Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:19]3[CH2:20][CH:17]([CH2:18]3)[C:8]3[NH:9][C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:11][C:7]=3[C:6]=2[CH:21]=1.[C:22](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O.C(OCC)(=O)C>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:19]3[CH2:18][CH:17]([CH2:20]3)[C:8]3[N:9]([CH3:22])[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:11][C:7]=3[C:6]=2[CH:21]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1nc2c([nH]1)C1CC(C1)c1ccc(I)cc1-2
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)c1nc2c(n1C)C1CC(C1)c1ccc(I)cc1-2
Temperature: 40 °C
Yield: 18.1 %

Procedure:
To a solution of ethyl 9-iodo-3,4,5,6-tetrahydro-4,6-methanobenzo[3,4]cyclohepta[1,2-d]imidazole-2-carboxylate (500 mg, 1.27 mmol) in N,N-dimethylformamide (5 mL) was introduced potassium carbonate (175 mg, 1.27 mmol) and methyl iodide (270 mg, 1.90 mmol). The reaction mixture was warmed to 40° C. for 3 hr. After concentration of the reaction mixture in vacuo, the residue was suspended in ethyl acetate (50 mL) and washed with saturated aqueous sodium bicarbonate (2×10 mL), water (10 mL) and brine (10 mL). The organic extract was filtered at this stage to furnish the title compound (94 mg, 0.23 mmol) as a colorless solid of high purity. Following drying over sodium sulfate, the filtrate was re-filtered and concentrated in vacuo to furnish additional title compound of slightly lower purity (395 mg at 93% purity LC-UV215). This material was carried through to the next synthetic step without further purification. The higher purity batch was analysed for characterisation purposes: 1H NMR (500 MHz, CDCl3) δ 1.49 (t, J=7.09 Hz, 3H), 1.68-1.74 (m, 2H), 2.89-2.99 (m, 2H), 3.50 (td, J=7.49, 3.94 Hz, 1H), 3.60 (td, J=8.28, 3.63 Hz, 1H), 3.95 (s, 3H), 4.47 (q, J=7.04 Hz, 2H), 6.80 (d, J=7.88 Hz, 1H), 7.41 (dd, J=7.88, 1.89 Hz, 1H), 8.82 (s, 1H); M+1=409.
Reaction SMILES: Br[C:2]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[C:5]2[C:6]([Cl:11])=[N:7][C:8]([Cl:10])=[CH:9][C:4]=2[N:3]=1.Cl.[O:25]1[CH2:30][CH2:29][NH:28][CH:27]2[CH2:31][CH2:32][CH2:33][CH:26]12.[F-].[K+].CCN(C(C)C)C(C)C>C(OCC)(=O)C.CS(C)=O>[Cl:11][C:6]1[C:5]2[N:12]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[C:2]([N:28]3[CH2:29][CH2:30][O:25][C@@H:26]4[CH2:33][CH2:32][CH2:31][C@@H:27]34)=[N:3][C:4]=2[CH:9]=[C:8]([Cl:10])[N:7]=1
Reactant: C1CC2NCCOC2C1
Reactant: FC(F)(F)c1ccc(Cn2c(Br)nc3cc(Cl)nc(Cl)c32)cc1
Agent: Cl
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: FC(F)(F)c1ccc(Cn2c(N3CCO[C@@H]4CCC[C@H]43)nc3cc(Cl)nc(Cl)c32)cc1
Temperature: 90 °C

Procedure:
To a vial were added 2-bromo-4,6-dichloro-3-(4-(trifluoromethyl)benzyl)-3H-imidazo[4,5-c]pyridine (200 mg, 0.47 mmol), octahydrocyclopenta[b][1,4]oxazine hydrochloride (purchased from Enamine); 147 mg, 0.9 mmol), potassium fluoride (81 mg, 1.41 mmol), DIEA (246 μL, 1.41 mmol), and DMSO (2 mL). The vial was sealed and heated to 90° C. for 1 hour. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-60% ethyl acetate/hexanes, linear gradient) to afford 4,6-dichloro-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[4-(trifluoromethyl)benzyl]-3H-imidazo[4,5-c]pyridine (racemate). MS APCI calc'd. for C21H19Cl2F3N4O [M+H]+ 471. found 471.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:9]=[C:10]([C:22]#[C:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][C:31]([O:33]C)=[O:32])=[CH:26][CH:25]=2)[CH:11]=[C:12]2[C:17]=1[O:16][C:15]([CH3:19])([CH3:18])[CH2:14][C:13]2([CH3:21])[CH3:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+].Cl>C(O)C.O1CCCC1.O>[C:1]([O:5][C:6]([C:8]1[CH:9]=[C:10]([C:22]#[C:23][C:24]2[CH:25]=[CH:26][C:27]([CH2:30][C:31]([OH:33])=[O:32])=[CH:28][CH:29]=2)[CH:11]=[C:12]2[C:17]=1[O:16][C:15]([CH3:18])([CH3:19])[CH2:14][C:13]2([CH3:21])[CH3:20])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)Cc1ccc(C#Cc2cc(C(=O)OC(C)(C)C)c3c(c2)C(C)(C)CC(C)(C)O3)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1cc(C#Cc2ccc(CC(=O)O)cc2)cc2c1OC(C)(C)CC2(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.2 %

