Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Br[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1B(O)O>O1CCCC1.C(=O)([O-])[O-].[Na+].[Na+].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:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1
Reactant: OB(O)c1ccccc1F
Reactant: Brc1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: Fc1ccccc1-c1ccncc1
Temperature: 25 °C

Procedure:
A mixture of 4-bromopyridine hydrochloride (7.5 g, 38.6 mmol) and 2-fluorobenzeneboronic acid (6.75 g, 48 mmol) in tetrahydrofuran (80 mL) and 2 M sodium carbonate (58 mL) was degassed with nitrogen for 20 min then tetrakis(triphenylphosphine)palladium(0) (1.34 g, 1.2 mmol) was added and the reaction heated at reflux for 24 h. The mixture was cooled to ambient temperature then partitioned between ethyl acetate and 10% sodium carbonate. The organics were washed with water and saturated sodium hydrogencarbonate, dried over anhydrous magnesium sulfate, filtered and pre-adsorbed onto silica. Purification by chromatography on silica eluting with isohexane (containing 0.5% triethylamine) on a gradient of ethyl acetate (20-40%) afforded 4-(2-fluorophenyl)pyridine as a yellow oil that crystallised on standing (6.26 g, 94%): δH (400 MHz, CDCl3) 7.17-7.22 (1H, m), 7.26 (1H, ddd, J 8, 8 and 1), 7.38-7.44 (1H, m), 7.47-7.50 (3H, m), 8.68 (2H, d, J 4); m/z (ES+) 174 (M++H).
Reaction SMILES: [F:1][CH:2]([F:14])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH:11]([F:13])[F:12].[N+:15]([O-])([OH:17])=[O:16].C(=O)(O)[O-].[K+]>C(Cl)Cl>[F:1][CH:2]([F:14])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N+:15]([O-:17])=[O:16])=[CH:6][C:5]=1[O:10][CH:11]([F:13])[F:12]
Reactant: FC(F)Oc1ccccc1OC(F)F
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: [K+]
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(OC(F)F)c(OC(F)F)c1

Procedure:
A solution of 15 g of 1,2-bis(difluoromethoxy)benzene and 15 ml of 100% strength nitric acid in 150 ml of methylene chloride is stirred for 7 h at room temperature. The solution is neutralized with potassium bicarbonate solution and the organic phase is separated off. After chromatography on silica gel with cyclohexane/ethyl acetate (4:1), 1,2-bis(difluoromethoxy)-4-nitrobenzene is obtained, which is hydrogenated and acetylated analogously to Example 5a to yield N-[3,4-bis(difluoromethoxy)phenyl]-acetamide of m.p. 81°-83° C. Further reaction analogously to Example 5 gives N-[4,5-bis(difluoromethoxy)-2-nitrophenyl]-acetamide of m.p. 65°-67° C., N-[4,5-bis(difluoromethoxy)-2-nitro]-aniline of m.p. 107°-109° C., 4,5-bis(difluoromethoxy)-1,2-phenylenediamine dihydrochloride and the title compound of m.p. 285°-287° C. (decomposition; from isopropanol).
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[C:9]([C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)(=[O:11])[CH3:10]>C1COCC1>[CH3:10][C:9]1([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[CH2:4][O:11]1
Reactant: CC(=O)c1ccncc1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(c2ccncc2)CO1

