Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([NH:34][C:35]2[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=2)=[N:9][C:10]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([CH2:22][C:23]3[C:28]([F:29])=[CH:27][C:26]([O:30][CH2:31][CH3:32])=[CH:25][C:24]=3[F:33])[N:14]=2)=[N:11][CH:12]=1)(=O)=O.C(P(C1C=CC=CC=1)C1C=CC=CC=1)CCP(C1C=CC=CC=1)C1C=CC=CC=1.C([SiH](CC)CC)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:31]([O:30][C:26]1[CH:27]=[C:28]([F:29])[C:23]([CH2:22][N:15]2[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:13]([C:10]3[N:9]=[C:8]([NH:34][C:35]4[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=4)[CH:7]=[CH:12][N:11]=3)=[N:14]2)=[C:24]([F:33])[CH:25]=1)[CH3:32]
Reactant: CCOc1cc(F)c(Cn2nc(-c3ncc(OS(=O)(=O)C(F)(F)F)c(Nc4ccncc4)n3)c3ccccc32)c(F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC[SiH](CC)CC
Solvent: CN(C)C=O
Product: CCOc1cc(F)c(Cn2nc(-c3nccc(Nc4ccncc4)n3)c3ccccc32)c(F)c1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
100 mg of 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazol-3-yl]-4-(pyridin-4-ylamino)pyrimidin-5-yl trifluoromethanesulfonate (1-7-2, 0.165 mmol, 1. eq.), 0.74 mg of palladium (II) acetate (0.003 mmol, 0.02 eq.) and 1.36 mg of propane-1,3-diylbis(diphenylphosphane) were dissolved in 1 ml of DMF under a nitrogen atmosphere. The mixture was heated to 60° C. bath temperature. Then 0.66 ml of triethylsilane (0.41 mmol, 2.5 eq.) were added. The resulting mixture was stirred at 60° C. bath temperature for 18 hours. Then the mixture was partitioned between saturated aq. sodium hydrogen carbonate solution and dichloromethane. The phases were separated and the aqueous layer was extracted twice with dichloromethane. The combined organic layers were washed with brine, dried over a silicone filter and concentrated in vacuo. Preparative HPLC purification provided 16 mg (0.03 mmol, 20.1%) of the analytically pure target compound.
Reaction SMILES: Cl.[CH2:2]([NH2:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>C(Cl)(Cl)Cl>[CH2:2]([NH:9][S:25]([C:22]1[CH:21]=[CH:20][C:19]([O:18][CH3:17])=[CH:24][CH:23]=1)(=[O:27])=[O:26])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: NCc1ccccc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)NCc2ccccc2)cc1
Temperature: 0 °C
Yield: 95.6 %

Procedure:
Benzylamine hydrochloride (21.5 g, 150.0 mmol) was dissolved in chloroform (114 ml) and cooled to 0° C. Triethylamine (20.9 ml, 150.0 mmol) and 4-methoxybenzenesulfonyl chloride (10.3 g, 50.0 mmol) were added to the solution, and the mixture was reacted for 2 hours at room temperature, followed by for 1 hour at 60° C. After standing to cool, the reaction mixture was washed with 4N hydrochloric acid (200 ml×3), water (100 ml×2) and saturated brine (50 ml) successively. Then, the solvent was dried over sodium sulfate and evaporated out, to give N-benzyl-4-methoxybenzenesulfonamide (13.25 g, 96%).
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]=C(SC)C=C2OC1C=CC(NC(C2(C(NC3C=CC(F)=CC=3)=O)CC2)=O)=CC=1F.CS[C:43]([S:54][CH3:55])=[C:44]1[C:49](=[O:50])[O:48][C:47]([CH3:52])([CH3:51])[O:46][C:45]1=[O:53]>CCO>[CH3:14][O:13][C:12]1[CH:11]=[C:10]([NH:9][C:43]([S:54][CH3:55])=[C:44]2[C:49](=[O:50])[O:48][C:47]([CH3:52])([CH3:51])[O:46][C:45]2=[O:53])[CH:5]=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc2nc(SC)cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)c2cc1OC
Reactant: CSC(SC)=C1C(=O)OC(C)(C)OC1=O
Solvent: CCO
Product: COc1ccc(NC(SC)=C2C(=O)OC(C)(C)OC2=O)cc1OC
Yield: 83 %