Procedure:
A solution of 6-(4-methoxycarbonylmethyl-phenylethynyl)-2,2,4,4-tetramethyl-chroman-8-carboxylic-acid tert-butyl ester (Intermediate 53, 0.014 g, 0.03 mmol) in ethanol (0.3 mL), tetrahydrofuran (0.3 mL) and water (0.3 mL) was treated with 1N lithium hydroxide (0.12 mL, 0.12 mmol) and the resulting reaction mixture was stirred at ambient temperature for 3 h. The reaction mixture was neutralized with 2N hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried-over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title product as a yellow oil (0.012 g, 88%).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:14][OH:15])([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[CH2:12]([O:11][C:9](=[O:10])[C:3]([CH2:2][O:1][S:24]([CH3:23])(=[O:26])=[O:25])([CH2:14][O:15][S:24]([CH3:23])(=[O:26])=[O:25])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:13]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)C(CO)(CO)C(=O)OCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(COS(C)(=O)=O)(COS(C)(=O)=O)C(=O)OCC
Temperature: -30 °C
Reaction time: 18 h

Procedure:
A solution of diethyl bis(hydroxymethyl)malonate (46.95 g, 0.21 moles) (prepared by the method of P. Block, Jr., Organic Synthesis, Collective Volume V, 381 (1973)) in methylene chloride (500 mL) was treated with triethyl amine (63 mL) and cooled to −30° C. A mixture of methylsulfonyl chloride (35 mL) in methylene chloride (40 mL) was added to the reaction mixture dropwise over 20 minutes and the reaction mixture was allowed to stir at room temperature for 18 hours. The reaction mixture was then poured into ice water and the product was extracted with methylene chloride. The organic extracts were washed with saturated aqueous sodium chloride and then dried over magnesium sulfate. The solvent was removed by rotary evaporation at reduced pressure and the residue was recrystallized from t-butylmethyl ether and hexane to give 2,2-bis-methylsulfonyloxymethyl-malonic acid diethyl ester (55.04 g).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10]1[NH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[C:14]([NH:19][CH3:20])[CH:13]=2.[F:21][CH:22]([F:26])[C:23](O)=[O:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>C(Cl)Cl>[F:21][CH:22]([F:26])[C:23]([N:19]([C:14]1[CH:13]=[C:12]2[C:17]([CH:18]=[C:10]([C:3]3[C:4]([O:8][CH3:9])=[N:5][CH:6]=[CH:7][C:2]=3[I:1])[NH:11]2)=[CH:16][CH:15]=1)[CH3:20])=[O:24]
Reactant: CNc1ccc2cc(-c3c(I)ccnc3OC)[nH]c2c1
Reactant: O=C(O)C(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Product: COc1nccc(I)c1-c1cc2ccc(N(C)C(=O)C(F)F)cc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.8 %