Procedure:
Sodium hydride (5.0 g of a 50% dispersion in oil) was added portionwise to a stirred suspension of trimethylsulphoxonium iodide (22.0 g) in THF (150 cm3) and the mixture was heated under reflux for 3 hours. After cooling to 40°, 4-acetyl-pyridine (10.0 g) was added and the mixture was again heated under reflux for 1 hour. The cooled mixture was evaporated in vacuo, partitioned between ether (100 cm3) and water (50 cm3) and the aqueous phase was further extracted with ether (2×50 cm3). The combined dried extracts were evaporated to afford 2-methyl-2-[4-pyridyl]oxirane as a crude oil.
Reaction SMILES: [Mg].Br[C:3]1[CH:4]=[C:5]([CH:18]([CH3:20])[CH3:19])[C:6]([O:16][CH3:17])=[C:7]([CH:9]([O:13]CC)OCC)[CH:8]=1.C[Mg]Br.[O:24]1[CH2:28]CCC1.Cl.[O:30]1CCCC1>>[CH:9]([C:7]1[CH:8]=[C:3]([CH:4]=[C:5]([CH:18]([CH3:19])[CH3:20])[C:6]=1[O:16][CH3:17])[C:28]([OH:24])=[O:30])=[O:13]
Reactant: CCOC(OCC)c1cc(Br)cc(C(C)C)c1OC
Reactant: C1CCOC1
Agent: C[Mg]Br
Agent: Cl
Agent: [Mg]
Product: COc1c(C=O)cc(C(=O)O)cc1C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To magnesium (2.43 g), tetrahydrofuran (100 mL), 5-bromo-1-diethoxymethyl-3-isopropyl-2-methoxybenzene (31.55 g) and a 0.97M methylmagnesium bromide-tetrahydrofuran solution (15 mL) were added, and then the mixture was stirred at room temperature for 2 hours. The reaction solution was cooled to 0° C. and stirred under a carbon dioxide atmosphere for 30 minutes, and then 2N hydrochloric acid (100 mL) was added and the reaction mixture was stirred at room temperature for 16 hours. The organic solvent was distilled off under reduced pressure, and then the mixture was extracted with diisopropylether. The organic layer was extracted with 1N sodium hydroxide (100 mL) added thereto, and then the aqueous layer was washed twice with diisopropylether. The aqueous layer was acidified with 4N hydrochloric acid added thereto, and then extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (15.85 g) as a brown solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[C:11](OC)=[O:12].[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH2:11][OH:12]
Reactant: COC(=O)c1n[nH]c2ccc(F)cc12
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: OCc1n[nH]c2ccc(F)cc12
Temperature: -10 °C
Reaction time: 1 h
Yield: 43.5 %

Procedure:
A solution of methyl 5-fluoro-1H-indazole-3-carboxylate (0.582 g, 3.00 mmol) in THF (20 mL) was cooled to −10° C., and added dropwise with a 1 M solution of diisobutylaluminum hydride in toluene (10.8 mL, 10.8 mmol) over 5 minutes. The reaction mixture was stirred at −10° C. for 1 hour, and then overnight at room temperature. The reaction mixture was added dropwise with saturated aqueous sodium sulfate under ice cooling to terminate the reaction, and then filtered through Celite. The filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol) to obtain (5-fluoro-1H-indazol-3-yl)methanol (0.217 g, 43%).
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:33]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:32])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:31])[C:13]=2[C@@H:14]2[CH2:20][CH2:19][C@@H:18]([NH:21]C(OC(C)(C)C)=O)[C@@H:17]([O:29][CH3:30])[CH2:16][O:15]2)[N:6]=1.[F:41][C:42]1[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][C:43]=1B(O)O>>[NH2:33][C:4]1[S:3][C:2]([C:43]2[CH:44]=[C:45]([CH3:48])[CH:46]=[CH:47][C:42]=2[F:41])=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:31])[C:13]=1[C@@H:14]1[CH2:20][CH2:19][C@@H:18]([NH2:21])[C@@H:17]([O:29][CH3:30])[CH2:16][O:15]1)=[O:32]
Reactant: Cc1ccc(F)c(B(O)O)c1
Reactant: CO[C@H]1CO[C@H](c2c(NC(=O)c3nc(Br)sc3NC(=O)OC(C)(C)C)cnn2C)CC[C@H]1NC(=O)OC(C)(C)C
Product: CO[C@H]1CO[C@H](c2c(NC(=O)c3nc(-c4cc(C)ccc4F)sc3N)cnn2C)CC[C@H]1N

Procedure:
Following the procedure for Example 101 starting from tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6R)-5-(tert-butoxycarbonylamino)-6-methoxy-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (Intermediate 98), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2-fluoro-5-methylphenyl)boronic acid gave 264. 1H NMR (400 MHz, DMSO-d6) δ 9.64 (s, 1H), 7.92-7.82 (m, 2H), 7.44 (br, 2H), 7.29-7.19 (m, 2H), 5.12 (t, J=5.4 Hz, 1H), 3.97-3.88 (m, 2H), 3.71 (s, 3H), 3.53-3.44 (m, 1H), 3.34-3.23 (m, 1H), 3.04 (s, 3H), 2.37 (s, 3H), 1.78-1.50 (m, 4H). LCMS (ES+) m/z 475 (M+1).
Reaction SMILES: C(O[C:4]([C:6]1[CH:11]=[C:10]([C:12]2[CH:13]=[N:14][CH:15]=[C:16]([F:18])[CH:17]=2)[CH:9]=[C:8]([CH3:19])[N:7]=1)=[O:5])C.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][N:22]=1>>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([NH:20][C:4]([C:6]2[CH:11]=[C:10]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([F:18])[CH:17]=3)[CH:9]=[C:8]([CH3:19])[N:7]=2)=[O:5])=[N:22][CH:23]=1
Reactant: CCOC(=O)c1cc(-c2cncc(F)c2)cc(C)n1
Reactant: Nc1ccc(Cl)cn1
Product: Cc1cc(-c2cncc(F)c2)cc(C(=O)Nc2ccc(Cl)cn2)n1