Procedure:
Synthesis of N-(4-{[6,7-bis(methyloxy)-2-(methylthio)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide Commercially available 5-(bis-methylsulfanyl-methylene)-2,2-dimethyl-[1,3]dioxane-4,6-dione (3.5 g, 14 mmol) and 3,4-dimethoxyoaniline (2.2 g, 14 mmol) were reflux in EtOH (20 mL) for 2 hours. The EtOH was removed under reduced pressure and EtOAc was added to the residue. The product was filtered and washed with cold EtOAc (3×). 5-[(3,4-dimethoxy-phenylamino)-methylsulfanyl-methylene]-2,2-dimethyl-[1,3]dioxane-4,6-dione was obtained as a white solid (1.7 g, 47% yield) and used without further purification. LCMS: m/z 352 (M−H)−.
Reaction SMILES: [NH:1]=[C:2]1[NH:6][C:5]([C:11]([F:14])([F:13])[F:12])([C:7]([F:10])([F:9])[F:8])[C:4](=[C:15]([F:20])[C:16]([F:19])([F:18])[F:17])[S:3]1.C(N(CC)CC)C.[Cl:28][C:29]1[CH:30]=[C:31]([CH:35]=[C:36]([Cl:38])[CH:37]=1)[C:32](Cl)=[O:33]>C1(C)C=CC=CC=1>[Cl:28][C:29]1[CH:30]=[C:31]([CH:35]=[C:36]([Cl:38])[CH:37]=1)[C:32]([NH:1][C:2]1[S:3][C:4](=[C:15]([F:20])[C:16]([F:17])([F:18])[F:19])[C:5]([C:7]([F:10])([F:9])[F:8])([C:11]([F:12])([F:13])[F:14])[N:6]=1)=[O:33]
Reactant: N=C1NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(NC1=NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In toluene (10 ml) were dissolved 2-imino-4,4-bis(trifluoromethyl)-5-(tetrafluoroethylidene)-1,3-thiazolidine (1.0 g) and triethylamine (1.0 ml), and 3,5-dichlorobenzoyl chloride (1.5 g) was gradually added thereto and the mixture was stirred at room temperature for 3 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:13]([CH2:14][CH:15]([C:21]([O:23]CC)=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][N:11]=[C:10]1[S:26][CH2:27][CH2:28][CH3:29].C(=O)([O-])[O-].[Na+].[Na+].C(O)C.Cl>C(Cl)Cl.O>[C:16]([CH:15]([CH2:14][C:13]1[N:9]([CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:10]([S:26][CH2:27][CH2:28][CH3:29])=[N:11][CH:12]=1)[C:21]([OH:23])=[O:22])([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCCSc1ncc(CC(C(=O)OCC)C(=O)OCC)n1Cc1ccccc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: CCCSc1ncc(CC(C(=O)O)C(=O)OCC)n1Cc1ccccc1Cl

Procedure:
A solution of diethyl [1-{(2-chlorophenyl)methyl}-2- propylthio-1H-imidazol-5-yl]methylmalonate (0.62 g, 1.41 mmol), sodium carbonate (1.5 g, 14.2 mol), ethanol (10 mL) and water (10 mL) was stirred at 25° C. for 18 hours, then heated for 15 minutes on a steam bath. The mixture was cooled, neutralized with aqueous hydrochloric acid solution, and the product was extracted-into methylene chloride, washed with water, dried and concentrated to 0.425 g of product. Crystallization from ethyl acetate/hexane provided 0.23 g 55%) of 2-carbethoxy-3-[1-{(2-chlorophenyl)methyl}-2- propylthio-1H-imidazol-5-yl]propanoic acid; mp 118°-120° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C@H:10]3[CH2:15][CH2:14][C@H:13]([N:16]4[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]Cl>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C@H:10]3[CH2:15][CH2:14][C@H:13]([N:16]4[CH2:21][CH2:20][N:19]([CH2:27][C:26]5[CH:29]=[CH:30][CH:31]=[C:24]([O:23][CH3:22])[CH:25]=5)[CH2:18][CH2:17]4)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: c1cc([C@H]2CC[C@H](N3CCNCC3)CC2)cc2c1OCO2
Reactant: COc1cccc(CCl)c1
Product: COc1cccc(CN2CCN([C@H]3CC[C@H](c4ccc5c(c4)OCO5)CC3)CC2)c1

