Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[O:5][C:6]1[C:7]2[CH:31]=[CH:30][NH:29][C:8]=2[N:9]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][CH:20]3[CH2:23][N:22]([CH2:24][CH2:25][F:26])[CH2:21]3)=[CH:15][C:14]=2[O:27][CH3:28])[N:11]=1.C(N(C(C)C)CC)(C)C.C(Cl)Cl.[C:47](Cl)(=[O:50])[CH:48]=[CH2:49]>C1COCC1>[F:26][CH2:25][CH2:24][N:22]1[CH2:23][CH:20]([NH:19][C:16]2[CH:17]=[CH:18][C:13]([NH:12][C:10]3[N:11]=[C:6]([O:5][C:4]4[CH:3]=[C:2]([NH:1][C:47](=[O:50])[CH:48]=[CH2:49])[CH:34]=[CH:33][CH:32]=4)[C:7]4[CH:31]=[CH:30][NH:29][C:8]=4[N:9]=3)=[C:14]([O:27][CH3:28])[CH:15]=2)[CH2:21]1
Reactant: C=CC(=O)Cl
Reactant: COc1cc(NC2CN(CCF)C2)ccc1Nc1nc(Oc2cccc(N)c2)c2cc[nH]c2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: C=CC(=O)Nc1cccc(Oc2nc(Nc3ccc(NC4CN(CCF)C4)cc3OC)nc3[nH]ccc23)c1

Procedure:
A 50 mL-round-bottom flask with a magnetite was charged with N1-(4-(3-aminophenoxy)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-N4-(1-(2-fluoroethyl)azetidin-3-yl)-2-methoxybenzene-1,4-diamine (125 mg, 0.27 mmol), diisopropylethylamine (43 mg, 0.33 mmol) and DCM (20 mL). The mixture was cooled with an ice bath until the temperature was below 0° C., and a solution of acryloyl chloride (33 mg, 0.33 mmol) in THF (2 mL) was added dropwise over 5 minutes. The title compound is isolated and purified by preparative HPLC or preparative LC/MS, or by other standard purification techniques.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.Cl[C:26](Cl)([O:28][C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[CH3:37][C:38]1[CH:39]=[C:40](CO)[CH:41]=[CH:42][CH:43]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:28][CH2:26][C:42]2[CH:41]=[CH:40][CH:39]=[C:38]([CH3:37])[CH:43]=2)=[C:18]([CH3:24])[CH:17]=1
Reactant: Cc1cccc(CO)c1
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)OCc4cccc(C)c4)cc3C)c2cc1OC
Yield: 82.4 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (100 mg) was added to toluene (10 ml) and triethylamine (1 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (140 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, (3-methylphenyl)methanol (57 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (120 mg, yield 76%).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13]Cl)=[CH:9][C:8]=1C)[CH:4]=[CH2:5].[N:16]1([CH2:21][CH2:22][OH:23])[CH:20]=[CH:19][N:18]=[N:17]1.[CH3:24]N(C=O)C>>[CH2:3]([O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][O:23][CH2:22][CH2:21][N:16]2[CH:20]=[CH:19][N:18]=[N:17]2)=[C:11]([CH3:24])[CH:12]=1)[CH:4]=[CH2:5]
Reactant: C=CCOc1ccc(CCl)cc1C
Reactant: OCCn1ccnn1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: C=CCOc1ccc(COCCn2ccnn2)c(C)c1
Reaction time: 5 h
Yield: 86 %

