Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.[CH2:5]([O:12][C:13]1[C:20]([CH3:21])=[CH:19][C:16]([CH2:17]O)=[CH:15][C:14]=1[CH3:22])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH:23](=[N:30][C:31]1[N:32]=[CH:33][NH:34][C:35]=1[C:36]([NH2:38])=[O:37])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>Cl[Si](C)(C)C.CN(C)C=O.O>[CH:23](=[N:30][C:31]1[N:32]=[CH:33][N:34]([CH2:17][C:16]2[CH:19]=[C:20]([CH3:21])[C:13]([O:12][CH2:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)=[C:14]([CH3:22])[CH:15]=2)[C:35]=1[C:36]([NH2:38])=[O:37])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Cc1cc(CO)cc(C)c1OCc1ccccc1
Reactant: NC(=O)c1[nH]cnc1N=Cc1ccccc1
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Cn2cnc(N=Cc3ccccc3)c2C(N)=O)cc(C)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.48 ml of dimethylsulfoxide was added to a solution of 1.49 g (6.15 mmol) of 4-benzyloxy-3,5-dimethylbenzyl alcohol in 40 ml of chlorotrimethylsilane, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under vacuum. The concentrate was dissolved in ethyl acetate, washed with distilled water and saturation brine, and dried over anhydrous magnesium sulfate. The residue obtained by concentrating the dry product under vacuum was dissolved in 30 ml of N,N-dimethylformamide. This solution was mixed with a suspension of 0.88 g (4.1 mmol) of 4-benzylideneamino-5-imidazolecarboxamide and 2.27 g (16.4 mmol) of potassium carbonate in 30 ml of N,N-dimethylformamide. After the addition of 1.64 ml of distilled water, the mixture was heated for 10 minutes and stirred overnight. The reaction solution was concentrated under vacuum and distilled water was added to the concentrate to precipitate a crude product. The precipitate was collected by filtration using a funnel glass filter. The solid obtained was washed with distilled water and toluene, and dried under vacuum to obtain 4-benzylidene amino-1-(4-benzyloxy-3,5-dimethylbenzyl)-5-imidazole carboxamide. The resulting compound was suspended in 25 ml of 1,4-dioxane and 25 ml of 1N aqueous solution of hydrochloric acid was added, followed by stirring overnight. The reaction solution was washed with ether, added 25 ml of methanol, and neutralized with 4N aqueous solution of sodium hydroxide. The organic solvent was evaporated under vacuum and the residue was allowed to stand overnight in a refrigerator. The precipitated solid was collected by filtration, washed with distilled water, and dried to obtain 1.10 g of 4-amino-1-(4-benzyloxy-3,5-dimethylbenzyl)-5-imidazole carboxamide (yield 86%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18](=[O:22])[C@@H:19]([OH:21])[CH3:20])[CH2:14][CH2:13]3)=[C:8]([CH3:23])[C:6]=2[N:7]=1.B(O)(O)[C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[N:33][CH:32]=1>>[OH:21][C@@H:19]([CH3:20])[C:18]([N:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[S:10][C:5]3[C:4]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[N:3][C:2]([C:31]4[CH:32]=[N:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=4)=[N:7][C:6]=3[C:8]=2[CH3:23])[CH2:13][CH2:14]1)=[O:22]
Reactant: Cc1c(CN2CCN(C(=O)[C@H](C)O)CC2)sc2c(N3CCOCC3)nc(Cl)nc12
Reactant: COc1ccc(B(O)O)cn1
Product: COc1ccc(-c2nc(N3CCOCC3)c3sc(CN4CCN(C(=O)[C@H](C)O)CC4)c(C)c3n2)cn1
Yield: 74 %

