Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH:18]1[CH2:22][CH2:21][C:20](=[O:23])[O:19]1)[CH2:10][C@H:11]([CH3:17])[CH2:12][CH2:13]C(O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.O>C1C=CC=CC=1.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH:18]1[CH2:22][CH2:21][C:20](=[O:23])[O:19]1)[CH2:10][CH:11]([CH3:17])[CH:12]=[CH2:13])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](CCC(=O)O)CC(NC(=O)OC(C)(C)C)C1CCC(=O)O1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: O
Solvent: c1ccccc1
Product: C=CC(C)C[C@H](NC(=O)OC(C)(C)C)C1CCC(=O)O1
Temperature: 25 °C

Procedure:
A mixture of 2.19 g (6.67 mmol) (R)-6-tert-butoxycarbonylamino-4-methyl-6-(5-oxo-tetra-hydro-furan-2-yl)-hexanoic acid, 0.293 g (1.46 mmol) copper(II)acetate monohydrate, 0.2 ml pyridine and 5.4 g (12.0 mmol) Pb(OAc)4 in 45 ml benzene is refluxed under nitrogen for 18 h. The mixture is cooled to rt, water is added and the organic phase is washed with water and 5% aqueous NaHCO3. The organic phase is dried with Na2SO4, filtered and evaporated. The residue is purified by chromatography on silica gel (EtOAc/hexane 1:6 and 1:4) to yield the title compound.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[C:7]1(OB(O)O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>C1(C)C=CC=CC=1>[C:7]1([C:2]2[S:3][CH:4]=[CH:5][N:6]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: OB(O)Oc1ccccc1
Reactant: Brc1nccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: c1ccc(-c2nccs2)cc1
Yield: 67.2 %

Procedure:
2-Bromothiazole (1.2 mmol, 0.11 mL) and phenylboric acid (1.2 mmol, 0.146 g) were added to a solution of potassium carbonate (2M, 1.2 mL) and ethanol (0.6 mL) in deoxygenated toluene (12 mL). The resulting mixture was degassed for 30 minutes, then tetrakistriphenylphosphine palladium (0.036 mmol, 0.042 g) was added and the solution heated at reflux for 48 hours. The solids were removed by filtration and the solution extracted with toluene (5x), dried (MgSO4), filtered and concentrated. The residue was subjected to flash chromatography (hexane followed with 5% ethyl acetate/hexane and then 10% ethyl acetate/hexane) to afford 0.13 g (69%) of 2-phenylthiazole.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:8]([F:9])=[C:7](F)[N:6]=[C:5]([F:11])[C:4]=1[F:12].O.[NH2:14][NH2:15]>C(O)C>[OH:1][CH2:2][C:3]1[C:8]([F:9])=[C:7]([NH:14][NH2:15])[N:6]=[C:5]([F:11])[C:4]=1[F:12]
Reactant: NN
Reactant: OCc1c(F)c(F)nc(F)c1F
Solvent: CCO
Solvent: O
Product: NNc1nc(F)c(F)c(CO)c1F

Procedure:
To a solution of 1.0 g (0.0055 mole) of 4-hydroxymethyl-2,3,5,6-tetrafluoropyridine (from Example 5) in 50 ml of ethanol was added 0.2 g (0.004 mole) of hydrazine hydrate. This mixture was stirred for approximately twenty-four hours during which a white precipitate formed. The reaction mixture was filtered, and the filtrate was concentrated by evaporating the solvent under reduced pressure. Water and ether were added to this residue. The ether layer was separated, dried, and the solvent evaporated, leaving a yellow solid, (4-hydroxymethyl-2,3,5-trifluoropyridin-6-yl)hydrazine. The structure and nmr data are set forth in Table 1C.
Reaction SMILES: [C:1]([CH:3]1[CH2:5][CH:4]1[C:6]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][O:20][CH2:21][O:22][CH3:23])[CH:14]=1)=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])#[N:2]>C(OCC)(=O)C.[Pd]>[C:1]([CH:3]1[CH2:5][CH:4]1[CH:6]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][O:20][CH2:21][O:22][CH3:23])[CH:14]=1)[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])#[N:2]
Reactant: CCOC(=O)C=C(c1cccc(COCOC)c1)C1CC1C#N
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(c1cccc(COCOC)c1)C1CC1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.1 %