Procedure:
1.122 g (46.7 mmol) 95% Sodium hydride were given at −50° C. to a solution of 5.630 g (31.2 mmol) 1-allyloxy-4-chloromethyl-2-methyl-benzene and 3.525 g (31.2 mmol) 2-(1H-[1,2,3]-triazol-1-yl)-ethanol in DMF. The mixture was allowed to warm slowly to r. t., stirred for 5 hours. The mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was dried over Na2SO4 and the solvent was distilled off under reduced pressure to yield 7.30 g (86%) 1-[2-(4-Allyloxy-2-methyl-benzyloxy)-ethyl]-1H-[1,2,3]triazole as yellow oil which was used without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:11]=[C:10]([C:12]([O:14]CC)=[O:13])[O:9][N:8]=2)[CH:2]=1.O.[OH-].[Na+]>O1CCOCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:11]=[C:10]([C:12]([OH:14])=[O:13])[O:9][N:8]=2)[CH:2]=1
Reactant: CCOC(=O)c1cc(-c2cccnc2)no1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cc(-c2cccnc2)no1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
300 mg (1.38 mmol) of ethyl 3-(pyridin-3-yl)-1,2-oxazole-5-carboxylate (for preparation see Chem. Heterocyclic Comp. 2000, 36, 1226-1231) were dissolved in 20 ml of dioxane. While cooling with ice, 7 ml of water and 0.35 ml of 45% aqueous sodium hydroxide solution were added to the solution. The mixture was stirred at room temperature for two hours, then the dioxane was removed on a rotary evaporator under reduced pressure. Ice-water was added to the residue, and it was acidified with concentrated hydrochloric acid. The solution was stirred at room temperature overnight, and the precipitated solid was filtered off with suction and dried.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N+:15]=3[O-])[C:7]=2[CH:21]=1)#[N:2].P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:18]1[CH:17]=[CH:16][N:15]=[C:14]([CH:8]2[C:7]3[CH:21]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=3[O:11][C:10]([CH3:13])([CH3:12])[CH2:9]2)[CH:19]=1
Reactant: CC1(C)CC(c2cccc[n+]2[O-])c2cc(C#N)ccc2O1
Reactant: O=P(Cl)(Cl)Cl
Product: CC1(C)CC(c2cc(Cl)ccn2)c2cc(C#N)ccc2O1
Temperature: 80 °C

Procedure:
1 g of 2-(6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)pyridine N-oxide was dissolved in 15 ml of phosphorus oxychloride, heated at 80° C. for 2 hours and allowed to cool to room temperature overnight. The phosphorus oxychloride was removed in vacuo and the residue was taken up in sodium bicarbonate solution and ethyl acetate. The aqueous phase was extracted several times with ethyl acetate and the combined ethyl acetate solutions were dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel. Elution with ethyl acetate/petroleum ether (1:4) gave 271 mg of 4-(6-chloro-2-pyridyl)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile and elution with ethyl acetate/petroleum ether (1:2) gave 170 mg of 4-(4-chloro-2 -pyridyl)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile.
Reaction SMILES: [F:1][C:2]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([OH:17])=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].[C:31]([O:35][C:36](=[O:42])[NH:37][CH2:38][CH2:39][CH2:40]Br)([CH3:34])([CH3:33])[CH3:32].CCOC(C)=O>CN(C=O)C>[F:1][C:2]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH2:40][CH2:39][CH2:38][NH:37][C:36](=[O:42])[O:35][C:31]([CH3:34])([CH3:33])[CH3:32])=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1
Reactant: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2cc1O
Reactant: CC(C)(C)OC(=O)NCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2cc1OCCCNC(=O)OC(C)(C)C
Temperature: 90 °C
Reaction time: 3 h

Procedure:
To a solution of 4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-quinolin-7-ol (511 mg, 1.55 mmol, 1.0 eq.) and potassium carbonate (428 mg, 3.1 mmol, 2.0 eq.) in dry DMF (10 mL) was added tert-butyl(3-bromopropyl)carbamate (480 mg, 2.01 mmol, 1.3 eq.). The mixture was stirred for 3 h at 90° C. and then cooled to RT. EtOAc was added and the organic phase was washed three times with water. The organic phase was dried over MgSO4 and solvents were removed in vacuo. The desired product R1 was obtained as brown oil and was used without further purification in the next step. MS (ES) C24H26FN3O7 requires: 487. Found: 488 (M+H)+.
Reaction SMILES: Cl.Cl.[CH:3]([C@:6]1([C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][N:21]=3)[CH2:16][CH2:15]2)=[O:13])[CH2:10][CH2:9][C@@H:8]([NH2:11])[CH2:7]1)([CH3:5])[CH3:4].[CH3:30][CH:31]1[C:36](=O)[CH2:35][CH2:34][O:33][CH2:32]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CCOC(C)=O>[CH:3]([C@:6]1([C:12]([N:14]2[CH2:15][CH2:16][N:17]([C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:27])[F:28])[CH:23]=[CH:22][N:21]=3)[CH2:18][CH2:19]2)=[O:13])[CH2:10][CH2:9][C@@H:8]([NH:11][CH:36]2[CH2:35][CH2:34][O:33][CH2:32][CH:31]2[CH3:30])[CH2:7]1)([CH3:5])[CH3:4]
Reactant: CC1COCCC1=O
Reactant: CC(C)[C@]1(C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)CC[C@@H](N)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1COCCC1N[C@@H]1CC[C@@](C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)(C(C)C)C1
Reaction time: 8 h
Yield: 67.5 %