Procedure:
(S)-1-(4-((2-Chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (60 mg) was reacted with 35 mg of 6-methoxypyridin-3-yl-3-boronic acid via General Procedure A to give 51.7 mg of 204. MS (Q1) 513.3 (M)+.
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][O:15][N:16]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:21][CH:20]=2)[CH3:18])=[CH:7][CH:6]=1.[OH-].[Na+]>O1CCCC1.C(O)C>[C:25]([C:22]1[CH:21]=[CH:20][C:19]([C:17](=[N:16][O:15][CH2:14][CH2:13][CH2:12][O:11][C:8]2[CH:7]=[CH:6][C:5]([CH2:4][C:3]([OH:29])=[O:2])=[CH:10][CH:9]=2)[CH3:18])=[CH:24][CH:23]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: COC(=O)Cc1ccc(OCCCON=C(C)c2ccc(C(C)(C)C)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(=NOCCCOc1ccc(CC(=O)O)cc1)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.5 %

Procedure:
To a solution of (4-{3-[1-(4-tert-butyl-phenyl)-ethylideneaminooxy]-propoxy}-phenyl)-acetic acid methyl ester (3.55 mmol) in tetrahydrofuran/ethanol (3/2) (20 mL) was added 1 M sodium hydroxide solution (6 mL, 6 mmol) and the reaction was stirred overnight at room temperature. It was concentrated to a small volume, acidified to pH 1 with 1M hydrochloric acid solution and extracted with ethyl acetate. The combined organics were washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography using ethyl acetate/hexanes (20/80)+1% formic acid to afford the title compound (0.620 g, 46%) as a light yellow solid. mp=98.7-99.7° C.; mass spectrum (−ESI, M−H) m/z 382. 1H NMR (400 MHz, DMSO-d6); δ 12.20 (bs, 1H), 7.55 (d, 2H), 7.38 (d, 2H). 7.14 (d, 2H), 6.87 (d, 2H), 4.25 (t, 2H), 4.05 (t, 2H), 3.47 (s, 2H), 2.16 (s, 3H), 2.09 (m, 2H), 1.25 (s, 9H). Elemental analysis: Calcd. for C23H29NO4: C, 72.04; H, 7.62; N, 3.65, Found: C, 71.43; H, 7.87; N, 3.52.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3[C:14]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([N:21]5[CH2:29][C:28]6[C:23](=[CH:24][C:25]([Cl:30])=[CH:26][CH:27]=6)[C:22]5=[O:31])[C:16]=4[CH3:32])=[CH:13][N:12]=[C:11]([C:33]([NH2:35])=[O:34])[C:7]=3[NH:8]2)=[CH:4][CH:3]=1.[O:36]1[CH2:40][CH2:39][C:38](=O)[CH2:37]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C1COCC1.CS(C)=O.CO.O.CCOC(C)=O>[Cl:30][C:25]1[CH:24]=[C:23]2[C:28]([CH2:29][N:21]([C:17]3[C:16]([CH3:32])=[C:15]([C:14]4[C:6]5[C:5]6[C:9](=[CH:10][C:2]([NH:1][CH:38]7[CH2:39][CH2:40][O:36][CH2:37]7)=[CH:3][CH:4]=6)[NH:8][C:7]=5[C:11]([C:33]([NH2:35])=[O:34])=[N:12][CH:13]=4)[CH:20]=[CH:19][CH:18]=3)[C:22]2=[O:31])=[CH:27][CH:26]=1
Reactant: Cc1c(-c2cnc(C(N)=O)c3[nH]c4cc(N)ccc4c23)cccc1N1Cc2ccc(Cl)cc2C1=O
Reactant: O=C1CCOC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CO
Product: Cc1c(-c2cnc(C(N)=O)c3[nH]c4cc(NC5CCOC5)ccc4c23)cccc1N1Cc2ccc(Cl)cc2C1=O
Reaction time: 8 h
Yield: 2.8 %