Procedure:
A solution of [2-(4-iodo-2-methoxy-pyridin-3-yl)-1H-indol-6-yl]-methyl-amine (30 mg, 0.08 mmol) in CH2Cl2 (5 mL) was added 2,2-difluoroacetic acid (11 mg, 0.12 mmol) and HATU (45 mg, 0.12 mol). The solution was stirred at 25° C. for 1 h and poured into water. The aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. Filtration followed by concentration in vacuo gave a brown solid. Flash chromatography (70/30 hexanes/ethyl acetate) afforded 2,2-difluoro-N-[2-(4-iodo-2-methoxy-pyridin-3-yl)-1H-indol-6-yl]-N-methyl-acetamide (12 mg, 33%) as a white solid. MH+ 457.8.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[H-].[Na+].[CH2:13]([O:15][C:16](=[O:24])[CH:17](Cl)[C:18](=O)[CH:19]([CH3:21])[CH3:20])[CH3:14].C([O-])(=O)C.[NH4+:29]>CN(C=O)C>[CH2:13]([O:15][C:16]([C:17]1[O:8][C:6]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=2)=[N:29][C:18]=1[CH:19]([CH3:21])[CH3:20])=[O:24])[CH3:14]
Reactant: CCOC(=O)C(Cl)C(=O)C(C)C
Reactant: [NH4+]
Reactant: O=C(O)c1ccc(Br)cc1
Agent: CC(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1oc(-c2ccc(Br)cc2)nc1C(C)C
Temperature: 90 °C
Reaction time: 18 h
Yield: 54.6 %

Procedure:
A solution of 4-bromo-benzoic acid (34.0 g, 0.169 mol) in DMF (450 mL) is treated at ambient temperature portionwise with NaH (6.4 g, 0.16 mol, 60% oil dispersion). The suspension is heated to 90° C. and 2-choro-4-methyl-3-oxo-pentanoic acid ethyl ester (27.7 g, 0.144 mol) is added neat. The remaining chloride is washed into the reaction flask using DMF (25 mL). The reaction mixture is stirred for 18 h, cooled, and treated with water (600 mL). The mixture is extracted with EtOAc (750 mL). The organic layer is washed with brine (2×250 mL), dried (Na2SO4), and concentrated to a foam (56 g). This diester is dissolved in acetic acid (500 mL), treated at ambient temperature with ammonium acetate (80 g, 1.0 mol)1 and heated at 120° C. for 20 h. The reaction mixture is cooled, concentrated, and partitioned between EtOAc (500 mL) and saturated NaHCO3 solution (3×125 mL). The organic layer is dried (Na2SO4), and concentrated. The crude product is purified by silica gel flash chromatography using hexanes:ethyl acetate (6:1) to give the title compound (26.6 g, 55%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:31])[C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:18][CH2:17][C@H:16]([O:19][C:20]4[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][C:21]=4[F:29])[C:15]3=[O:30])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.Cl.[NH:66]1[CH2:70][CH2:69][C@@H:68]([OH:71])[CH2:67]1>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([F:31])[C:5]([N:8]2[CH2:9][CH2:10][CH:11]([N:14]3[CH2:18][CH2:17][C@H:16]([O:19][C:20]4[CH:28]=[CH:27][C:23]([C:24]([N:66]5[CH2:70][CH2:69][C@@H:68]([OH:71])[CH2:67]5)=[O:25])=[CH:22][C:21]=4[F:29])[C:15]3=[O:30])[CH2:12][CH2:13]2)=[N:6][CH:7]=1
Reactant: O=C(O)c1ccc(O[C@H]2CCN(C3CCN(c4ncc(Cl)cc4F)CC3)C2=O)c(F)c1
Reactant: O[C@@H]1CCNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(O[C@H]2CCN(C3CCN(c4ncc(Cl)cc4F)CC3)C2=O)c(F)c1)N1CC[C@@H](O)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 32.7 %

Procedure:
To a solution of (S)-4-(1-(1-(5-chloro-3-fluoropyridin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yloxy)-3-fluorobenzoic acid (Example 153, Step B; 0.10 g, 0.22 mmol) in DMF (2 mL) was added HATU (0.17 g, 0.44 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.12 mL, 0.66 mmol) and the reaction was stirred for 20 minutes at ambient temperature. (R)-pyrrolidin-3-ol hydrochloride (0.058 g, 0.66 mmol) was added and the reaction was stirred for 2 hours at ambient temperature. The reaction was diluted with EtOAc (30 mL), washed with HCl (1N, 10 mL), NaOH (1N, 10 mL), water (10 mL), and brine (10 mL), dried over MgSO4, filtered and concentrated under vacuum. The crude material was purified by reverse phase HPLC. The combined fractions were diluted with EtOAc (50 mL) and washed with 1 N NaOH (10 mL), water (10 mL), and brine (10 mL), dried over MgSO4, filtered and concentrated under vacuum to give (S)-1-(1-(5-chloro-3-fluoropyridin-2-yl)piperidin-4-yl)-3-(2-fluoro-4-((R)-3-hydroxypyrrolidine-1-carbonyl)phenoxy)pyrrolidin-2-one (0.038 g, 0.072 mmol, 33% yield). Mass spectrum (apci) m/z=521.0 (M+H).
Reaction SMILES: [CH3:1][CH:2]([CH2:20][CH3:21])[CH2:3][O:4][C:5]([C:7]1(O)[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][CH2:8]1)=[O:6].[Br:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]Br.C(=O)([O-])[O-:31].[K+].[K+]>CC(C)=O>[CH3:1][CH:2]([CH2:20][CH3:21])[CH2:3][O:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([O:31][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][Br:22])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)=[O:6]
Reactant: CCC(C)COC(=O)C1(O)C=CC(c2ccccc2)=CC1
Reactant: O=C([O-])[O-]
Reactant: BrCCCCCCBr
Agent: [K+]
Solvent: CC(C)=O
Product: CCC(C)COC(=O)c1ccc(-c2ccc(OCCCCCCBr)cc2)cc1
Yield: 60.3 %