Procedure:
To a solution of (1R,3S)-3-isopropyl-3-({4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}carbonyl)cyclopentanamine dihydrochloride (140 mg, 0.31 mmol), 3-methyltetrahydro-4H-pyran-4-one (70 mg, 0.61 mmol) and triethylamine (0.21 mL, 1.5 mmol) in methylene chloride (10 mL) was added sodium triacetoxyborohydride (190 mg, 0.92 mmol). After being stirred overnight, the reaction mixture was diluted with EtOAc and washed with saturated Na2CO3. The aqueous layer was extracted with EtOAc three times. The combined organic layers were dried (MgSO4), concentrated and purified by flash chromatography on silica gel (EtOAc to 1% Et3N/EtOAc to 5% Et3N/EtOAc) to give 101 mg of product. The product was further separated by chiral HPLC to give isomer 1 and isomer 2. MS calculated for C25H37F3N4O2 (M+1) 483; found 483.2.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[C:22](=[O:23])[N:21]2[CH:17]([CH2:18][CH:19]([O:24][C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=[CH:27][N:26]=3)[CH2:20]2)[C:16](=[O:35])[NH:15][C:14]2([C:36]([NH:38][S:39]([CH:42]3[CH2:44][CH2:43]3)(=[O:41])=[O:40])=[O:37])[CH:12]([CH2:13]2)[CH:11]=[CH:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.CCN(C(C)C)C(C)C.Cl[C:55]([O:57][CH:58]([CH3:60])[CH3:59])=[O:56]>C1(C)C=CC=CC=1>[CH:58]([O:57][C:55](=[O:56])[NH:3][CH:4]1[C:22](=[O:23])[N:21]2[CH:17]([CH2:18][CH:19]([O:24][C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=[CH:27][N:26]=3)[CH2:20]2)[C:16](=[O:35])[NH:15][C:14]2([C:36]([NH:38][S:39]([CH:42]3[CH2:43][CH2:44]3)(=[O:40])=[O:41])=[O:37])[CH:12]([CH2:13]2)[CH:11]=[CH:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)([CH3:60])[CH3:59]
Reactant: CC(C)OC(=O)Cl
Reactant: NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(Oc3nccc4ccccc34)CN2C1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CC(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(Oc3nccc4ccccc34)CN2C1=O
Yield: 78.2 %

Procedure:
Prepared from cyclopropanesulfonic acid [14-amino-18-(isoquinolin-1-yloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]nonadec-7-ene-4-carbonyl)-amide bis hydrochloride (50 mg, 0.075 mmol), 44 mL (0.25 mmol) of DIPEA and 0.10 mL (0.1 mmol) of 1 M isopropyl chloroformate in toluene (Aldrich) as described in the procedure above to give 40 mg (78%) of a white solid. Preparative HPLC condition: YMC XTERRA, S5, 30×50 mm, gradient: 50% B to 100% B. 15 min. hold 2 min. flow rate 40 mL/min) NMR (300 MHz, CD3OD) δ. LC-MS (Method A, retention time: 3.32 min), MS m/z 682 (M++1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:31])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[CH:15]=[CH:14][S:13][C:12]=1[C:16]([NH:18][C:19]1C=C2OCOC2=C[C:20]=1[C:28](=O)C)=[O:17])(=[O:10])=[O:9].[NH2:32][C:33]1[CH:38]=[CH:37]C(C)=CN=1.NC1C=C2OCOC2=CC=1C(=O)C>>[Cl:1][C:2]1[C:3]([CH3:31])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[CH:15]=[CH:14][S:13][C:12]=1[C:16]([NH:18][C:19]1[N:32]=[CH:33][C:38]([CH3:37])=[CH:28][CH:20]=1)=[O:17])(=[O:9])=[O:10]
Reactant: Cc1ccc(N)nc1
Reactant: CC(=O)c1cc2c(cc1NC(=O)c1sccc1S(=O)(=O)Nc1onc(C)c1Cl)OCO2
Agent: CC(=O)c1cc2c(cc1N)OCO2
Product: Cc1ccc(NC(=O)c2sccc2S(=O)(=O)Nc2onc(C)c2Cl)nc1