Procedure:
To a solution of ethyl 3-(2-cyanocyclopropyl)-3-(3-((methoxymethoxy)methyl)phenyl)acrylate (490 mg) obtained in Example 86, step 4, in ethyl acetate (8 mL) was added 10% palladium-activated carbon (100 mg) and, under a hydrogen atmosphere, the mixture was stirred at room temperature for 1 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a crude product (459 mg) of the title compound as a colorless oil. This compound was used for the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[O:13][N:12]=[C:11]([C:14]([O-:16])=O)[N:10]=1.Cl.[Cl:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH:23]=[C:22]2[CH2:28][CH2:29][NH2:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C1COCC1.[OH-].[Na+].O.CN(C=O)C>[Cl:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH:23]=[C:22]2[CH2:28][CH2:29][NH:30][C:14]([C:11]1[N:10]=[C:9]([C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[F:1])[O:13][N:12]=1)=[O:16]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: O=C([O-])c1noc(-c2cc(F)ccc2F)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1noc(-c2cc(F)ccc2F)n1
Yield: 12.2 %

Procedure:
This compound was prepared according to method F with 5-(2,5-difluorophenyl)-1,2,4-oxadiazole-3-carboxylate (0.075 g; 0.346 mmol) in THF (1 mL) and sodium hydroxide in water (2M, 1 mL); 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.080 g; 0.346 mmol), HATU (0.131 g; 0.346 mmol), N,N diisopropylethylamine (0.149 mL; 0.865 mmol), in DMF (4 mL). The crude mixture was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) and preparative HPLC method 2 to yield 0.017 g (12%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-(2,5-difluorophenyl)-1,2,4-oxadiazole-3-carboxamide as a white solid.
Reaction SMILES: CS(O[C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][C:8]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])([CH2:9]3)[CH2:7]1)[CH2:13]2)(=O)=O.[NH2:24][C:25]1[N:30]=[CH:29][CH:28]=[CH:27][N:26]=1>>[C:20]([O:19][C:17](=[O:18])[NH:16][C:8]12[CH2:14][CH:12]3[CH2:11][CH:10]([CH2:15][C:6]([NH:24][C:25]4[N:30]=[CH:29][CH:28]=[CH:27][N:26]=4)([CH2:13]3)[CH2:7]1)[CH2:9]2)([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)NC12CC3CC(C1)CC(OS(C)(=O)=O)(C3)C2
Reactant: Nc1ncccn1
Product: CC(C)(C)OC(=O)NC12CC3CC(C1)CC(Nc1ncccn1)(C3)C2
Reaction time: 0.25 h