Procedure:
To a light burgundy, homogeneous solution of 7-amino-4-(3-(6-chloro-1-oxoisoindolin-2-yl)-2-methylphenyl)-9H-pyrido[3,4-b]indole-1-carboxamide (0.0695 g, 0.144 mmol), dihydrofuran-3(2H)-one (0.050 g, 0.577 mmol) and acetic acid (0.041 mL, 0.721 mmol) in dichloromethane (1.602 mL) and THF (1.602 mL) was added sodium triacetoxyborohydride (0.122 g, 0.577 mmol). The reaction was stirred overnight. Water (2 mL) was added, and the solution was stirred at room temperature for 10 min. EtOAc (50 mL) and water (20 mL) were added. After separation of layers, the organic layer was washed with sat. aq. NaHCO3, brine (20 mL), dried over MgSO4, and concentrated in vacuo to give a residue which was diluted with DMSO (0.2 mL) and MeOH (0.8 mL) and purified by reverse phase HPLC. The appropriate fractions were collected, basified with NaHCO3 (solid), and concentrated in vacuo. The residue was extracted with CH2Cl2 (3×). The combined extract was dried over Na2SO4 and concentrated in vacuo to give the desired product (0.00234 g, 4.03 μmol, 2.79% yield) as a tan solid. LC/MS (M+H)=552.24.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[C:23]([O-])([O-])=O.[K+].[K+]>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.O1CCOCC1>[Cl:1][C:2]1[C:3]([CH3:23])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Cl)c1
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ncc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1Cl
Temperature: 110 °C
Reaction time: 72 h

Procedure:
5,6-dichloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 43.2, 500 mg, 1.424 mmol), trimethylboroxime (179 mg, 1.424 mmol), Pd(PPh3)4, (165 mg, 0.142 mmol), K2CO3 (295 mg, 2.136 mmol) and dioxane (4069 μL) were added to a vial, which was sealed, evacuated/purged with argon and the RM was stirred at 110° C. for 72 h. The RM was filtered through a pad of Celite®, which was washed with EtOAc. The combined filtrates were evaporated to dryness under reduced pressure and the residue was purified by flash chromatography (Silica gel column, 24 g, cyclohexane/EtOAc-EtOH (9:1)+0.1% NH4OH, gradient from 5% to 25% EtOAc-EtOH (9:1)+0.1% NH4OH) and recrystallized from cyclohexane/EtOAc to afford the title compound as a light yellow solid. UPLC-MS (Condition 1) tR=2.76 min, m/z=331.0 [M+H]+, m/z=329.0 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.64 (s, 3H) 7.39 (d, J=9.05 Hz, 2H) 7.87 (d, J=9.05 Hz, 2H) 8.38 (d, J=1.71 Hz, 1H) 8.94 (d, J=1.96 Hz, 1H) 10.60 (s, 1H).
Reaction SMILES: [H-].[Na+].[CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12])([CH3:5])[CH3:4].[P:13]([Cl:17])(Cl)(Cl)=[S:14]>C1(C)C=CC=CC=1>[P:13]([Cl:17])([O:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[CH:3]([CH3:5])[CH3:4])([O:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[CH:3]([CH3:5])[CH3:4])=[S:14]
Reactant: CC(C)c1ccccc1O
Reactant: S=P(Cl)(Cl)Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)c1ccccc1OP(=S)(Cl)Oc1ccccc1C(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (38.0 g of 80% suspension in mineral oil) was added to a stirred solution of 2-isopropylphenol (139.2 g) and thiophosphoryl chloride (84.5 g) in toluene (500 cm3) at such a rate that the reaction temperature did not rise above 65° C. After stirring for a further 0.5 hr at ambient temperature, the solution was extracted twice with water (250 cm3 portions). separated, dried (MgSO4) and concentrated by distillation of solvents under reduced pressure yielding crude bis(2-isopropylphenyl) chlorothiophosphate, a brown oil (164.2 g); 51P NMR in CDCl3, singlet 53.0 ppm downfield of H3PO4). Of this material, 54.0 g were reacted with ammonia by the procedure of Example 9 yielding crude bis(2-isopropylphenyl)thiophosphoramide) (50.0 g; 31 pNmr, singlet δ=58.8 ppm).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][C:3]1=[O:7].[Li+].[C-:9]#[C:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1>[CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][C:3]1([C:9]#[C:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[OH:7]
Reactant: CC1CCCC1=O
Reactant: [C-]#Cc1ccccc1
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1CCCC1(O)C#Cc1ccccc1
Temperature: 0 °C
Yield: 60 %