Procedure:
N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(3-methyl-6-pyridyl)aminocarbonyl]thiophene-3-sulfonamide was prepared by the method set forth for N-(4-chloro-3-methyl-5-isoxazolyl)2-{[2-acetyl-4,5-(methylenedioxy)phenyl]aminocarbonyl}thiophene-3-sulfonamide (EXAMPLE 148), except that 2-amino-5-picoline was used in stead of 2′-amino-4′,5′-(methylenedioxy)acetophenone, N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(3-methyl-6-pyridyl)aminocarbonyl]thiophene-3-sulfonamide was obtained, via HPLC purification of the crude reaction mixture, as a bright yellow powder (17% yield, m.p. 158-160° C.).
Reaction SMILES: [O:1]1[C:6]2[C:7]3[CH2:13][CH2:12][CH2:11][C:8]=3[CH:9]=[CH:10][C:5]=2[CH2:4][CH2:3][CH:2]1[CH2:14][NH:15][CH2:16][CH2:17][CH2:18][NH2:19].[ClH:20].CS[C:23]1[NH:24][CH:25]=[CH:26][N:27]=1>C(O)C>[OH2:1].[ClH:20].[ClH:20].[NH:27]1[CH2:26][CH2:25][N:24]=[C:23]1[NH:19][CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH:2]1[CH2:3][CH2:4][C:5]2[CH:10]=[CH:9][C:8]3[CH2:11][CH2:12][CH2:13][C:7]=3[C:6]=2[O:1]1.[NH:27]1[CH2:26][CH2:25][N:24]=[C:23]1[NH:19][CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH:2]1[CH2:3][CH2:4][C:5]2[CH:10]=[CH:9][C:8]3[CH2:11][CH2:12][CH2:13][C:7]=3[C:6]=2[O:1]1.[ClH:20].[ClH:20]
Reactant: NCCCNCC1CCc2ccc3c(c2O1)CCC3
Reactant: CSc1ncc[nH]1
Agent: Cl
Solvent: CCO
Product: O
Product: c1cc2c(c3c1CCC3)OC(CNCCCNC1=NCCN1)CC2
Yield: 58.5 %

Procedure:
A mixture of intermediate (15-a) (0.02 mol) and 2-methylthioimidazole monohydrochloride (0.02 mol) in ethanol (100 ml) was stirred and refluxed for 16 hours. The solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2 /CH3OH/(CH3OH/NH3) 90/9/1). The pure fractions were collected and the solvent was evaporated. The residue was dissolved in 2-propanol and converted into the hydrochloric acid salt (1:2) with HCl/2-propanol. The salt was filtered off and dried, yielding 2.4 g of (±)-N-(4,5-dihydro-1H-imidazol-2-yl)-N'-[(2,3,4,7,8,9-hexahydrocyclopenta[h]-1-benzopyran-2-yl)methyl]-1,3-propanediamine dihydrochloride hemihydrate; mp. 189.7° C. (comp. 9-a).
Reaction SMILES: O[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[Cl:22])[N:3]=1.S(Cl)([Cl:25])=O.CN(C)C=O>O>[Cl:25][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[Cl:22])[N:3]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)nc1O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)nc1Cl
Yield: 50 %

Procedure:
5.0 g of 2-hydroxy-3-nitro-6-(2-chloro-4-trifluoromethylphenoxy)pyridine prepared in Preparation Example 3, 3.55 g of thionyl chloride, and 0.2 ml of dimethylformamide were charged in a flask, and the mixture was allowed to react at 80° C. for 4 hours while stirring. After completion of the reaction, the reaction product was poured into water, followed by subjecting to purification in the same manner as in Preparation Example 2 to obtain 2.64 g of a titled compound having a melting point of 53° to 59° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C@H:6]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[C:5]2[C:14]([CH3:21])=[C:15]([NH2:20])[C:16]([CH3:19])=[C:17]([CH3:18])[C:4]=2[O:3]1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]([CH3:35])C(O)=O)=[CH:27][CH:26]=1.[C:36](OCC)(=[O:38])C.CCCCCC>>[CH3:23][O:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:31][CH2:35][C:36]([NH:20][C:15]2[C:16]([CH3:19])=[C:17]([CH3:18])[C:4]3[O:3][C:2]([CH3:22])([CH3:1])[C@H:6]([C:7]4[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][CH:12]=4)[C:5]=3[C:14]=2[CH3:21])=[O:38])=[CH:29][CH:30]=1
Reactant: CCOC(C)=O
Reactant: COc1ccc(C(C)C(=O)O)cc1
Reactant: Cc1ccc([C@@H]2c3c(C)c(N)c(C)c(C)c3OC2(C)C)cc1
Solvent: CCCCCC
Product: COc1ccc(CCC(=O)Nc2c(C)c(C)c3c(c2C)[C@@H](c2ccc(C)cc2)C(C)(C)O3)cc1
Yield: 21 %