Procedure:
70 mmols (19.9 g) of said ester 1a, 100 mmols (24.4 g) of 1,6-dibromohexane and 150 mmols (20.7 g) of potassium carbonate were refluxed in 400 ml of acetone for 8 hours. The reaction mixture was filtered and then purified by column chromatography to obtain 4'-(6-bromohexyloxy)biphenyl-4-carboxylic acid 2-methylbutyl ester (ether 5b; 18.9 g, yield 60%, [α]23D=+2.93 (chloroform)).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.I[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1cccc(I)c1
Reactant: Clc1ccc2cc[nH]c2c1
Product: Cc1cccc(-n2ccc3ccc(Cl)cc32)c1

Procedure:
Prepared by Procedure C and Scheme O using 6-chloro-1H-indole and 1-iodo-3-methylbenzene: ESMS m/e: 241.9 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH2:13])=[O:12])=[C:5]2[S:14]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)(=[O:16])=[O:15].C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>ClCCl.C(#N)C>[CH3:30][S:31]([O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH2:13])=[O:12])=[C:5]2[S:14]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)(=[O:16])=[O:15])(=[O:33])=[O:32]
Reactant: NC(=O)c1[nH]c2ccc(O)cc2c1S(=O)(=O)N1CCOCC1
Reactant: CS(=O)(=O)Cl
Solvent: CC#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Oc1ccc2[nH]c(C(N)=O)c(S(=O)(=O)N3CCOCC3)c2c1
Reaction time: 1 h

Procedure:
To a solution of 5-hydroxy-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide from Example 50 (37 mg, 0.12 mmol) in 3 mL of dichloromethane/acetonitrile (1:1) was added triethylamine (0.048 mL, 0.34 mmol) and methanesulfonyl chloride (0.0098 mL, 0.13 mmol). After one hour, another portion of methanesulfonyl chloride (0.005 mL) was added. After another 10 minutes, the mixture was partitioned between ethyl acetate and saturated NH4Cl solution, and the organic layer was washed with saturated NaHCO3 solution and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resulting solid was triturated with acetonitrile/methanol (1:1) to give the titled compound as a white solid. Proton NMR for the product was consistent with the titled compound. HRMS (ES) exact mass calculated for C14H18N3O7S2 (M+H+): 404.0581. Found 404.0620.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][NH:8][C:9](=[O:12])[C:10]=2[N:11]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].C(O)(=O)C>O1CCOCC1.O.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>[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]=[CH:7][NH:8][C:9](=[O:12])[C:10]=3[N:11]=2)=[CH:16][CH:15]=1
Reactant: O=c1[nH]cnc2ccc(Cl)nc12
Reactant: OB(O)c1ccc(F)cc1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: O=c1[nH]cnc2ccc(-c3ccc(F)cc3)nc12
Temperature: 25 °C
Yield: 90.4 %