Procedure:
The title compound was prepared from trans 1-[4-(1,3-benzodioxol-5-yl)-1-cyclohexyl]piperazine and 3-methoxybenzyl chloride by the method described in example 15 to give the product (67%, mp: 93°-96° C.). Calc'd for C25H32N2O3 : C, 73.50%; H, 7.90%; N, 6.86%. Found: C, 73.23%; H, 7.92%; N, 6.99%.
Reaction SMILES: Br[C:2]1[C:3](=[O:32])[N:4]([CH2:19][C@@H:20]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:21][O:22]C(=O)C)[C:5](=[O:18])[N:6]([CH2:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])[C:7]=1[CH3:8].[F:33][C:34]1[C:39]([O:40][CH3:41])=[CH:38][CH:37]=[CH:36][C:35]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].N#N>O1CCOCC1.O>[F:33][C:34]1[C:39]([O:40][CH3:41])=[CH:38][CH:37]=[CH:36][C:35]=1[C:2]1[C:3](=[O:32])[N:4]([CH2:19][C@@H:20]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:21][OH:22])[C:5](=[O:18])[N:6]([CH2:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])[C:7]=1[CH3:8]
Reactant: COc1cccc(B(O)O)c1F
Reactant: CC(=O)OC[C@@H](Cn1c(=O)c(Br)c(C)n(Cc2c(F)cccc2F)c1=O)c1ccccc1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cccc(-c2c(C)n(Cc3c(F)cccc3F)c(=O)n(C[C@H](CO)c3ccccc3)c2=O)c1F
Yield: 66.8 %

Procedure:
To compound 8a (4.05 g, 8 mmol) in dioxane/water (100/50 mL) was added 2-fluoro-3-methoxyphenylboronic acid (2.04 g, 12 mmol) and Na2CO3 (5.08 g, 48 mmol). The reaction mixture was deoxygenated with N2 for 10 min, tetrakis(triphenylphosine) palladium (0) (924 mg, 0.8 mmol) was added and the reaction mixture was heated at 100° C. overnight under the protection of N2. The reaction mixture was partitioned between brine and EtOAc. The organic layer was dried (sodium sulfate), evaporated and purified by flash chromatography (silica, 50% EtOAc/hexanes) to give compound 8b (2.73 g, 66.9%). MS (CI) m/z 511.1 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH2:6][CH2:5][CH:4]([C:7]([CH3:9])=[CH2:8])[C:3]=1[CH2:10][C:11]([CH3:18])([CH3:17])[CH2:12][O:13][C:14](=[O:16])[CH3:15]>C(O)C.[Ni]>[CH3:1][C:2]1[CH2:6][CH2:5][CH:4]([CH:7]([CH3:9])[CH3:8])[C:3]=1[CH2:10][C:11]([CH3:17])([CH3:18])[CH2:12][O:13][C:14](=[O:16])[CH3:15]
Reactant: C=C(C)C1CCC(C)=C1CC(C)(C)COC(C)=O
Agent: [Ni]
Solvent: CCO
Product: CC(=O)OCC(C)(C)CC1=C(C)CCC1C(C)C
Yield: 85 %