Procedure:
Using (+)-(3R)-2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amine obtained in Reference Example 134 and -4-methoxyphenylpropionic acid, the title compound was synthesized in the same manner as in Reference Example 359. Yield 21%. Melting point: 170-172° C. (ethyl acetate-hexane).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][N:10]1[CH:14]=[C:13](B2OC(C)(C)C(C)(C)O2)[CH:12]=[N:11]1.Cl[C:25]1[CH:26]=[CH:27][C:28]2[N:29]([C:31]([CH2:34][C:35]3[CH:36]=[C:37]4[C:42](=[CH:43][C:44]=3[F:45])[N:41]=[CH:40][CH:39]=[CH:38]4)=[CH:32][N:33]=2)[N:30]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.CCOC(C)=O.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>[F:45][C:44]1[CH:43]=[C:42]2[C:37]([CH:38]=[CH:39][CH:40]=[N:41]2)=[CH:36][C:35]=1[CH2:34][C:31]1[N:29]2[N:30]=[C:25]([C:13]3[CH:12]=[N:11][N:10]([CH2:9][CH2:8][O:7][CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)[CH:14]=3)[CH:26]=[CH:27][C:28]2=[N:33][CH:32]=1
Reactant: Fc1cc2ncccc2cc1Cc1cnc2ccc(Cl)nn12
Reactant: CC1(C)OB(c2cnn(CCOC3CCCCO3)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Fc1cc2ncccc2cc1Cc1cnc2ccc(-c3cnn(CCOC4CCCCO4)c3)nn12

Procedure:
A solution of [2-(tetrahydro-pyran-2-yloxy)-ethyl]-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (Stage 171.4, 77 mg, 0.240 mmol), 6-(6-chloro-imidazo[1,2-b]pyridazin-3-ylmethyl)-7-fluoro-quinoline (Stage 173.1, 55 mg, 0.160 mmol), PdCl2(PPh3)2 (5.6 mg) and 2 M K2CO3 (0.216 mL) in DME (0.5 mL was stirred at 90° C. for 2 h under argon atmosphere. The RM was then diluted with EtOAc and washed with saturated aqueous NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered, evaporated to dryness and the residue was purified (CombiFlash® Companion System®, with RediSep® silica gel column, DCM/DCM/MeOH 9:1=100:0->0:100) to afford the title compound (tR 3.97 min (conditions 3), MH+=473.1).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:10][OH:11].C(=O)([O-])[O-].[K+].[K+]>CO>[CH:1](=[N:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: ON=Cc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 99 %

Procedure:
10.6 g of benzaldehyde, 7.0 g of hydroxylamine HCl salt and 14.0 g of potassium carbonate were suspended in 200 ml of methanol, and were stirred at room temperature for 5 hours. The reaction mixture was filtered, and the methanol was distilled off under reduced pressure. The residue thus obtained was purified by silica gel column chromatography to obtain 12.0 g of the above identified compound as a white crystal (yield 99%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7](=[O:10])[CH2:8][CH3:9])[CH:2]=1.[BH4-].[Na+].O>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([OH:10])[CH2:8][CH3:9])[CH:2]=1
Reactant: CCC(=O)c1cccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCC(O)c1cccnc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 1-(pyridin-3-yl)propan-1-one (2.46 g, 18.20 mmol, purchased from Lancaster Synthesis Ltd.) in MeOH (15 mL) at rt under N2 atmosphere was added sodium borohydride powder (0.690 g, 18.20 mmol). After stirring at rt for 1.5 hr, to the reaction solution was added water (20 ml). The resulting mixture was stirred for 4 min, extracted with EtOAc (20 mL×3). The organic layers were combined, washed with water, sat. aq. NaCl solution and dried over MgSO4. Removal of the solvents provided the crude title compound as white solid. Mass Spectrum (ESI) m/z=138.0 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[OH:14].C1(=O)O[CH2:18][CH2:17][O:16]1.[I-].[K+].CN(C)C=O>C(OCC)(=O)C>[OH:16][CH2:17][CH2:18][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[OH:14]
Reactant: Oc1ccccc1-c1ccccc1O
Reactant: O=C1OCCO1
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: OCCOc1ccccc1-c1ccccc1O
Temperature: 150 °C
Reaction time: 4 h