Procedure:
2-Methylcyclopentanone (1.96 g, 19.9 mmol), dissolved in 10 mL of freshly distilled THF, was added dropwise via an additional funnel to an ice-bath cooled solution containing 25 mmol of lithium phenylacetylide (25 mL×1.0M) in 10 mL of THF. The reaction mixture during the addition was maintained at 0° C. and also kept under nitrogen purging. The reaction was maintained for an additional 2 hours at 0° C. and thenstirred at room temperature for 18 hour. The THF solution was quenched by ice water mixture containing excess amounts of NH4Cl. The aqueous solution was extracted by diethyl ether (2×75 mL). The ether layer was washed with water (3×50 mL) and dried with MgSO4. Accordingto GC analysis the conversion to the product was 80%. The product was isolated by means of silica gel column chromatography (40-140 mesh). The unreacted keetone was eluted as the first fraction with hexanes. The second fraction gave the product with diethyl ether as the eluant. After acomplete solvent evaporation under vacuum, a solid was obtained in 60% yield (2.37 g). The product was characterized by spectroscopy: 1H-NMR (CDCl3) δ61.14 (d, 3H), 1.43 (m, 1H), 1.80 (m, 2H), 2.13 (m, 4H), 7.31 (m, 3H), 7.44 (m, 2H); IR (nujol) 3300 (s), 1600 (m), 1450 (s), 1425 (m), 1400 (w), 1190 (m), 1070 (s), 1040 (s), 950 (m), 910 (m), 750 (s), 690 (s) cm-1 ; MS m/z (rel. int.) Isomer A, 200 (M+, 12), 185 (M-CH3, 23), 182 (16), 171 (100), 167 (14), 1676 (12), 165 (15), 157 (12), 155 (18), 153 (16), 152 (13), 143 (20), 142 (15), 141 (49), 139 (10), 129 (69), 128 (65), 127 (24), 115 (56), 91 (29), 101 (11), 77 (22); Isomer B, 200 (M+, 17), 157 (50), 144 (39), 143 (14), 130 (17), 129 (100),117 (14), 115 (38), 102 (19), 91 (17), 77 (18); HR mass: Calcd; 200.1201. Found; 200.1603.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH3:19])[CH:13]=2)=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.C([N-]C(C)C)(C)C.[Li+].Br[CH2:29][CH2:30][CH2:31][S:32][C:33]1[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=1>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:9]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH3:19])[CH:13]=2)=[O:11])[CH2:29][CH2:30][CH2:31][S:32][C:33]2[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: Cc1ccc(C(=O)Cc2cc(F)cc(F)c2)cc1C
Reactant: COC(=O)c1ccc(SCCCBr)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(SCCCC(C(=O)c2ccc(C)c(C)c2)c2cc(F)cc(F)c2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 47.6 %