Procedure:
The title compound, was prepared from 5-Fluoro-6′-methyl-[3,4′]bipyridinyl-2′-carboxylic acid ethyl ester in accordance with the general method of example 26, step 6 using 2-Amino-5-chloropyridine instead of 3-chloroaniline to yield the final compound as a white solid, MS (ISP): m/e=343.1, 345.0 (M+H)+.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[Cl:10][C:11]1[CH:33]=[CH:32][C:14]([NH:15][CH2:16][C:17]2[CH:31]=[CH:30][C:20]([O:21][C:22]([CH3:29])([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([N:15]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:21][C:22]([CH3:28])([CH3:29])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:30][CH:31]=2)[CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:32][CH:33]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CNc2ccc(Cl)cc2)cc1
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(CN(Cc2ccccc2)c2ccc(Cl)cc2)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 83.4 %

Procedure:
3.47 g of benzyl bromide is added dropwise to a mixture of 6 g of ethyl 2-[4-(4-chloroanilinomethyl)phenoxy]-2-methylpropionate hydrochloride, 3.24 g of potassium carbonate and 90 ml of dimethylformamide, and the resulting mixture is stirred at 60° C. for 3 hours. The reaction mixture is poured into 300 ml of ice-water and is extracted three times with 100 ml of ethyl acetate and twice with 50 ml of the same. The extract is washed with a saturated aqueous solution of sodium chloride and then dried. The solvent is distilled off from the dried extract, and the residue (7.5 g) is purified by column chromatography with 150 g of silica gel, using chloroform as a developer, to give 5.7 g of ethyl 2-[4-{N-(4-chlorophenyl)-N-benzylaminomethyl}phenoxy]-2-methylpropionate. The product is dissolved in 100 ml of ether, and dried hydrogen chloride gas is introduced into the solution. The resulting crystals are collected by filtration and recrystallized from isopropyl alcohl to give 4.3 g of ethyl 2-[4-{N-(4-chlorophenyl)-N-benzylaminomethyl}phenoxy]-2-methylpropionate hydrochloride, mp 137° to 141° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[N:16]=[N:17][C:18]([CH2:36][CH2:37][CH2:38][CH3:39])=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[C:23]([C:34]#[N:35])[CH:22]=3)[CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:40]([Sn](C)(C)C)=[N+:41]=[N-:42].C1(C)C=CC=CC=1.Cl>O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[N:16]=[N:17][C:18]([CH2:36][CH2:37][CH2:38][CH3:39])=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH:28]4[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]4)=[C:23]([C:34]4[NH:42][N:41]=[N:40][N:35]=4)[CH:22]=3)[CH:20]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCc1nnc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1-c1ccc(OC2CCCCC2)c(C#N)c1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCc1nnc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1-c1ccc(OC2CCCCC2)c(-c2nnn[nH]2)c1
Temperature: 110 °C
Yield: 99.9 %