Procedure:
10 g of the product from Example 4 in solution in ethanol were partially hydrogenated at 50° C under a hydrogen pressure of 100 bars, in the presence of 1 g of Raney nickel, to give the above compound. Yield 85%, boiling point 70°-76° C/0.05 mm Hg, nD25 : 1.4622. Somewhat blander odor than the analogous isopropenyl compound (see Example 4).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH2:8])[N:5]2[N:9]=[CH:10][N:11]=[C:4]2[N:3]=1.[Na+].[I-:13].CC1C=CC(S([N-]Cl)(=O)=O)=CC=1.O.O.O.[Na+]>C(O)(=O)C>[I:13][C:7]1[C:2]([CH3:1])=[N:3][C:4]2[N:5]([N:9]=[CH:10][N:11]=2)[C:6]=1[NH2:8]
Reactant: [I-]
Reactant: Cc1cc(N)n2ncnc2n1
Agent: Cc1ccc(S(=O)(=O)[N-]Cl)cc1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1nc2ncnn2c(N)c1I
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
To a stirring mixture of 3:05 g (20.4 mmol) of 5-methyl[1,2,4]triazolo[1,5-a]pyrimidin-7-amine (prepared as described in Kano; Makisumi; Chem. Pharm. Bull.; 6; 1958; 583, 585) in 50 mL of acetic acid at room temperature was added NaI (3.2 g, 21.5 mmol). Chloramine-T trihydrate (6.0 g, 21.5 mmol) was then added portion wise. The resulting mixture was then stirred for 1 h at room temperature. Most of the organic solvent was removed on a rotavap. The mixture was taken up in 40 mL of CH3CN and filtered. The solid collected was washed with diethyl ether and dried in vacuum oven to give the title compound as a light yellow solid (4.93 g, 88% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9](O)[CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1.CCN(S(F)(F)[F:30])CC>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([F:30])[CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(C(O)c2ccc(F)cc2F)CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(F)c2ccc(F)cc2F)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a 78° C. solution of tert-butyl 4-((2,4-difluorophenyl)(hydroxy)methyl)piperidine-1-carboxylate (200 mg, 0.611 mmol) in DCM (3.055 mL) was added DAST (242 μL, 1.833 mmol). The mixture was stirred at −78° C. for 30 min, then quenched with MeOH. Flash silica gel chromatography using a gradient of 0% to 100% EtOAc in hexanes gave tert-butyl 4-((2,4-difluorophenyl)fluoromethyl)piperidine-1-carboxylate as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[CH2:5][N:6]([CH3:8])[CH3:7].[Mg].[CH2:13]=[O:14]>O1CCCC1>[CH3:7][N:6]([CH2:5][C:4]1[CH:3]=[C:2]([CH:11]=[CH:10][CH:9]=1)[CH2:13][OH:14])[CH3:8]
Reactant: CN(C)Cc1cccc(Br)c1
Reactant: C=O
Agent: [Mg]
Solvent: C1CCOC1
Product: CN(C)Cc1cccc(CO)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 78 %

Procedure:
3-Bromo-N,N-dimethylbenzylamine (21.4 g) was reacted with magnesium turnings (2.4 g) in dry tetrahydrofuran (75 ml). The mixture was cooled to 0° and gaseous formaldehyde (generated by heating 15 g paraformaldehyde in a stream of argon) was passed over the stirred solution. Tetrahydrofuran (25 ml) was added and the mixture was stirred at room temperature for 2.5 hours and acidified to pH 1. The mixture was extracted with aqueous 3N hydrochloric acid, and the aqueous extracts were made alkaline with aqueous sodium hydroxide and extracted with ether. The ether extracts were evaporated to give 3-(dimethylaminomethyl)benzyl alcohol (14.78 g, 78%).
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:32][S:33]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1B(O)O)(=[O:35])=[O:34].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>CN(C)C=O.C(Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:19]([N:18]1[C:14]([C:12]2[N:13]=[C:6]3[C:5]4[CH:22]=[CH:23][C:2]([C:37]5[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=5[S:33]([CH3:32])(=[O:35])=[O:34])=[CH:3][C:4]=4[O:10][CH2:9][CH2:8][N:7]3[CH:11]=2)=[N:15][CH:16]=[N:17]1)([CH3:21])[CH3:20]
Reactant: CS(=O)(=O)c1ccccc1B(O)O
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(-c3ccccc3S(C)(=O)=O)cc1OCC2
Temperature: 180 °C
Yield: 13.9 %