Procedure:
A sample of 2-(3,5-difluorophenyl)-1-(3,4-dimethylphenyl)ethanone [CAS 1450736-61-4] (5.0 g, 19.2 mmole) was dissolved in THF and cooled to −78° C. Lithium diisopropyl amide (10.6 mL, 1.1 eq.) was added dropwise and the resulting mixture was stirred for 30 minutes. A solution of methyl 4-[(3-bromopropyl)thio]benzoate [CAS 134520-57-3] (6.1 g, 1.1 eq) in THF was then added dropwise and the reaction mixture was allowed to stir overnight. It was then refluxed at 90° C. overnight. The reaction mixture was cooled to room temperature, then to 0° C. after which it was quenched with 1M HCl to pH 2. The resulting mixture was extracted with EtOAc (3×100 mL) and the combined organic layers were washed with saturated NaCl, dried with MgSO4, filtered, concentrated and purified by MPLC to give 4.28 g (48%) of Intermediate
Reaction SMILES: [NH2:1][CH:2]1[C:24](=[O:25])[N:4]2[C:5]([C:21]([OH:23])=[O:22])=[C:6]([CH2:9][S:10][C:11]3[N:15]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])[N:14]=[N:13][N:12]=3)[CH2:7][S:8][C@H:3]12.[CH2:26]([O:29][N:30]=[C:31]([C:35]1[N:36]=[C:37]([NH:40][C:41](=[O:46])[C:42]([F:45])([F:44])[F:43])[S:38][CH:39]=1)[C:32](O)=[O:33])[C:27]#[CH:28].C[N+](C)=CCl.[Cl-].P(Cl)(Cl)(Cl)=O>CN(C)C=O>[CH2:26]([O:29][N:30]=[C:31]([C:35]1[N:36]=[C:37]([NH:40][C:41](=[O:46])[C:42]([F:45])([F:43])[F:44])[S:38][CH:39]=1)[C:32]([NH:1][CH:2]1[C:24](=[O:25])[N:4]2[C:5]([C:21]([OH:23])=[O:22])=[C:6]([CH2:9][S:10][C:11]3[N:15]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])[N:14]=[N:13][N:12]=3)[CH2:7][S:8][C@H:3]12)=[O:33])[C:27]#[CH:28]
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CCC(=O)O)CS[C@H]12
Reactant: C#CCON=C(C(=O)O)c1csc(NC(=O)C(F)(F)F)n1
Agent: C[N+](C)=CCl
Agent: [Cl-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: C#CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CCC(=O)O)CS[C@H]12)c1csc(NC(=O)C(F)(F)F)n1
Yield: 87.1 %

Procedure:
7-Amino-3-[1-(2-carboxyethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (1.93 g) and 2-(2-propynyloxyimino)-2-[2-(2,2,2-trifluoroacetamido)thiazol-4-yl]acetic acid (syn isomer) (1.61 g) were reacted in the presence of Vilsmeier reagent prepared from dimethylformamide and phosphorus oxychloride to give 7-[2-(2-propynyloxyimino)-2-{2-(2,2,2-trifluoroacetamido)thiazol-4-yl}acetamido]-3-[1-(2-carboxyethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer)(3.0 g).
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH2:14][CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][N:20]([C:23]4(SC)[N:28]=[CH:27][C:26]([F:29])=[CH:25][NH:24]4)[CH2:19][CH2:18]3)[O:13][CH2:12][CH2:11][O:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C>[Ni].O.CCO>[ClH:1].[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH2:14][CH2:15][CH2:16][N:17]3[CH2:18][CH2:19][N:20]([C:23]4[N:24]=[CH:25][C:26]([F:29])=[CH:27][N:28]=4)[CH2:21][CH2:22]3)[O:10][CH2:11][CH2:12][O:13]2)=[CH:5][CH:4]=1
Reactant: CSC1(N2CCN(CCCC3(c4ccc(F)cc4)OCCO3)CC2)N=CC(F)=CN1
Agent: [Ni]
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: Fc1ccc(C2(CCCN3CCN(c4ncc(F)cn4)CC3)OCCO2)cc1
Yield: 23.9 %