Procedure:
To a 2000 ml 3 neck round bottom equipped with an overhead stirrer, temperature probe, heating mantel was added 2,2′-dihydroxy-biphenyl (500 g, 2.68 mole, 1.0 eq), ethylene carbonate (520.2 g, 5.9 mole, 2.2 eq.), potassium iodide (5 g, 0.03 mole, 0.01 eq.), N,N-dimethyl formamide (DMF) (47 g, 50 ml) and heated to 150° C. The reaction was monitored by GC and after 4 hours the reaction was complete. The reaction was cooled to 40° C., added 1000 ml ethyl acetate and washed 3 times with 500 ml sodium chloride brine. The ethyl acetate was dried over MgSO4, filtered and concentrated in vacuo to recover a dark brown product (736 g, 99%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=O)[CH2:2][CH3:3].[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>C1(C)C=CC=CC=1.B(F)(F)F.CCOCC>[C:5]1([C:1]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:2][CH3:3])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C1CCNCC1
Reactant: CCC(=O)c1ccccc1
Agent: FB(F)F
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC=C(c1ccccc1)N1CCCCC1
Yield: 62.2 %

Procedure:
In 30 ml of toluene, 2.68 g of propiophenone, 5.30 g of piperidine and 0.14 g of boron trifluoride etherate were dissolved. The mixture was treated in a manner similar to Example 1 to obtain 2.50 g of the desired enamine (yield: 50%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:13][CH2:12][CH2:11][C:10]2=O)[CH:6]=[CH:7][CH:8]=1.[C:15]([CH:20]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:17][CH2:18][CH3:19])=[O:16]>>[CH2:18]([O:17][C:15](=[O:16])[CH2:20][C:10]1[CH2:11][CH2:12][CH2:13][C:9]=1[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:19]
Reactant: COc1cccc(C2CCCC2=O)c1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(=O)CC1=C(c2cccc(OC)c2)CCC1
Yield: 81.4 %

Procedure:
Reflux a solution of 2-(3-methoxy-phenyl)-cyclopentanone (4.34 g 22.8 mmoles), and (carboethoxymethylene)-triphenylphosphorane (14.31 g, 41.1 mmoles) in 130 ml of xylenes for 15 hours. Concentrate in vacuo at 40° C. and slurry with ether. Remove triphenyl phosphine oxide by vacuum filtration, and chromatographed on silica with 14% ethyl acetate/hexanes. to yield the 4.83 g of the titled compound. 1H NMR (CDCl3): 7.26 (m, 1H), 6.9 (m, 2H), 6.8 (m, 1H), 4.17 (q, J=7.2, 2H), 3.81 (s, 3H), 3.22 (s, 2H), 2.76 (m, 2H), 2.58 (m, 2H), 1.95 (m, 2H) 1.28 (m, 3H).
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([NH:8][C:9](=[O:13])[O:10][CH2:11][CH3:12])=[C:5]([C:14]([NH:16][CH2:17][CH2:18][OH:19])=[O:15])[CH:4]=1)[CH3:2].[C:20]([Si:24](Cl)([CH3:26])[CH3:25])([CH3:23])([CH3:22])[CH3:21].C(N(CC)CC)C.C(Cl)Cl>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[Si:24]([O:19][CH2:18][CH2:17][NH:16][C:14]([C:5]1[CH:4]=[C:3]([CH2:1][CH3:2])[S:7][C:6]=1[NH:8][C:9](=[O:13])[O:10][CH2:11][CH3:12])=[O:15])([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)Nc1sc(CC)cc1C(=O)NCCO
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Nc1sc(CC)cc1C(=O)NCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
A mixture of ethyl (5-ethyl-3-{[(2-hydroxyethyl)amino]carbonyl}-2-thienyl)carbamate (0.22 g), tert-butyl(chloro)dimethylsilane (0.15 mL), triethylamine (0.1 g), N,N-dimethylpyridin-4-amine (0.012 g) and methylene chloride (10 mL) was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as colorless crystals (0.35 g, 95%).