Procedure:
The mixture of 1.04 g (3 mmole) of 3-[(tert-butoxycarbonyl)amino]-1-adamantyl methanesulphonate and 1.0 g (10.5 mmole) 2-aminopyrimidine are melted at 140° C. After 15 minutes of stirring the melt is cooled down and purified by column chromatography (n-hexane—ethyl acetate—chloroform 2:1: 1). The product is white crystalline material, 0.7 g (68%). Mp.: 163-165° C. 1H-NMR (DMSO-d6): 1.36 (s, 9H), 1.52 (s, 2H), 1.71 (d, 2H), 1.86 (d, 4H), 2.07 (m, 4H), 2.25 (m, 2H), 6.38 (s, 1H), 6.49 (t, 3H), 6.58 (s, 1H), 8.22 (d, 2H).
Reaction SMILES: C(N(CC)CC)C.Br[C:9]1[CH:10]=[C:11]([C@:15]([C@@H:23]2[CH2:28][CH2:27][CH2:26][N:25]([C:29]([NH:31][C@H:32]([CH2:40][N:41]([CH3:51])[C:42]([O:44][CH2:45][CH2:46][Si:47]([CH3:50])([CH3:49])[CH3:48])=[O:43])[CH2:33][CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[O:30])[CH2:24]2)([OH:22])[CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH3:21])[CH:12]=[CH:13][CH:14]=1.[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].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.CN(C=O)C.CO>[CH:34]1([CH2:33][C@H:32]([NH:31][C:29]([N:25]2[CH2:26][CH2:27][CH2:28][C@@H:23]([C@@:15]([C:11]3[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=3)[C:42]([O:44][CH3:45])=[O:43])([OH:22])[CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH3:21])[CH2:24]2)=[O:30])[CH2:40][N:41]([CH3:51])[C:42]([O:44][CH2:45][CH2:46][Si:47]([CH3:48])([CH3:50])[CH3:49])=[O:43])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: COCCCC[C@@](O)(c1cccc(Br)c1)[C@@H]1CCCN(C(=O)N[C@@H](CC2CCCCC2)CN(C)C(=O)OCC[Si](C)(C)C)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CN(C)C=O
Product: COCCCC[C@@](O)(c1cccc(C(=O)OC)c1)[C@@H]1CCCN(C(=O)N[C@@H](CC2CCCCC2)CN(C)C(=O)OCC[Si](C)(C)C)C1
Temperature: 70 °C
Reaction time: 8 h
Yield: 53.3 %

Procedure:
Triethylamine (50 μL) was added to a stirred suspension of (3R)-3-((S)-1-(3-bromophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-1-cyclohexyl-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-yl)piperidine-1-carboxamide (21.0 mg, 0.03 mmol), Pd(dppf)Cl2 (5 mg) and Pd(PPh3)4 (5 mg) in 4:1 DMF/MeOH (2 mL). A carbon monoxide atmosphere was established in the reaction vessel and the mixture was stirred at 70° C. overnight. After cooling to ambient temperature, the mixture was extracted with EtOAc (2×5 mL) and the combined organic layers were washed with 1 N aq HCl (2×1 mL) and concentrated. The residue was purified by preparative HPLC to give methyl 3-((S)-1-((R)-1-((S)-1-cyclohexyl-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-ylcarbamoyl)-piperidin-3-yl)-1-hydroxy-5-methoxypentyl)benzoate (5.4 mg, 27%). MS m/z 698 (M+Na+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)(=[O:10])=[O:9])[CH:5]=[C:4](Br)[N:3]=1.[CH3:22][NH2:23]>O1CCOCC1.C(O)C>[Br:1][C:2]1[N:3]=[C:4]([NH:23][CH3:22])[CH:5]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: O=S(=O)(c1cccc(C(F)(F)F)c1)c1cc(Br)nc(Br)c1
Reactant: CN
Solvent: CCO
Solvent: C1COCCO1
Product: CNc1cc(S(=O)(=O)c2cccc(C(F)(F)F)c2)cc(Br)n1
Temperature: 25 °C
Reaction time: 0.3 h
Yield: 81 %

Procedure:
0.222 g (0.0005 mol) of 2,6-dibromo-4-(3-trifluoromethylbenzenesulphonyl)-pyridine was dissolved in 10 ml of dioxane and treated with 1.25 ml of 8M methylamine in ethanol. The mixture was stirred at room temperature for 18 mins., the solvents were then removed and the residue was chromatographed on silica gel with ethyl acetate/hexane 1:19 and subsequently 1:9. There was obtained 0.16 g (81%) of [6-bromo-4-(3-trifluoromethylbenzenesulphonyl) -pyridin-2-yl]-methylamine as yellow crystals; m.p.: 115-117° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)=[O:4].Br[C:15]1[N:19]=[CH:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=2)[N:16]=1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>C(Cl)Cl.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:30][C:27]([F:28])([F:29])[O:26][C:23]1[CH:22]=[CH:21][C:20]([N:17]2[CH:18]=[N:19][C:15]([C:8]3[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=3)=[N:16]2)=[CH:25][CH:24]=1
Reactant: FC(F)(F)Oc1ccc(-n2cnc(Br)n2)cc1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 100 °C
Yield: 52.5 %