Procedure:
1-[3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl]-4-(5-fluoro-2-methylthio-2-pyrimidinyl)piperazine hydrochloride (7.45 g, 0.0.17 mole), triethylamine (3.05 g, 0.034 mole) and 2 teaspoons of Raney Nickel in water were mixed in EtOH (125 mL) and refluxed 18 h. The hot reaction mixture was filtered and the filtrate was concentrated in vacuo to about 1/5 volume. A crude crystalline product was obtained by filtration and its recrystallization from 20-25 mL EtOH gave 1.6 g of solid, m.p. 220°-222° C. This solid was converted to the hydrochloride salt in EtOH using ethanolic HCl. Filtration and drying gave 1.6 g of product, m.p. 242°-244° C.
Reaction SMILES: ClC1C(OCC2(C(F)(F)F)CCCCC2)=C[C:5](F)=[C:6]([CH:14]=1)C(OC(C)(C)C)=O.Cl[C:29]1[C:30]([O:43][CH2:44][CH:45]2[CH2:50][CH2:49][CH2:48][C:47]([CH3:52])([CH3:51])[CH2:46]2)=[CH:31][C:32]([F:42])=[C:33]([CH:41]=1)[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35]>>[CH:14]1([C:29]2[C:30]([O:43][CH2:44][CH:45]3[CH2:50][CH2:49][CH2:48][C:47]([CH3:52])([CH3:51])[CH2:46]3)=[CH:31][C:32]([F:42])=[C:33]([CH:41]=2)[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:6][CH2:5]1
Reactant: CC1(C)CCCC(COc2cc(F)c(C(=O)OC(C)(C)C)cc2Cl)C1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(OCC2(C(F)(F)F)CCCCC2)cc1F
Product: CC1(C)CCCC(COc2cc(F)c(C(=O)OC(C)(C)C)cc2C2CC2)C1

Procedure:
Following the procedure as described in Example 158 step 3 and making variations as required to replace tert-butyl 5-chloro-2-fluoro-4-((1-(trifluoromethyl)-cyclohexyl)methoxy)benzoate with tert-butyl 5-chloro-4-((3,3-dimethylcyclohexyl)-methoxy)-2-fluorobenzoate, the title compound was obtained as colorless oil (2.45 g, 75%): MS (ES+) m/z 399.2 (M+23).
Reaction SMILES: C(OC([N:8]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:25]=[C:24]([C:26]3[CH:31]=[CH:30][C:29]([C:32]4[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=4)=[CH:28][CH:27]=3)[O:23][N:22]=2)=[CH:17][CH:16]=1)[CH2:9][C:10]([O:12][CH3:13])=[O:11])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:38][C:35]1[CH:34]=[CH:33][C:32]([C:29]2[CH:28]=[CH:27][C:26]([C:24]3[O:23][N:22]=[C:21]([C:18]4[CH:19]=[CH:20][C:15]([CH2:14][NH:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:16][CH:17]=4)[N:25]=3)=[CH:31][CH:30]=2)=[CH:37][CH:36]=1
Reactant: COC(=O)CN(Cc1ccc(-c2noc(-c3ccc(-c4ccc(C)cc4)cc3)n2)cc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)CNCc1ccc(-c2noc(-c3ccc(-c4ccc(C)cc4)cc3)n2)cc1
Yield: 65 %

Procedure:
Prepared using General Procedure 8. To a stirring solution of methyl 2-((tert-butoxycarbonyl)(4-(5-(4′-methyl-[1,1′-biphenyl]-4-yl)-1,2,4-oxadiazol-3-yl)benzyl)amino)acetate INT-76 (518 mg, 1.01 mmol) in DCM (10 mL) was added TFA (1 mL) at room temperature. After 2 h the reaction mixture was evaporated to dryness. The crude product was purified by chromatography, eluting with 0.7 M ammonia in MeOH/DCM. The mixture was concentrated in vacuo to afford 272 mg (65%) of methyl 2-((4-(5-(4′-methyl-[1,1′-biphenyl]-4-yl)-1,2,4-oxadiazol-3-yl)benzyl)amino)acetate INT-77 as a white solid. LCMS-ESI (m/z) calculated for C25H23N3O3: 413; found 414 [M+H]+, tR=1.89 min (Method 10). Compound 495 was prepared from INT-77 and INT-23 using General Procedures 6 then 9. Compound 498 was prepared from INT-77 and INT-15 using General Procedures 6 then 9.
Reaction SMILES: CS(C)=O.[F:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[N+:22]([O-:24])=[O:23])=[CH:16][CH:15]=2)=[N:10][CH:11]=1.[BH4-].[Na+]>C(O)(=O)C>[F:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][N+:22]([O-:24])=[O:23])=[CH:16][CH:15]=2)=[N:10][CH:11]=1
Reactant: O=[N+]([O-])/C=C/c1ccc(COc2ccc(F)cn2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: O=[N+]([O-])CCc1ccc(COc2ccc(F)cn2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.7 %