Procedure:
A solution of 8-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene 194 (0.050 g, 0.13 mmol) and crushed Potassium phosphate (0.0851 g, 0.401 mmol) in N,N-Dimethylformamide (0.5 mL) was thoroughly degassed with N2. 2-Methylsulfonylphenylboronic acid (0.053 g, 0.27 mmol), Palladium Acetate (0.0015 g, 0.0067 mmol) and S-Phos (0.00686 g, 0.0167 mmol) were added and the mixture was heated in the microwave for 30 minutes at 180° C. The reaction was diluted with methylene chloride and filtered through celite. Saturated NH4Cl was added and the mixture was extracted 3 times with methylene chloride. The organic layers were combined, dried with Na2SO4 and concentrated. The crude was purified by reverse-phase HPLC to obtain 8.1 mg of 475 as a white solid. MS (ESI+) 450.1. 1H NMR (400 MHz, DMSO) δ 8.47 (d, J=8.3 Hz, 1H), 8.11 (dd, J=8.0, 1.1 Hz, 1H), 7.98 (s, 1H), 7.92 (s, 1H), 7.79 (td, J=7.5, 1.3 Hz, 1H), 7.70 (td, J=7.8, 1.3 Hz, 1H), 7.45 (dd, J=7.5, 1.1 Hz, 1H), 7.21 (dd, J=8.3, 1.8 Hz, 1H), 7.12 (d, J=1.7 Hz, 1H), 5.93 (hept, J=6.2 Hz, 1H), 4.57 (q, J=5.7 Hz, 4H), 2.93 (s, 3H), 1.50 (d, J=6.6 Hz, 6H)
Reaction SMILES: [BH4-].[Li+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH3:15])[C:10](=[O:16])[CH2:9][CH:8]2[CH2:17][C:18](OC)=[O:19]>O1CCCC1>[OH:19][CH2:18][CH2:17][CH:8]1[C:7]2[C:12](=[CH:13][CH:14]=[C:5]([O:4][CH3:3])[CH:6]=2)[N:11]([CH3:15])[C:10](=[O:16])[CH2:9]1
Reactant: COC(=O)CC1CC(=O)N(C)c2ccc(OC)cc21
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(CCO)CC(=O)N2C
Temperature: 25 °C
Reaction time: 84 h