Procedure:
A mixture of 4-[6-butyl-5-(3-cyano-4-cyclohexyloxy-phenyl)-pyridazin-3-yloxy]-piperidine-1-carboxylic acid tert-butyl ester (Example 67, 0.944 mmol, 505 mg), azidotrimethyltin (3.78 mmol, 802 mg, 97%) and toluene (9 mL) was heated at 110° C. for 48 h. More azidotrimethyltin (0.95 mmol, 201 mg, 97%) was added and the reaction mixture was heated at 110° C. for another 24 h. The reaction mixture was stirred with aq. 0.41 N HCl (11.5 mL), diluted with water (30 mL) and extracted with DCM (2×40 mL). The combined DCM extracts were dried over sodium sulfate. Purification by column chromatography on silica gel using 0-7.5% MeOH in DCM gave 4-{6-butyl-5-[4-cyclohexyloxy-3-(1H-tetrazol-5-yl)-phenyl]-pyridazin-3-yloxy}-piperidine-1-carboxylic acid tert-butyl ester as light brown solid (545 mg).
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][C@H:10]([N:13]([CH:21]2[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]2)[C:14](=[O:20])[C:15]([CH3:19])([CH3:18])[CH2:16][OH:17])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[C:1]([N:8]1[CH2:12][CH2:11][C@H:10]([N:13]([CH:21]2[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]2)[C:14](=[O:20])[C:15]([CH3:19])([CH3:18])[CH:16]=[O:17])[CH2:9]1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC1(C)CCC(N(C(=O)C(C)(C)CO)[C@H]2CCN(C(=O)OC(C)(C)C)C2)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC1(C)CCC(N(C(=O)C(C)(C)C=O)[C@H]2CCN(C(=O)OC(C)(C)C)C2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.1 %

Procedure:
To a solution of (3S)-1-Boc-3-[(4,4-dimethylcyclohexyl)(3-hydroxy-2,2-dimethylpropanoyl)amino]pyrrolidine (1.05 g, 2.7 mmol) prepared in Step B of Example A8 in DCM was added Dess-Martin periodinane (1.35 g, 3.17 mmol), and stirred at rt for 2 h. After the reaction finished, the solvent was concentrated in vacuo, sodium thiosulfate aqueous solution and EtOAc were added and stirred at rt for 30 min, and extracted with EtOAc. The organic layer was dried over MgSO4, concentrated in vacuo at rt, and purified by column chromatography (eluent: EtOAc/Hex=1/3) to give the title compound (960 mg, 90%).
Reaction SMILES: [CH:1]([O:3][CH2:4][CH2:5][NH:6][C:7]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:8]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O)=[CH2:2].[O:22]1[C:26](=O)[CH2:25][NH:24]C1=O.Cl.N>C(Cl)Cl.O>[ClH:21].[CH:1]([O:3][CH2:4][CH2:5][N:6]1[C:7]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:8]=2[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:24][CH2:25][C:26]1=[O:22])=[CH2:2]
Reactant: O=C1CNC(=O)O1
Reactant: C=COCCNc1ccc(Cl)cc1C(=O)c1ccccc1
Agent: Cl
Agent: N
Solvent: ClCCl
Solvent: O
Product: C=COCCN1C(=O)CN=C(c2ccccc2)c2cc(Cl)ccc21

Procedure:
To a solution of 0.3g of 2-(β-vinyloxyethyl)amino-5-chlorobenzophenone in 20 ml of dry methylene chloride is added 0.27g of oxazolidin-2,5-dione. To the mixture is added 20 ml of etheral hydrogen chloride under cooling. The mixture is allowed to stand at room temperature with occasional stirring. The reaction mixture is poured into water, basified with aqueous ammonia and extracted with methylene chloride. The extracts are combined and dried over sodium sulfate, and the solvent is removed under reduced pressure. The residue is dissolved in ether and treated with ethanolic hydrogen chloride to give 1-(β-vinyloxyethyl)-5-phenyl-7-chloro-1,3-dihydro-2H-1,4-benzodiazepin-2-one hydrochloride, m.p. 213° - 215° C (dec). Recrystallization from isopropanolchloroform gives colorless prisms, m.p. 216° - 218° C (dec.).
Reaction SMILES: NC1C=CC(C2C=CC(F)=CC=2F)=CC=1.Cl.N([O-])=O.[Na+].[Li+].[Cl-].C(OC(=O)/C=C/C)C.[CH2:31]([O:33][C:34](=[O:53])[C:35](Cl)=[C:36]([C:38]1[CH:43]=[CH:42][C:41]([C:44]2[CH:49]=[CH:48][C:47]([F:50])=[CH:46][C:45]=2[F:51])=[CH:40][CH:39]=1)[CH3:37])[CH3:32]>[Zn].C(O)(=O)C.CC(C)=O.O>[CH2:31]([O:33][C:34](=[O:53])[CH:35]=[C:36]([C:38]1[CH:43]=[CH:42][C:41]([C:44]2[CH:49]=[CH:48][C:47]([F:50])=[CH:46][C:45]=2[F:51])=[CH:40][CH:39]=1)[CH3:37])[CH3:32]
Reactant: CCOC(=O)C(Cl)=C(C)c1ccc(-c2ccc(F)cc2F)cc1
Agent: C/C=C/C(=O)OCC
Agent: Cl
Agent: Nc1ccc(-c2ccc(F)cc2F)cc1
Solvent: CC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C=C(C)c1ccc(-c2ccc(F)cc2F)cc1
Reaction time: 14 h