Procedure:
To a solution of 6-chloro-pyrido[3,2-d]pyrimidin-4(3H)one (1.0 g, 5.5 mmol) in dioxane (80 ml) and water (20 ml) was added 4-fluorophenylboronic acid (770 mg, 5.5 mmol), K2CO3 (2.28 g, 16.5 mmol), and tetrakis(triphenylphosphine)palladium(0) (290 mg, 0.25 mmol). The mixture was heated at reflux for 20 hours. After cooling to room temperature, the reaction mixture was neutralized to pH 5-6 with acetic acid, concentrated to a small volume, filtered and washed with water to yield a crude product. The crude residue was purified by silica gel flash chromatography, the mobile phase being a mixture of methanol and dichloromethane, in a volume ratio of 1:30, yielding the title compound as a white solid (1.2 g, yield: 90%) which was characterised by its mass spectrum as follows: MS (m/z): 242 ([M+H]+, 100).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[C:27]([O:30][C:31]1[CH:40]=[C:39]([CH3:41])[C:38]([Br:42])=[CH:37][C:32]=1[C:33]([O:35][CH3:36])=[O:34])(=[O:29])[CH3:28]>C(Cl)(Cl)(Cl)Cl>[C:27]([O:30][C:31]1[CH:40]=[C:39]([CH2:41][Br:8])[C:38]([Br:42])=[CH:37][C:32]=1[C:33]([O:35][CH3:36])=[O:34])(=[O:29])[CH3:28]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc(Br)c(C)cc1OC(C)=O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(Br)c(CBr)cc1OC(C)=O

Procedure:
NBS (0.71 g, 4.01 mmol) and benzoyl peroxide (0.07 g, 0.20 mmol) were added to a solution of methyl 2-(acetyloxy)-5-bromo-4-methylbenzoate (may be prepared as described in Description 3; 1.15 g, 4.01 mmol) in carbon tetrachloride (20 ml). The mixture was heated at reflux for 18 hours, cooled and the solvent removed in vacuo. Purification by SP4 (10-20% ethyl acetate/hexane) yielded the title compound as a pale yellow oil. 1.38 g.
Reaction SMILES: CSC.[CH3:4][C:5](=[CH2:11])[CH2:6][CH2:7][CH2:8][Mg]Br.[CH:12]#[C:13][CH3:14].C(OP(OCC)OCC)C.[C:25](=[O:27])=[O:26]>CN(P(N(C)C)(N(C)C)=O)C.CCOCC>[CH3:4]/[C:5](/[CH2:6][CH2:7][CH2:8][C:13]([CH3:14])=[CH2:12])=[CH:11]/[C:25]([OH:27])=[O:26]
Reactant: O=C=O
Reactant: C=C(C)CCC[Mg]Br
Reactant: C#CC
Agent: CCOP(OCC)OCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOCC
Solvent: CSC
Product: C=C(C)CCC/C(C)=C\C(=O)O
Reaction time: 1.5 h

Procedure:
A solution of 4.7 g (23.0 mmol) of cuprous bromide/dimethyl sulfide complex (prepared as in Example 1C), 20 ml of ether and 42 ml of dimethyl sulfide, under nitrogen, is cooled to about -50°. A 0.41 M solution of 4-methyl-4-penten-1-yl magnesium bromide (51 ml, 21.9 mmol) (prepared as in Example 1B) is added over a 1 hr period. The reaction is stirred approximately 1.5 hr, and then about 4 ml propyne is added and the mixture is warmed to -20°. After 1 hr, 25 ml of HMPA and triethylphosphite are added, followed by excess carbon dioxide. The mixture is warmed to -15° and placed in a CCl4 /CO2 bath, and carbon dioxide is bubbled into the reaction overnight. The reaction is worked up by adding (NH4)2SO4, then filtered. The remaining solid is extracted with ether 4X and filtered. The filtrate (organic and aqueous phases) is salted with NaCl and extracted 3X with ether. The combined ether layers are extracted 3X with NaOH, and the NaOH layers are washed with ether, then acidified with H2SO4. The aqueous layer is salted out (NaCl), extracted with ether, washed with brine and dried over NaSO4 to yield (Z)-3,7-dimethyl-2,7-octadienoic acid.
Reaction SMILES: [CH3:1][C:2]1[C:8]([OH:9])=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4].[Cl:10]N1C(=O)CCC1=O>CC#N>[Cl:10][C:7]1[CH:6]=[CH:5][C:3]([OH:4])=[C:2]([CH3:1])[C:8]=1[OH:9]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1c(O)cccc1O
Solvent: CC#N
Product: Cc1c(O)ccc(Cl)c1O

Procedure:
To a solution of 2-methyl resorcinol (1 eq) in MeCN (5 ml) was added N-chlorosuccinimide (1 eq) and refluxed under nitrogen overnight. The yellow solution was concentrated in vacuo and purified by flash chromatography to give 4-chloro-2-methyl-benzene-1,3-diol as a solid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]#[CH:12].Br[C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH:16]=[O:17]>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]#[C:12][C:21]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=[O:17]
Reactant: O=Cc1ccccc1Br
Reactant: C#Cc1ccc2ccccc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: O=Cc1cccc(C#Cc2ccc3ccccc3c2)c1