Procedure:
Lithium borohydride (100 ml of a 2.0M solution in tetrahydrofuran) was added to a solution of 34.6 g of 1,2,3,4-tetrahydro-6-methoxy-1-methyl-2-oxo-4-quinoline acetic acid, methyl ester in 330 ml of tetrahydrofuran. The mixture was stirred at room temperature for 84 hours, cooled to 0° C., quenched with 10% aqueous hydrochloric acid, and concentrated. The aqueous layer was basified with potassium carbonate and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to afford 3,4-dihydro-4-(2-hydroxyethyl)-6-methoxy-1-methyl-2(1H)-quinolinone.
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:11][CH2:12][CH2:13][N:14]([C:21]([N:23]1[C:27]2[CH:28]=[C:29](OC)[CH:30]=[CH:31][C:26]=2[N:25]=[C:24]1[S:34]([CH2:36][C:37]1[C:42]([CH3:43])=[C:41]([O:44][CH3:45])[C:40]([CH3:46])=[CH:39][N:38]=1)=[O:35])=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:10])[CH3:9].[O:47]1CCC[CH2:48]1>>[C:8]([O:11][CH2:12][CH2:13][N:14]([C:21]([N:23]1[C:27]2[CH:28]=[CH:29][C:30]([O:47][CH3:48])=[CH:31][C:26]=2[N:25]=[C:24]1[S:34]([CH2:36][C:37]1[C:42]([CH3:43])=[C:41]([O:44][CH3:45])[C:40]([CH3:46])=[CH:39][N:38]=1)=[O:35])=[O:22])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)(=[O:10])[CH3:9]
Reactant: C1CCOC1
Reactant: COc1ccc2nc(S(=O)Cc3ncc(C)c(OC)c3C)n(C(=O)N(CCOC(C)=O)c3ccccc3)c2c1
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)nc(S(=O)Cc1ncc(C)c(OC)c1C)n2C(=O)N(CCOC(C)=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of bis(trichloromethyl)carbonate (0.291 g) in tetrahydrofuran (10 mL) was added dropwise a solution of pyridine (0.243 mL) in tetrahydrofuran (1 mL) under ice-cooling. The reaction solution was stirred for 30 minutes under ice-cooling, and 2-anilinoethyl acetate hydrochloride (0.647 g) obtained in Reference Synthetic Example 27 was added thereto. A solution of triethylamine (0.419 mL) in tetrahydrofuran (1 mL) was added dropwise, and stirred at room temperature for 3 hrs. The reaction solution was concentrated under reduced pressure, and to the residue was added water (20 mL), and then extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (15 mL), and dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). To the solution were added 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole (0.829 g), triethylamine (0.669 mL) and 4-dimethylaminopyridine (0.012 g), and stirred at 60° C. for 14 hrs. The reaction solution was concentrated under reduced pressure, and to the residue was added water (40 mL), and extracted with ethyl acetate (80 mL). The ethyl acetate layer was washed with saturated brine (15 mL), and dried over anhydrous magnesium sulfate. After concentrating under reduced pressure, the residue was purified with basic silica gel column chromatography (eluted with ethyl acetate:hexane=1:2) to give a mixture of 1:1 of title compound and 2-[[[6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl](phenyl)amino]ethyl acetate as colorless amorphous solid (1.10 g).
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH3:13])[C:7](=[NH:14])[S:6]1)([CH3:4])([CH3:3])[CH3:2].[C:15]1([C:21]2([C:27](O)=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:10]([C:8]1=[CH:9][N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[S:6]/[C:7]/1=[N:14]\[C:27]([C:21]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:28])[CH2:11][CH2:12][CH3:13]
Reactant: O=C(O)C1(c2ccccc2)CCCCC1
Reactant: CCCCc1cn(C(C)(C)C)sc1=N
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)C1(c2ccccc2)CCCCC1

Procedure:
The product from Example 92B and 1-phenylcyclohexanecarboxylic acid (Aldrich) were processed using the method described in Example 92C to afford the title compound. 1H NMR (DMSO-d6) δ 0.90 (t, J=7.3 Hz, 3H), 1.20-1.77 (m, 21H), 2.61-2.69 (m, 4H), 7.10-7.15 (m, 1H), 7.21-7.27 (m, 2H), 7.35-7.39 (m, 2H), 8.51 (s, 1H). MS (ESI+) m/z 399 (M+H)+. Anal. calcd. for C24H34N2OS: C, 72.32; H, 8.60; N, 7.03. Found: C, 72.24; H, 8.59; N, 7.10.
Reaction SMILES: Cl[C:2]1[N:28]=[CH:27][CH:26]=[CH:25][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[C:9]([O:17][CH2:18][CH2:19][N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[CH:8]=1)=[O:5].CCN(C(C)C)C(C)C.[F:38][C:39]1[CH:46]=[CH:45][C:42]([CH2:43][NH2:44])=[CH:41][CH:40]=1>CCOCC>[F:38][C:39]1[CH:46]=[CH:45][C:42]([CH2:43][NH:44][C:2]2[N:28]=[CH:27][CH:26]=[CH:25][C:3]=2[C:4]([NH:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[C:9]([O:17][CH2:18][CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:8]=2)=[O:5])=[CH:41][CH:40]=1
Reactant: NCc1ccc(F)cc1
Reactant: O=C(Nc1ccc(C(F)(F)F)c(OCCN2CCCC2)c1)c1cccnc1Cl
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(C(F)(F)F)c(OCCN2CCCC2)c1)c1cccnc1NCc1ccc(F)cc1
Temperature: 130 °C