Procedure:
20.5 g. of 4-amino-2',4'-difluorobiphenyl are dissolved in a mixture of 25 ml. of 35% hydrochloric acid, 50 ml. of acetic acid and 120 ml. of water. The solution is cooled to 0° and 6.9 g. of NaNO2 are added in portions. Subsequently, a solution of 1.5 g. of Cu2Cl2, 0.9 g. of LiCl and 100 g. of crotonic acid ethyl ester in 900 ml. of acetone is added drop-wise at -10° to the stirred mixture under a N2 atmosphere. The mixture is stirred for 4 hours more at 0°-5° and for 14 hours at 20° and extracted with benzene. The extract is washed and evaporated to give 20 g. of crude 2-chloro-3-(2',4'-difluoro-4-biphenylyl)-2-butenoic acid ethyl ester. This is dissolved in 250 ml. of acetic acid to which 50 g. of zinc dust are added. The mixture is stirred for 3 hours at 20° and filtered. After the customary work up, 3-(2',4'-difluoro-4-biphenylyl)-2-butenoic acid ethyl ester, m.p. 54°-56°, is obtained from the filtrate.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([NH2:26])[CH2:24][CH3:25])=[CH:4][CH:3]=1.[F:27][CH:28]([F:32])[C:29](O)=[O:30].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O.O>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([NH:26][C:29](=[O:30])[CH:28]([F:32])[F:27])[CH2:24][CH3:25])=[CH:4][CH:3]=1
Reactant: CCC(N)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reactant: O=C(O)C(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCC(NC(=O)C(F)F)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 120 h
Yield: 32 %

Procedure:
A mixture of 1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-amine (150 mg, <0.366 mmol), difluoroacetic acid (0.0346 mL, 0.55 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (158 mg, 0.824 mmol), 1-hydroxybenzotriazole monohydrate (126 mg, 0.823 mmol) and triethylamine (0.15 mL, 1.07 mmol) in N,N-dimethylformamide (5.0 mL) was stirred at room temperature for 5 days. Water was added to the reaction mixture at room temperature and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 25-75% ethyl acetate/n-hexane gradient mixture and recrystallization from ethyl acetate/diisopropyl ether to give the title compound (56.3 mg, 0.115 mmol, 32%) as colorless crystals.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[F:4][C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][CH2:11]/[C:12]/2=[CH:15]\[C:16](Cl)=[O:17])=[CH:7][CH:6]=1>ClCCl.C(OCC)(=O)C>[F:4][C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][CH2:11]/[C:12]/2=[CH:15]\[C:16]([N:2]([CH3:3])[CH3:1])=[O:17])=[CH:7][CH:6]=1
Reactant: CNC
Reactant: O=C(Cl)/C=C1\CCCc2ccc(F)cc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN(C)C(=O)/C=C1\CCCc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 69.4 %