Procedure:
A microwave vial was charged with (4-(methoxycarbonyl)phenyl)boronic acid (70.1 mg, 0.390 mmol), 3-bromo-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (100 mg, 0.325 mmol), aqueous Na2CO3 (1 M, 1.298 mL, 1.298 mmol), and Pd(PPh3)4 (37.5 mg, 0.032 mmol). The reaction vial was capped and evacuated/backfilled with nitrogen gas (3×). DME (2 mL) was added, the vial was capped, heated at 100° C. for 15 minutes (min) in a Biotage Initiator® microwave reactor with external IR-sensor temperature monitoring from the side of the vessel. The reaction mixture was cooled to RT, and diluted with CH2Cl2 (3 mL) and water. The organic and aqueous phase was separated with a phase separator, and the organics were concentrated in vacuo. Purification via flash column chromatography using EtOAc/hexanes as eluent yielded the title compound as a white solid (62 mg, 52%): 1H NMR (400 MHz, CDCl3) δ 8.60 (s, 1H), 8.28 (m, 2H), 8.15 (m, 2H), 7.81 (m, 2H), 7.41 (m, 2H), 3.96 (s, 3H); 19F NMR (376 MHz, CDCl3) δ −58.02; ESIMS m/z 364 ([M+H]+).
Reaction SMILES: CC1(C)[O:6][C:5](=[CH:7][C:8]([N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[O:11][CH3:12])=[O:9])[C:4](=[O:21])O1.[CH3:23][N:24]1[C:28]([C:29]([F:32])([F:31])[F:30])=[CH:27][C:26]([C:33]2[S:37][C:36]([S:38]([NH2:41])(=[O:40])=[O:39])=[CH:35][CH:34]=2)=[N:25]1>>[F:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][N:10]([O:11][CH3:12])[C:8](=[O:9])[CH:7]=[C:5]([OH:6])[C:4]([NH:41][S:38]([C:36]2[S:37][C:33]([C:26]3[CH:27]=[C:28]([C:29]([F:31])([F:30])[F:32])[N:24]([CH3:23])[N:25]=3)=[CH:34][CH:35]=2)(=[O:40])=[O:39])=[O:21])=[CH:19][CH:18]=1
Reactant: Cn1nc(-c2ccc(S(N)(=O)=O)s2)cc1C(F)(F)F
Reactant: CON(Cc1ccc(F)cc1)C(=O)C=C1OC(C)(C)OC1=O
Product: CON(Cc1ccc(F)cc1)C(=O)C=C(O)C(=O)NS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)n(C)n2)s1

Procedure:
2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-benzyl)-N-methoxy-acetamide was treated with 5-(1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl)-thiophene-2-sulfonic acid amide as described in the preparation of compound 1 to yield the title compound. 1H NMR (500 MHz, CDCl3) δ: 3.66 (s, 3), 4.03 (s, 3), 4.76 (s, 2), 6.50 (s, 1), 6.71 (s, 1), 7.00 (m, 2), 7.20 (m, 1), 7.25 (m, 2), 7.93 (m, 1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1.[C:19]([NH2:22])(=[S:21])[CH3:20]>>[CH3:1][O:2][C:3]([C:4]1[N:22]=[C:19]([CH3:20])[S:21][C:5]=1[C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1)=[O:18]
Reactant: COC(=O)C(=O)C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: CC(N)=S
Product: COC(=O)c1nc(C)sc1-c1ccc(C(F)(F)F)cc1

Procedure:
prepared by reaction of 3-chloro-3-(4-trifluoromethyl-phenyl)-2-oxo-propionic acid methyl ester with thioacetamide. LC-MS: tR=0.99 min; [M+H]+=301.99.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:5](=[C:7]([CH2:11][OH:12])[CH:8]=[CH:9][CH:10]=2)[CH:6]=1.CS(C)=O.C(Cl)(=O)C(Cl)=O>C(N(CC)CC)C>[CH3:1][C:2]1[O:3][C:4]2[C:5](=[C:7]([CH:11]=[O:12])[CH:8]=[CH:9][CH:10]=2)[CH:6]=1
Reactant: Cc1cc2c(CO)cccc2o1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1cc2c(C=O)cccc2o1
Yield: 93.4 %

Procedure:
2-Methyl-benzofuran-4-methanol (3.34 g, 21 mmol) was oxidized using DMSO, oxalyl chloride, and triethyl amine similar to the above procedures to give the product as a clear oil (3.14 g, 93%).
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([N:12]1[CH2:16][C@@H:15]([CH2:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[O:14][C:13]1=[O:26])[CH3:11])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[Cl:25][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[O:18][CH2:17][C@H:15]1[O:14][C:13](=[O:26])[N:12]([C@@H:10]([CH3:11])[CH2:9][OH:8])[CH2:16]1
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)N1C[C@@H](COc2cccc(Cl)c2)OC1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@@H](CO)N1C[C@@H](COc2cccc(Cl)c2)OC1=O
Yield: 59.5 %

Procedure:
A procedure similar to that described in Preparation 5(b) was repeated, except that 2.00 g of 3-[2-t-butyldimethylsilyloxy-1(S)-methylethyl]-5(S)-(3-chlorophenoxymethyl)oxazolidin-2-one (prepared as described in Preparation 39), 15 ml of tetrabutylammonium fluoride (26% w/v in tetrahydrofuran) and 20 ml of anhydrous tetrahydrofuran were used, to give 0.85 g of the title compound, melting at 67° C. to 70° C. and having [α]D =+57.0° (methanol, c=1.055).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.Br[CH2:11][CH:12]1[CH2:17][CH2:16][Si:15]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])(C2C=CC=CC=2)[CH2:14][CH2:13]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:11][C@H:12]2[CH2:17][CH2:16][Si@H:15]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:14][CH2:13]2)=[C:4]([F:9])[CH:3]=1
Reactant: Oc1ccc(Cl)cc1F
Reactant: CCCCCCC[Si]1(c2ccccc2)CCC(CBr)CC1
Product: CCCCCCC[Si@H]1CC[C@H](COc2ccc(Cl)cc2F)CC1

Procedure:
The general procedure of Example 9 was repeated using 4-chloro-2-fluorophenol and 4-bromomethyl-1-n-heptyl-1-phenyl-1-silacyclohexane, thereby obtaining the intended compound.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([SH:8])=[CH:6][CH:7]=1.Cl.Cl[CH2:11][C:12]1[N:16]([CH2:17][CH2:18][CH3:19])[CH:15]=[N:14][N:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:1][C:2]1[N:3]=[N:4][C:5]([S:8][CH2:11][C:12]2[N:16]([CH2:17][CH2:18][CH3:19])[CH2:15][NH:14][N:13]=2)=[CH:6][CH:7]=1
Reactant: CCCn1cnnc1CCl
Reactant: Nc1ccc(S)nn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCN1CNN=C1CSc1ccc(N)nn1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 84.5 %

Procedure:
3-amino-6-mercaptopyridazine (0.5 g), 3-chloromethyl-4-propyl-4H-1,2,4-triazole hydrochloride (0.57 g) and potassium carbonate (0.8 g) were added to N,N-dimethylformamide (5 ml), and the mixture was stirred for 4.5 hours at room temperature. The solvent was distilled off, and to the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by basic silica gel column chromatography (elution solvent: methanol/ethyl acetate), to give 3-amino-6-[(4-propyl-1H-1,2,4-triazol-3-yl)methylthio]pyridazine (0.62 g) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH2:9][O:10][C:11]2[CH:16]=[C:15]([CH:17]([CH3:19])[CH3:18])[CH:14]=[CH:13][C:12]=2[CH3:20])=[C:4]([CH3:21])[N:3]=1.[CH3:22][O-:23].[Na+]>CO>[Cl:1][C:2]1[N:7]=[C:6]([O:23][CH3:22])[C:5]([CH2:9][O:10][C:11]2[CH:16]=[C:15]([CH:17]([CH3:19])[CH3:18])[CH:14]=[CH:13][C:12]=2[CH3:20])=[C:4]([CH3:21])[N:3]=1
Reactant: C[O-]
Reactant: Cc1ccc(C(C)C)cc1OCc1c(C)nc(Cl)nc1Cl
Agent: [Na+]
Solvent: CO
Product: COc1nc(Cl)nc(C)c1COc1cc(C(C)C)ccc1C
Reaction time: 1 h

Procedure:
A solution of ˜70% 2,4-dichloro-5-(5-isopropyl-2-methyl-phenoxymethyl)-6-methyl-pyrimidine (2.64 g, ˜5.68 mmol) is cooled to −5° C. under nitrogen with magnetic stirring. A 0.5 M solution of NaOMe in MeOH (11.4 mL) is added in rapid dropwise fashion. After 1 h, reaction is complete based on LC/MS analysis. The reaction mixture is evaporated at reduced pressure, diluted with DCM (15 mL), filtered and evaporated to obtain a pale yellow oil consisting of an isomeric mixture of mono-methoxy adducts. Purification on silica gel (10-60% EtOAc/Hexanes) provides a colorless oil containing the desired isomer. (first to elute) plus impurity from the starting material. 1H NMR (400 MHz, CDCl3) δ 7.06 (d, J=8 Hz, 1H), 6.82 (s, 1H), 6.78 (d, J=8 Hz, 1H), 5.05 (s, 2H), 4.04 (s, 3H), 2.80 (m, 1H), 2.55 (s, 3H), 2.13 (s, 3H), 1.26 (d, J=6.8 Hz, 6H); LC-MS found 321.1 (MH+), rt=1.73 min, Method 2.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[OH:15][C:16]1[CH:17]=[CH:18][C:19]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[C:20]([CH:30]=1)[C:21]([NH:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)=[O:22].[CH3:39][N:40]1[CH2:45][CH2:44][CH:43](O)[CH2:42][CH2:41]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1>[CH3:39][N:40]1[CH2:45][CH2:44][CH:43]([O:15][C:16]2[CH:17]=[CH:18][C:19]([O:31][CH2:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[C:20]([CH:30]=2)[C:21]([NH:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[O:22])[CH2:42][CH2:41]1
Reactant: O=C(Nc1cccnc1)c1cc(O)ccc1OCc1ccccc1
Reactant: CN1CCC(O)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CN1CCC(Oc2ccc(OCc3ccccc3)c(C(=O)Nc3cccnc3)c2)CC1
Temperature: 115 °C
Reaction time: 8 h

Procedure:
A solution of DIAD (0.30 ml, 1.56 mmol) in toluene (1 ml) was added dropwise to a solution of 5-hydroxy-2-[(phenylmethyl)oxy]-N-3-pyridinylbenzamide (may be prepared as described in Example 29; 200 mg, 0.624 mmol), 1-methyl-4-piperidinol (79 mg, 0.687 mmol) and Ph3P (409 mg, 1.561 mmol) in toluene under nitrogen at 0° C. The reaction mixture was stirred at 115° C. overnight. The mixture was then cooled and concentrated. The residue was added to water and extracted with ethyl acetate (3×60 ml). The organic phase was washed with saturated brine (30 ml), dried over sodium sulphate and evaporated in vacuo to give the crude product. The crude product was purified by Pre-TCL (DCM:methanol=8:1) to yield the title compound as a yellow solid. 36 mg.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][CH2:5][C@@H:4]1[C:13]1[CH:25]=[CH:24][C:16]([CH2:17][N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[CH:15][CH:14]=1.[CH3:26][O:27][C:28](=[O:37])[C:29]1[CH:34]=[CH:33][C:32]([CH:35]=O)=[CH:31][CH:30]=1.C([BH3-])#N.[Na+].CCN(C(C)C)C(C)C>CO.C(O)(=O)C>[CH3:26][O:27][C:28](=[O:37])[C:29]1[CH:34]=[CH:33][C:32]([CH2:35][N:21]2[CH2:20][CH2:19][N:18]([CH2:17][C:16]3[CH:15]=[CH:14][C:13]([C@@H:4]4[O:3][C:8]5[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=5[O:6][CH2:5]4)=[CH:25][CH:24]=3)[CH2:23][CH2:22]2)=[CH:31][CH:30]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: c1ccc2c(c1)OC[C@H](c1ccc(CN3CCNCC3)cc1)O2
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(CN2CCN(Cc3ccc([C@H]4COc5ccccc5O4)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 1-[(S)-4-(2,3-dihydro-benzo[1,4]dioxin-2-yl)-benzyl]-piperazine dihydrochloride (80 mg, 0.21 mmol), 4-formyl-benzoic acid methyl ester (41 mg, 0.25 mmol), sodium cyanoborohydride (26 mg, 0.42 mmol), and DIPEA (0.07 mL, 0.42 mmol) in MeOH (5 mL) is treated with 2 drops of acetic acid. The resulting mixture is stirred at room temperature for 16 h, concentrated, diluted with water, and extracted with ethyl acetate. The organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated. The residue is purified by flash chromatography eluting with a gradient of 0-10% MeOH in DCM to give 4-{4-[(S)-4-(2,3-dihydro-benzo[1,4]dioxin-2-yl)-benzyl]-piperazin-1-ylmethyl}-benzoic acid methyl ester.
Reaction SMILES: S1(CCCC1)(=O)=O.P(Cl)(Cl)(Cl)=O.[C:13]([C:15]1[C:16](O)=[C:17]2[C:27]3[CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23][C:22]=3[S:21][C:18]2=[N:19][CH:20]=1)#[N:14].[Cl-:36].[Na+]>C(N(CC)CC)C>[Cl:36][C:16]1[C:15]([C:13]#[N:14])=[CH:20][N:19]=[C:18]2[S:21][C:22]3[CH2:23][N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:25][CH2:26][C:27]=3[C:17]=12
Reactant: [Cl-]
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc3ncc(C#N)c(O)c23)C1
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O=P(Cl)(Cl)Cl
Solvent: O=S1(=O)CCCC1
Product: CC(C)(C)OC(=O)N1CCc2c(sc3ncc(C#N)c(Cl)c23)C1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 51 %

Procedure:
To sulfolane (10 mL) was added phosphoryl chloride (1.39 g, 9.05 mmol) at rt. Triethylamine (0.92 g, 9.05 mmol) was added dropwise with cooling. tert-Butyl 3-cyano-4-hydroxy-5,8-dihydrothieno[2,3-b:5,4-c′]dipyridine-7(6H)-carboxylate from Example 52A (1.00 g, 3.02 mol) was added, and the mixture was heated to 70° C. for 1.5 h. The mixture was cooled to rt, and triethylamine (2.3 mL) was added. A semi-saturated aqueous sodium chloride solution (10 L) was added whilst cooling with an ice-bath. The mixture was stirred at rt for 30 min and then extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and the solvent was removed in vacuo. Toluene was added, and the mixture was washed with water. The organic layer was again dried over sodium sulfate, and the solvent was removed in vacuo. After crystallization, the product was triturated with water, collected by suction filtration and dried to yield 543 mg (51%) of the title compound.