (94 mg, 0.14 mmol), Na2CO3 (1.4 mL, 2.0 M aqueous, 2.8 mmol) and acetonitrile (1.5 mL) in a nitrogen-filled capped vial was stirred at 100° C. for 1.5 h, cooled, concentrated and purified by silica gel flash chromatography (hexanes-EtOAc, 3:1 to 2:1 v/v) to provide the title compound: LCMS 374.1 [M−OH]+; 1H NMR (400 MHz, CDCl3) δ 8.16 (s, 1H), 8.06 (t, J=7.9 Hz, 1H), 7.77 (d, J=7.6 Hz, 1H), 7.59-7.41 (m, 5H), 4.51 (s, 2H), 4.36 (q, J=7.1 Hz, 2H), 1.40 (t, J=7.1 Hz, 3H).
Reaction SMILES: Cl.N=C1C=CN([C:9]2[N:10]=[CH:11][C:12]3[CH:18]=[C:17]([C:19]4[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([O:27][CH3:28])[CH:20]=4)[C:16](=[O:29])[N:15]([CH2:30][CH3:31])[C:13]=3[N:14]=2)C=C1.C(=O)([O-])[O-].[K+].[K+].[NH2:38][C:39]1[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=1>CS(C)=O>[N:42]1[CH:43]=[CH:44][C:39]([NH:38][C:9]2[N:10]=[CH:11][C:12]3[CH:18]=[C:17]([C:19]4[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([O:27][CH3:28])[CH:20]=4)[C:16](=[O:29])[N:15]([CH2:30][CH3:31])[C:13]=3[N:14]=2)=[CH:40][CH:41]=1
Reactant: CCn1c(=O)c(-c2cc(OC)cc(OC)c2)cc2cnc(-n3ccc(=N)cc3)nc21
Reactant: Nc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCn1c(=O)c(-c2cc(OC)cc(OC)c2)cc2cnc(Nc3ccncc3)nc21
Temperature: 100 °C
Reaction time: 0.67 h

Procedure:
To a stirred solution of 330 g (0.75 mol) of 2-(4-imino-4H-pyridin-1-yl)-6-(3,5-dimethoxyphenyl)-8-ethyl-8H-pyrido[2,3-d]pyrimidin-7-one hydrochloride in 1.5 L of dimethylsulfoxide were added in one portion 114 g (0.825 mol) of powdered potassium carbonate, followed by the addition of a solution of 2.8 g (0.03 mol; 0.05 eq) 4-aminopyridine in 50 mL of dimethylsulfoxide. The reaction mixture was heated to 100° C., and aliquots were removed after 1 hour and analyzed by reverse phase high pressure liquid chromatography (RP-HPLC) (YMC-AQ column, 60:40 CH3CN/0.02 M SDS, pH 2.2, 1.0 mL/min, 254 nm). After 40 minutes, the reaction was shown to produce the title compound, plus a dimer-like compound of the formula
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[NH2:19][CH:20]1[CH:27]2[CH2:28][C:23]3([OH:30])[CH2:24][CH:25]([CH2:29][CH:21]1[CH2:22]3)[CH2:26]2>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([NH:19][CH:20]2[CH:21]3[CH2:29][CH:25]4[CH2:24][C:23]([OH:30])([CH2:28][CH:27]2[CH2:26]4)[CH2:22]3)=[O:15])=[CH:4][CH:3]=1
Reactant: NC1C2CC3CC1CC(O)(C3)C2
Reactant: O=C(O)c1cccc(OCc2ccc(Cl)nc2)c1
Product: O=C(NC1C2CC3CC1CC(O)(C3)C2)c1cccc(OCc2ccc(Cl)nc2)c1

Procedure:
Prepared from 3-(6-chloro-pyridin-3-ylmethoxy)-benzoic acid and 4-amino-1-hydroxyadamantane. 1H NMR (400 MHz, CDCl3): δ 8.49 (d, 1H), 7.78 (dd, 1H), 7.42-7.44 (m, 1H), 7.38 (t, 2H), 7.32 (d, 1H), 7.10 (dd, 1H), 6.32 (d, 1H), 5.12 (s, 2H), 4.19-4.24 (m, 1H), 3.13 (br. s., 2H), 2.26 (br. s., 2H), 2.21 (br. s., 1H), 1.95 (d, 2H), 1.73-1.85 (m, 6H), 1.59 (d, 2H).