Procedure:
To a dimethyl sulfoxide (49 mL) solution of 5-fluoro-2-(4-((E)-nitro-vinyl)benzyloxy)-pyridine (2.9 g, 10.6 mmol) described in Manufacturing Example 56-1-3 and acetic acid (2.9 mL) was added sodium borohydride (642 mg, 17 mmol) at room temperature while cooling appropriately. This mixture was stirred for 1 hour at room temperature. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH-silica gel column chromatography (heptane:ethyl acetate=10:1) to obtain the title compound (1.63 g, 56%).
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=[CH:4][NH:3]1.S(=O)(=O)(O)O.[CH:16]1C=CC=CC=1>CO>[O:1]=[C:2]1[C:7]([C:8]([O:10][CH3:16])=[O:9])=[CH:6][CH:5]=[CH:4][NH:3]1
Reactant: c1ccccc1
Reactant: O=C(O)c1ccc[nH]c1=O
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1ccc[nH]c1=O

Procedure:
A mixture containing 27.8 g of 1,2-dihydro-2-oxo-3-pyridinecarboxylic acid, 3.0 ml of concentrated sulfuric acid in 500 ml of methanol, and 300 ml of benzene are heated under reflux for 2.5 hours. A Dean-Stark trap is then attached, and the azeotrope collected is removed periodically in 25 ml fractions over a period of 28 hours. The remaining solvent is removed by evaporation under reduced pressure and the solid residue suspended in 500 ml of cold water. The suspension is filtered (from which unreacted starting material can be recovered) and the filtrate continuously extracted with methylene chloride. The extracts are concentrated under reduced pressure to yield the title compound as a white solid which, upon recrystallization from,,l 4 L..of benzene, yields 19.48 g (64%) of methyl 2-oxo-1,2-dihydro 3-pyridinecarboxylate: m.p. 148°-151° C.; NMR (DMSO-d6, 80 MHz) delta 3.72 (s, 3H), 6.25 (dd, 1H, J=7.1 Hz, J=6.3 Hz), 7.64 (dd, 1H, J=6.3 Hz, J=2.2 Hz), 8.03 (dd, 1H, J=7.1 Hz, J=2.2 Hz).
Reaction SMILES: C([O-])(=O)C.[NH4+].Cl.[CH2:7]([O:9][C:10]1[C:15]([NH2:16])=[C:14]([O:17][CH2:18][CH3:19])[C:13]([NH2:20])=[CH:12][C:11]=1[Cl:21])[CH3:8].O.C(N(CC)CC)C>[Pd].C(O)C.C(O)=O>[ClH:21].[NH2:16][C:15]1[C:14]([O:17][CH2:18][CH3:19])=[C:13]([NH2:20])[CH:12]=[CH:11][C:10]=1[O:9][CH2:7][CH3:8]
Reactant: CCOc1c(N)cc(Cl)c(OCC)c1N
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O=CO
Solvent: O
Product: CCOc1ccc(N)c(OCC)c1N
Temperature: 70 °C

Procedure:
The mixture consisting of 7.7 g of ammonium acetate, 3.8 g of 10% palladium on charcoal, 0.025 mole (7.6 g) of 2,4-diethoxy-3,5-diaminochlorobenzene hydrochloride in 42 ml of ethanol containing 5 ml of water was heated to 70° C. with stirring. 7.5 g of triethylamine were added and then, 3.1 g of formic acid were added dropwise. After 20 additional minutes of heating at 80° C., the reaction mixture was filtered while hot. The filtrate was evaporated to dryness. Upon addition of ethyl acetate, the inorganic salts were precipitated and removed by filtration. 10 ml of a 7N alcoholic solution of hydrochloric acid were added to the filtrate which was dried over sodium sulphate. The expected product precipitated; it was recrystallized from a 6N hydrochloric acid solution.