Procedure:
Dimethylamine (3 ml, 0.045 mol, Kodak) was added to a chilled (ice bath) solution of (E)-2-(7-fluoro-1,2,3,4-tetrahydro-1-naphthylidene)acetyl chloride (2.3 g, 0.010 mol) in dichloromethane (35 ml). The reaction was warmed to 25° C. and stirred for 1.5 h. The volatiles were removed by spin evaporation in vacuo to give a beige residue. This residue was dissolved in ethyl acetate (200 ml), washed with deionized water (50 ml), and the organic layer was concentrated by spin evaporation in vacuo. The residue was chromatographed on Silica Gel 60 using a step gradient from ethyl acetate-hexanes/1:5 to ethyl acetate. Fractions containing (e)-2-(7-fluoro-1,2,3,4-tetrahydro-1-naphthylidene)-N,N-dimethylacetamide were combined and concentrated by spin evaporation in vacuo to a white solid. Recrystallization from dichloromethane-hexanes gave 1.62 g (70%) of (E)-2-(7-fluoro-1,2,3,4-tetrahydro-1-naphthylidene)-N,N-dimethylacetamide as a white crystalline solid; m.p., 66-70° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]3[CH:25]=[CH:24][CH:23]=[CH:22][C:11]=3[O:12][CH2:13][CH2:14][O:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][O:17]3)[C:2]1=2.C(OB(OC(C)C)OC(C)C)(C)C.C([N-]C(C)C)(C)C.[Li+].[Cl:47][C:48]1[N:53]=[C:52](Cl)[C:51]([F:55])=[CH:50][N:49]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.C(Cl)(Cl)Cl.C(O)(C)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:47][C:48]1[N:53]=[C:52]([C:5]2[S:1][C:2]3[C:9]([C:10]4[CH:25]=[CH:24][CH:23]=[CH:22][C:11]=4[O:12][CH2:13][CH2:14][O:15][CH:16]4[CH2:21][CH2:20][CH2:19][CH2:18][O:17]4)=[CH:8][CH:7]=[CH:6][C:3]=3[CH:4]=2)[C:51]([F:55])=[CH:50][N:49]=1
Reactant: c1ccc(-c2cccc3ccsc23)c(OCCOC2CCCCO2)c1
Reactant: Fc1cnc(Cl)nc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)OB(OC(C)C)OC(C)C
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CC(C)O
Product: Fc1cnc(Cl)nc1-c1cc2cccc(-c3ccccc3OCCOC3CCCCO3)c2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.4 %

Procedure:
In a 500-mL round bottom flask, cool a solution of 2-[2-(2-benzo[b]thiophen-7-yl-phenoxy)-ethoxy]-tetrahydropyran (500 mg, 1.41 mmol) and triisopropylborate (530 mg, 2.82 mmol) in THF (30 mL) to −70° C. under N2. To the solution, add lithium diisopropylamide (2 M in THF, 1.41 mL, 2.82 mmol) gradually over a period of 30 min. Stir the mixture continually for an additional 1 h in the cooling bath. Gradually transfer the mixture into a refluxing solution of 2,4-dichloro-5-fluoropyrimidine (353 mg, 2.12 mmol), Pd(dppf)Cl2 (57.6 g, 0.07 mmol) and sodium carbonate (2 M in water, 1.8 mL, 3.6 mmol) in THF (20 mL) over a period of 30 min. Reflux for an additional 1 h. Cool the mixture to RT and dilute with chloroform/IPA (3/1) and water. Wash the organic layer with aqueous saturated sodium chloride. Dry over sodium sulfate. Concentrate in vacuo. Purify the residue by FCC (20% ethyl acetate in hexane) to give the title compound (550 mg, 80%). MS (ES) m/z 507 [M+Na]+.
Reaction SMILES: [CH3:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[C:17]([O:24][CH2:25][CH:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH:16]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[NH:55]1[CH2:60][CH2:59][O:58][CH2:57][CH2:56]1>CN(C=O)C>[CH3:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([N:55]2[CH2:60][CH2:59][O:58][CH2:57][CH2:56]2)=[O:21])=[C:17]([O:24][CH2:25][CH:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH:16]=1
Reactant: C1COCCN1
Reactant: Cc1c(COc2ccc(C(=O)O)c(OCC3CCOCC3)c2)[nH]c2ccccc2c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(COc2ccc(C(=O)N3CCOCC3)c(OCC3CCOCC3)c2)[nH]c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 93.7 %

Procedure:
4-[(3-Methyl-4-oxo-1,4-dihydroquinolin-2-yl)methoxy]-2-(tetrahydro-2H-pyran-4-ylmethoxy)benzoic acid (67 mg) and 1-hydroxybenzotriazole hydrate (25 mg) were dissolved in DMF (1.3 mL). To this solution were sequentially added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (33 mg) and morpholine (15 mg), and the mixture was stirred at room temperature for 12 hours. A saturated aqueous sodium hydrogen carbonate solution (5 mL) to the reaction mixture, followed by extraction with ethyl acetate (50 mL). The organic layer was washed sequentially with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform/methanol=15/1) to obtain 3-methyl-2-{[4-(morpholin-4-ylcarbonyl)-3-(tetrahydro-2H-pyran-4-ylmethoxy)phenoxy]methyl}quinolin-4(1H)-one (73 mg).