Procedure:
2-Chloro-N-[3-(2-pyrrolidin-1-yl-ethoxy)-4-trifluoromethyl-phenyl]-nicotinamide (199.1 mg), DIEA (252 μL) and 4-fluorobenzylamine (193 μL) were combined in a sealed tube and heated to 130° C. for 2 h. The mixture was purified on silica gel chromatography (2-3.5% MeOH/CH2Cl2). The desired fractions were concentrated in vacuo, and the residue was dissolved in Et2O and hexanes were added until the solution became cloudy. The solids were filtered, and dried. Additional material was obtained from the filtrate upon additional rounds of concentration, dissolving in Et2O and treatment with hexanes. M+H 503.4, Calc'd for C26H26N4O2F4-502.2.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:11]([CH2:28][CH3:29])[C:12]1[N:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N+:24]([O-])=O)[CH:15]=[C:14]([CH3:27])[N:13]=1.CO>[Fe].C(O)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:11]([CH2:28][CH3:29])[C:12]1[N:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[NH2:24])[CH:15]=[C:14]([CH3:27])[N:13]=1
Reactant: CCN(c1nc(C)cc(-c2ccccc2[N+](=O)[O-])n1)c1ccc(C(C)C)cc1Br
Agent: [Fe]
Solvent: CO
Solvent: CC(=O)O
Product: CCN(c1nc(C)cc(-c2ccccc2N)n1)c1ccc(C(C)C)cc1Br
Reaction time: 6 h

Procedure:
The product of Example 11 (778 mg), methanol (40.5 mL), acetic acid (13.5 mL) and iron powder (382 mg) were heated at reflux and stirred mechanically for 6 h. More iron powder (1.15 g) was added and the reaction was heated at reflux 2 more hours, after which it was cooled, filtered through celite, and concentrated to a thick black oil. Added ethyl acetate (200 mL) and water (100 mL), stirred, and filtered through celite. The layers were separated and the ethyl acetate dried over MgSO4 and concentrated to a thick yellow oil (754 mg). The oil was chromatographed on silica gel using ethyl acetate/hexane (1:9) as eluent. The title compound was obtained as an off-white solid (526 mg). CI-HRMS calc'd. for C22H26N4Br (M+H)+ : 425.134083. Found: 425.131850.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]([OH:17])[CH:8]=2)[CH2:3][CH2:2]1.[CH2:18]([C:27]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1)([OH:30])[C:28]#[CH:29])[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]([OH:17])[CH:8]=2)[CH2:5][CH2:6]1.[CH2:18]([C:27]1([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[O:30][C:9]2[CH:8]=[C:7]([N:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)[C:16]3[C:11]([C:10]=2[CH:29]=[CH:28]1)=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:19]1[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=1
Reactant: C#CC(O)(Cc1ccc(OC)cc1)Cc1ccc(OC)cc1
Agent: Oc1cc(N2CCOCC2)c2ccccc2c1
Solvent: Cc1ccccc1
Product: COc1ccc(CC2(Cc3ccc(OC)cc3)C=Cc3c(cc(N4CCOCC4)c4ccccc34)O2)cc1
Reaction time: 1.5 h

Procedure:
4-Morpholino-2-naphthol was prepared as described in Example 2(b). A mixture of 4-morpholino-2-naphthol (0.50 g;0.0022 mol), 1,1-dianisylprop-2-yn-1-ol (0.59 g; 0.0022 mol), acidic alumina Brockmann 1(4 g) and toluene (35.0 ml) was heated and stirred for 1.5 h, cooled, filtered and the solid washed with toluene. The filtrate was evaporated to give an orange crystalline solid which was washed with diethyl ether to give 3,3-dianisyl -6-morpholino-3H-naphtho[2,1-b]pyran as a white solid (0.61 g;58% yield), m.pt. 211°-213° C. ##STR21##