Procedure:
To a solution of 15.3 g of naphth-2-yl-acetylene and 16.65 g of -bromobenzaldehyde in 120 ml of absolute triethylamine were added at a bath temperature of 50° C. while stirring in an atmosphere of dry nitrogen 1.05 g of bis-(triphenylphosphine)-palladium(II) chloride and 0.07 g of copper(I) iodide. Then the mixture was stirred at a bath temperature of 70°-80° C. (TLC: petroleum ether/ether-5:1). When the reaction was finished the mixture was filtered, the residue washed with ethyl acetate and then the filtrates were evaporated in a vacuum. By column chromatography with petroleum ether/ether (4:1) the residue is purified to yield 15.1 g (65.5% of the theoretical yield) of the title compound in the form of crystals melting at 90°-92° C.
Reaction SMILES: [Cl:1][C:2](=[CH:6][C:7]1[CH:12]=[C:11]([C:13]2[C:17]([Cl:18])=[C:16]([O:19][CH:20]([F:22])[F:21])[N:15]([CH3:23])[N:14]=2)[C:10]([F:24])=[CH:9][C:8]=1[Cl:25])[C:3](Cl)=[O:4].C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:33][O:34][NH2:35]>C1(C)C=CC=CC=1.O>[CH3:33][O:34][NH:35][C:3](=[O:4])[C:2]([Cl:1])=[CH:6][C:7]1[CH:12]=[C:11]([C:13]2[C:17]([Cl:18])=[C:16]([O:19][CH:20]([F:21])[F:22])[N:15]([CH3:23])[N:14]=2)[C:10]([F:24])=[CH:9][C:8]=1[Cl:25]
Reactant: CON
Reactant: Cn1nc(-c2cc(C=C(Cl)C(=O)Cl)c(Cl)cc2F)c(Cl)c1OC(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CONC(=O)C(Cl)=Cc1cc(-c2nn(C)c(OC(F)F)c2Cl)c(F)cc1Cl
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A solution of 4.5 g (10 mmol) of 2-chloro-3-(2-chloro-5-(4-chloro-5-difluoromethoxy-1-methyl-1H-pyrazol-3-yl)-4-fluorophenyl)acryloyl chloride in 25 ml of toluene was treated with 25 ml of water, 14.4 g (0.1 mol) of potassium carbonate and 1.7 g (20 mmol) of methoxyamine hydrochloride. After the mixture had been stirred for 16 hours at approximately 20° C., it was heated for a further 2 hours at 40° C. The reaction mixture was subsequently diluted with 200 ml of toluene and 200 ml of water. The solids were then filtered off. The organic phase was dried over magnesium sulfate and finally concentrated. Yield: 3.1 g.
Reaction SMILES: N1C=CC=CC=1.[N:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[NH2:21])[CH:8]=1.[N:22]1([C:28]2[N:29]=[C:30]([CH2:35][C:36]([O-])=[O:37])[NH:31][C:32](=[O:34])[CH:33]=2)[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.[Na+]>CN(C)C=O>[N:22]1([C:28]2[N:29]=[C:30]([CH2:35][C:36]([NH:21][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[O:14][CH2:13][C:9]3[CH:8]=[N:7][CH:12]=[CH:11][CH:10]=3)=[O:37])[NH:31][C:32](=[O:34])[CH:33]=2)[CH2:23][CH2:24][O:25][CH2:26][CH2:27]1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Nc1ccccc1OCc1cccnc1
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1ccccc1OCc1cccnc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 37.2 %

Procedure:
2 ml of pyridine, 300 mg of N-[3-(dimethylamino)propyl]-M′-ethylcarbodiimide hydrochloride and 366 mg of 2-(pyridin-3-ylmethoxy)phenylamine are added to a solution of 250 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 2 of example 1, in 2 ml of N,N-dimethylformamide. The reaction mixture is stirred at ambient temperature for 20 hours, and then concentrated under reduced pressure. Water and ethyl acetate are added and the resulting mixture is thus stirred for 30 minutes. The precipitate formed is filtered off, and rised with water, ethyl ether and petroleum ether. The solid obtained is dried under vacuum. 150 mg of 2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]-N-[2-(pyridin-3-ylmethoxy)phenyl]acetamide are obtained in the form of a brown solid, the characteristics of which are the following: