Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([F:41])=[C:5]([C@@H:9]2[C@:13]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=3[F:23])([C:14]#[N:15])[C@H:12]([CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[NH:11][C@H:10]2[C:29]([N:31]2[CH2:36][CH2:35][CH:34]([CH2:37][C:38]([OH:40])=O)[CH2:33][CH2:32]2)=[O:30])[CH:6]=[CH:7][CH:8]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[OH:75][CH2:76][CH2:77][NH:78][CH3:79]>C(Cl)Cl>[Cl:2][C:3]1[C:4]([F:41])=[C:5]([C@@H:9]2[C@:13]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=3[F:23])([C:14]#[N:15])[C@H:12]([CH2:24][C:25]([CH3:27])([CH3:28])[CH3:26])[NH:11][C@H:10]2[C:29]([N:31]2[CH2:36][CH2:35][CH:34]([CH2:37][C:38]([N:78]([CH2:77][CH2:76][OH:75])[CH3:79])=[O:40])[CH2:33][CH2:32]2)=[O:30])[CH:6]=[CH:7][CH:8]=1
Reactant: CNCCO
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)N2CCC(CC(=O)O)CC2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCO)C(=O)CC1CCN(C(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of rac {1-[(2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-piperidin-4-yl}-acetic acid hydrochloride salt (80 mg, 0.127 mmol) in methylene chloride (5 mL), HATU (77 mg, 0.28 mmol) and DIPEA (94 uL, 0.54 mmol) were added followed by 2-hydroxy-ethyl-methyl amine (Oakwood, 20 mg, 0.27 mmol) and the mixture was stirred at rt overnight. The reaction was quenched with water and the mixture was extracted with methylene chloride (3×10 mL) and the extracts were combined and dried over sodium sulfate. The solvent was removed and the residue was chromatographed on a reverse phase HPLC (acetonitrile/water, 25-85%) to give a white solid. 46 mg.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][C:11]([OH:13])=[O:12])=[N:2]1.[CH3:14]COCC>CO>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[N:2]1
Reactant: CCOCC
Reactant: O=C(O)Cc1noc2ccccc12
Solvent: CO
Product: COC(=O)Cc1noc2ccccc12

Procedure:
A solution of 1,2-benzisoxazole-3-acetic acid (prepared according to G. Casini et al, J. Het. Chem. 6, 1969, 279) (18 g), ether saturated with dry HCI (150 ml) and methanol (200 ml) was stirred for 2 h at room temperature. Removal of the volatiles in vacuo gave methyl 1,2-benzisoxazole-3-acetate (17 g) as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([OH:34])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br.Br[CH2:37][C:38]1[CH:47]=[C:46]2[C:41]([CH:42]=[CH:43][CH:44]=[N:45]2)=[CH:40][CH:39]=1.[H-].[Na+]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([O:34][CH2:37][C:38]2[CH:47]=[C:46]3[C:41]([CH:42]=[CH:43][CH:44]=[N:45]3)=[CH:40][CH:39]=2)[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: BrCc1ccc2cccnc2c1
Reactant: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2O)cc1
Agent: Br
Agent: [H-]
Agent: [Na+]
Product: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3cccnc3c2)cc1

Procedure:
reacting the product of step c) with 7-bromomethyl-quinoline hydrobromide and sodium hydride to yield (3R,4R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-3-(quinolin-7-yl-methoxy)-piperidine-1-carboxylic acid tert-butylester;
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH2:16])([CH3:4])([CH3:3])[CH3:2].Cl[C:20](Cl)([O:22]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.O>C(Cl)Cl.CCCC(C)C>[C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:9](=[O:17])[C:10]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:16][C:20]1=[O:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CNC(=O)c1ccccc1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCCC(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Cn1c(=O)[nH]c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cooled (<5° C.) solution of (2-amino-benzoylamino)-acetic acid tert-butyl ester (33 g, 0.132 mol) in DCM (200 ml), a solution of triphosgene (14.08 g, 0.047 mol) in DCM (70 ml) is added dropwise over 30 minutes, keeping the temperature below 5° C. The resulting white/cream precipitate is treated dropwise with triethylamine (21 ml, 0.145 mol), keeping the temperature of the reaction below 5° C. The bright yellow reaction mixture is gradually allowed to warm to RT and stirred overnight. Water (250 ml) is added to the reaction mixture with stirring. Mixture is partitioned and the aqueous phase is washed with DCM (100 ml). The organic extracts are combined, washed with NaHCO3 (2×200 ml), water (2×150 ml), brine (200 ml), and concentrated in vacuo to give a pale orange solid. This is then slurried in isohexane for 30 minutes, filtered, then taken up in DCM (90 ml) with heating. The solution is then placed in the fridge over the weekend. The crystalline material formed is filtered and washed with a minimal amount of cold DCM to afford the title compound.
Reaction SMILES: [NH2:1][C:2]([C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[C:3]([C:6]#[N:7])[C:4]#[N:5].P([O-])(OCC)(SCC)=[S:18]>C(O)C.O>[NH2:1]/[C:2](/[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[C:3](/[C:4]#[N:5])\[C:6](=[S:18])[NH2:7]
Reactant: CCOP([O-])(=S)SCC
Reactant: N#CC(C#N)=C(N)c1ccc([N+](=O)[O-])cc1
Solvent: O
Solvent: CCO
Product: N#C/C(C(N)=S)=C(/N)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 94.5 %

Procedure:
A suspension of Example 96C (2.1 g, 9.8 mmol) and 90% diethyl dithiophosphate (1.8 mL, 10.8 mmol) in ethanol (15 mL) and water (15 mL) was heated to reflux for 24 hours, cooled to room temperature, poured into ice water (300 mL), and filtered. The filter cake was dried to provide 2.3 g (95% yield) of the desired product. MS(ESI(−)) m/e 247 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[O:9][CH2:10][CH2:11]Cl)=[CH:4][CH:3]=1.[NH:20]1[CH2:30][CH2:29][CH:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:22][CH2:21]1.C(=O)([O-])[O-].[Na+].[Na+]>[I-].[K+].C(C(C)=O)C(C)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[O:9][CH2:10][CH2:11][N:20]2[CH2:30][CH2:29][CH:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:22][CH2:21]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CCNCC1
Reactant: Fc1ccc(C(OCCCl)c2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: CCOC(=O)C1CCN(CCOC(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Yield: 71.1 %

Procedure:
1.43 g of 1-bis(4-fluorophenyl)methoxy-2-chloroethane and 1.00 g of ethyl isonipecotate were added to 10 ml of methyl isobutyl ketone, and the reaction mixture was then heated under reflux for 5 hours together with 2.0 g of sodium carbonate and 10 mg of potassium iodide. At the end of this time, the mixture was filtered and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by silica gel column chromatography. Elution with a 3:1 by volume mixture of hexane and ethyl acetate afforded 1.45 g (yield 71%) of the title compound as an oily substance.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][N:5]([CH2:7][C:8]([OH:10])=O)[C:4](=[O:11])[CH2:3]1.[NH2:12][CH2:13][C:14]([N:16]1[CH2:20][C:19](=[O:21])[NH:18][C:17]1([CH3:23])[CH3:22])=[O:15].C1CCC(N=C=NC2CCCCC2)CC1>CS(C)=O.O1CCCC1.O>[CH3:22][C:17]1([CH3:23])[NH:18][C:19](=[O:21])[CH2:20][N:16]1[C:14](=[O:15])[CH2:13][NH:12][C:8](=[O:10])[CH2:7][N:5]1[CH2:6][CH:2]([OH:1])[CH2:3][C:4]1=[O:11]
Reactant: O=C(O)CN1CC(O)CC1=O
Reactant: CC1(C)NC(=O)CN1C(=O)CN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CS(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)NC(=O)CN1C(=O)CNC(=O)CN1CC(O)CC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.9 %

Procedure:
Into an ice cold solution of 4-hydroxy-2-oxo-1-pyrrolidineacetic acid (0.95 g) and 1-(2-aminoacetyl)-2,2-dimethyl-4-imidazolidinone (1 g) in dimethylsulfoxide (30 ml) a solution of DCC (1,22 g) in tetrahydrofuran (10 ml) was added dropwise. The solution was stirred at room temperature overnight and then heated at 50° for 4 hours. After cooling the solution was diluted with water and the resulting precipitate was filtered off. The filtrate was evaporated to dryness under vacuum. The residue was dissolved in water and eluted on a column of Amberlite IR 120H (20 ml). The eluate was treated with Amberlite IRA 68 (10 ml), filtered and evaporated under vacuum. The residue was triturated with isopropanol to yield 0.4 g of the title compound, m.p. 227°-229° .
Reaction SMILES: [NH2:1][CH:2]1[CH:7]([OH:8])[CH2:6][CH2:5][CH2:4][CH:3]1[OH:9].C(N(C(C)C)CC)(C)C.[N:19]1([C:25]([NH:27][C@@H:28]([CH2:32][S:33]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)(=[O:35])=[O:34])[C:29](O)=[O:30])=[O:26])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[OH:9][CH:3]1[CH2:4][CH2:5][CH2:6][CH:7]([OH:8])[CH:2]1[NH:1][C:29]([C@@H:28]([NH:27][C:25]([N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)=[O:26])[CH2:32][S:33]([CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)(=[O:35])=[O:34])=[O:30]
Reactant: O=C(O)[C@H](CS(=O)(=O)Cc1ccccc1)NC(=O)N1CCOCC1
Reactant: NC1C(O)CCCC1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NC1C(O)CCCC1O)[C@H](CS(=O)(=O)Cc1ccccc1)NC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 10.7 %

Procedure:
A solution of 2-amino-cyclohexane-1,3-diol (0.55 g) in dimethylformamide (30 ml) was treated with diisopropylethylamine (1.6 ml, 9.2 mmol). After stirring at room temperature for 5 minutes the mixture was treated with (R)-2-[(morpholine-4-carbonyl)-amino]-3-phenylmethanesulfonyl-propionic acid (1.73 g, 4.86 mmol) followed by HATU (1.68 g, 4.42 mmol). This mixture was stirred at room temperature overnight and then evaporated. The residue was subjected to flash chromatography on silica eluting with ethyl acetate and then a mixture of ethyl acetate and methanol to give morpholine-4-carboxylic acid [(R)-1-(2,6-dihydroxy-cyclohexylcarbamoyl)-2-phenylmethanesulfonyl-ethyl]-amide as a white solid (210 mg). MS: 470 (MH+).
Reaction SMILES: C([O:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH:24]([CH3:26])[CH3:25])[N:16]=[CH:17][C:10]=2[N:9]([CH3:32])[C:8]1=[O:33])=O.O.O[Li].O>C1COCC1.CC(=O)OCC>[OH:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH:24]([CH3:26])[CH3:25])[N:16]=[CH:17][C:10]=2[N:9]([CH3:32])[C:8]1=[O:33]
Reactant: CC(C)CCc1c(-c2ccccc2C(C)C)ncc2c1c(=O)n(CCCOC=O)c(=O)n2C
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)CCc1c(-c2ccccc2C(C)C)ncc2c1c(=O)n(CCCO)c(=O)n2C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23.6 %

Procedure:
To a solution of 3-(5-isopentyl-6-(2-isopropylphenyl)-1-methyl-2,4-dioxo-1,2-dihydropyrido[3,4-d]pyrimidin-3(4H)-yl)propyl formate (10 mg, 0.022 mmol in THF (0.5 mL) and water (0.5 mL) was added LiOH.H2O (1.8 mg, 0.044 mmol). The reaction was stirred at RT for 30 min then diluted with EA (5 mL). The organic layer was washed with brine (5 mL), dried over Na2SO4 and concentrated to a residue which was purified by Prep HPLC to give 3-(3-hydroxypropyl)-5-isopentyl-6-(2-isopropylphenyl)-1-methylpyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione (2.2 mg, 23.6% yield) as a white solid. 1H NMR (CDCl3) δ: 8.66 (s, 1H), 7.41 (d, J=3.8 Hz, 2H), 7.26-7.23 (m, 1H), 7.11 (d, J=7.5 Hz, 1H), 4.28 (t, J=6.1 Hz, 2H), 3.72 (s, 3H), 3.65-3.54 (m, 2H), 3.35 (td, J=11.8, 4.5 Hz, 1H), 3.14 (t, J=6.6 Hz, 1H), 2.69 (d, J=11.9, 4.4 Hz, 1H), 2.53-2.40 (m, 1H), 2.04-1.91 (m, 2H), 1.45 (d, J=12.9, 6.4 Hz, 1H), 1.38-1.32 (m, 1H), 1.19 (d, J=6.9 Hz, 3H), 1.14 (dd, J=7.1, 4.8 Hz, 1H), 1.10 (d, J=6.8 Hz, 3H), 0.72 (d, J=6.6 Hz, 3H), 0.65 (d, J=6.6 Hz, 3H). LCMS: MH+ 424 and TR=3.102 min.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:10]([C:11]2[C:16]([CH3:17])=[CH:15][C:14]([O:18][CH2:19][C:20]3([OH:28])[CH2:25][CH2:24][S:23](=[O:27])(=[O:26])[CH2:22][CH2:21]3)=[CH:13][C:12]=2[CH3:29])=[CH:9][C:8]([CH2:30][N:31](S(C2C=CC=CC=2[N+]([O-])=O)(=O)=O)[C:32]2[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=[C:34]([F:45])[CH:33]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].SCC(O)=O.O.[OH-].[Li+]>CN(C)C=O.[Cl-].[Na+].O>[C:1]([NH:4][C:5]1[C:10]([C:11]2[C:16]([CH3:17])=[CH:15][C:14]([O:18][CH2:19][C:20]3([OH:28])[CH2:25][CH2:24][S:23](=[O:26])(=[O:27])[CH2:22][CH2:21]3)=[CH:13][C:12]=2[CH3:29])=[CH:9][C:8]([CH2:30][NH:31][C:32]2[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=[C:34]([F:45])[CH:33]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)CCc1ccc(N(Cc2ccc(NC(C)=O)c(-c3c(C)cc(OCC4(O)CCS(=O)(=O)CC4)cc3C)c2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1F
Agent: O=C(O)CS
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1ccc(NCc2ccc(NC(C)=O)c(-c3c(C)cc(OCC4(O)CCS(=O)(=O)CC4)cc3C)c2)cc1F
Temperature: 25 °C
Reaction time: 72 h
Yield: 91.6 %

Procedure:
To a solution of ethyl 3-(4-{({6-(acetylamino)-4′-[(4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy]-2′,6′-dimethylbiphenyl-3-yl}methyl)[(2-nitrophenyl)sulfonyl]amino}-2-fluorophenyl)propanoate (246 mg, 0.30 mmol) and mercaptoacetic acid (62.6 μL, 0.90 mmol) in N,N-dimethylformamide (2 mL) was added lithium hydroxide monohydrate (75.5 mg, 1.80 mmol), and the mixture was stirred at room temperature for 3 days. Brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=7/3-ethyl acetate) to give the title compound (176 mg, yield 92%) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[Br-].[CH3:14][C:15]1[C:16]([Zn+])=[N:17][CH:18]=[CH:19][CH:20]=1>C1COCC1.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>[CH3:14][C:15]1[C:16]([C:2]2[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5]([C:8]#[N:9])=[N:6][CH:7]=2)=[N:17][CH:18]=[CH:19][CH:20]=1
Reactant: N#Cc1ncc(Br)cc1[N+](=O)[O-]
Reactant: Cc1cccnc1[Zn+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: Cc1cccnc1-c1cnc(C#N)c([N+](=O)[O-])c1
Yield: 87.8 %

Procedure:
Heat a solution of 5-bromo-3-nitropyridine-2-carbonitrile (228 mg, 1.0 mmol), tetrakis(triphenylphosphine)palladium(0) (15 mg), 3-methyl-2-pyridylzinc bromide (0.5 M in THF, 3 mL, 1.5 mmol) in THF (5 mL) to 60° C. for 2 hours. Cool the solution and partition between ethyl acetate (10 mL) and saturated aqueous NaHCO3 (10 mL), Extract the aqueous solution with ethyl acetate (2×15 mL), wash with water (10 mL), brine (10 mL), dry (MgSO4) and evaporate to obtain the title compound as a pale yellow solid (211 mg, 88%).
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH2:7][OH:8])[C@@H:3]([OH:6])[CH2:4][OH:5].O(Cl)Cl.[P+5].CO[CH:16](OC)[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1>ClCCl>[CH3:1][C:2]1([CH3:9])[CH2:7][O:8][CH:16]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[O:6][C@H:3]1[CH2:4][OH:5]
Reactant: CC(C)(CO)[C@@H](O)CO
Reactant: COc1ccc(C(OC)OC)cc1
Agent: ClOCl
Agent: [P+5]
Solvent: ClCCl
Product: COc1ccc(C2OCC(C)(C)[C@H](CO)O2)cc1
Yield: 66.1 %

Procedure:
Following the general procedure for the transacetalization reaction of Description 6, 21.4 g (160.0 mmol) of (2R)-3,3-dimethylbutane-1,2,4-triol (6) was reacted in 400 mL of dichloromethane (DCM) in the presence of 932 μL (1.53 g, 10.0 mmol) of phosphorus(V) oxychloride (POCl3) with 45.6 g (250.0 mmol) of para-anisaldehyde dimethyl acetal. Two-fold purification by silica gel column chromatography using tert-butyl methyl ether (MTBE) and hexane (Hxn) mixtures as eluent (MTBE/Hxn=3:7→MTBE/Hxn=2:3→MTBE/Hxn=1:1→MTBE/Hxn=2:1→MTBE/Hxn=3:1) provided 26.7 g (66% yield) of the title compound (8a) as a pale-yellow liquid. Rf=0.26 (MTBE/Hxn=2:3). 1H NMR (400 MHz, CHCl3): δ=0.86 (s, 3H), 1.16 (s, 3H), 2.01-2.05 (m, 1H), 3.59-3.3.63 (m, 1H), 3.66-3.73 (m, 4H), 3.82 (s, 3H), 5.48 (s, 1H), 6.88-6.94 (m, 2H), 7.42-7.46 (m, 2H) ppm. MS (ESI) m/z: 253.1 (M+H)+. The analytical data for the compound was consistent with that given in the literature (Blakemore, et al., J. Org. Chem. 2005, 70, 5449-5460; and Shiina, et al., Bull. Chem. Soc. Jpn. 2001, 74, 113-122). Similar yields were obtained using camphorsulfonic acid (CSA) as the acidic catalyst.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.Br[C:12]1[CH:13]=[CH:14][C:15]2[O:26][C:25]3([CH2:31][CH2:30][CH:29]([O:32][CH3:33])[CH2:28][CH2:27]3)[C:18]3([N:22]=[C:21]([NH2:23])[C:20]([CH3:24])=[N:19]3)[C:16]=2[CH:17]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.Cl[Pd-]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:13]=[CH:14][C:15]3[O:26][C:25]4([CH2:27][CH2:28][CH:29]([O:32][CH3:33])[CH2:30][CH2:31]4)[C:18]4([N:22]=[C:21]([NH2:23])[C:20]([CH3:24])=[N:19]4)[C:16]=3[CH:17]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: COC1CCC2(CC1)Oc1ccc(Br)cc1C21N=C(C)C(N)=N1
Agent: Cl[Pd-]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COC1CCC2(CC1)Oc1ccc(-c3cccc(Cl)c3)cc1C21N=C(C)C(N)=N1
Temperature: 120 °C
Yield: 47 %

Procedure:
3-Chlorophenylboronic acid (47.7 mg, 0.31 mmol), 5′-bromo-4-methoxy-5″-methyldispiro-[cyclohexane-1,2′-[1]benzofuran-3′,2″-imidazol]-4″-amine (Example 29, 77 mg, 0.20 mmol) and (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(I) (8.37 mg, 10.18 μmol) were put in a microwave vial and dissolved in dry dioxane (2 mL). A 2M aq. solution of K2CO3 (0.204 mL, 0.41 mmol) was added, the mixture was degassed with nitrogen gas and the mixture was heated at 120° C. for 20 min in a microwave reactor. The mixture was combined with a second reaction from 10 mg (0.03 mmol) of 5′-bromo-4-methoxy-5″-methyldispiro[cyclohexane-1,2′-[1]benzofuran-3′,2″-imidazol]-4″-amine and concentrated. EtOAc (7 mL) and a sat. aq. solution of NaHCO3 (5 mL) was added and the phases were separated. The aqueous phase was extracted with EtOAc (5 mL) and the combined organic layers were dried over MgSO4, filtered and evaporated. The crude product was purified by preparative chromatography, yielding 38.5 mg of the title compound (41% yield). 1 H NMR (500 MHz, DMSO-d6) δ ppm 1.21 (m, 1 H), 1.46 (m, 3 H), 1.82 (m, 2 H), 1.98 (m, 2 H), 2.21 (s, 3 H), 3.09 (m, 1 H), 3.22 (s, 3 H), 6.71 (br. s., 2 H), 6.85 (d, 1 H), 6.98 (d, 1 H), 7.32 (m, 1 H), 7.40 (s, 1 H), 7.47 (m, 1 H), 7.51 (m, 1 H), 7.54 (s, 1 H); MS (APCI+) m/z 410 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([CH:13]([CH3:15])[CH3:14])[CH:12]=1)[O:9][C:8]([CH3:17])([CH3:16])[CH2:7][C:6]2([CH3:19])[CH3:18])#[CH:2].[CH2:20]([O:22][C:23](=[O:33])[CH:24]=[CH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28](I)[CH:27]=1)[CH3:21]>[Cu]I.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.C(N(CC)CC)C>[CH2:20]([O:22][C:23](=[O:33])[CH:24]=[CH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:2]#[C:1][C:3]2[CH:4]=[C:5]3[C:10](=[C:11]([CH:13]([CH3:14])[CH3:15])[CH:12]=2)[O:9][C:8]([CH3:17])([CH3:16])[CH2:7][C:6]3([CH3:18])[CH3:19])[CH:27]=1)[CH3:21]
Reactant: CCOC(=O)C=Cc1cccc(I)c1
Reactant: C#Cc1cc(C(C)C)c2c(c1)C(C)(C)CC(C)(C)O2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCOC(=O)C=Cc1cccc(C#Cc2cc(C(C)C)c3c(c2)C(C)(C)CC(C)(C)O3)c1

Procedure:
Following General Procedure B and using 6-ethynyl-8-isopropyl-2,2,4,4-tetramethylchroman (Intermediate 32, 0.05 g, 0.2 mmol), ethyl-3-iodo cinnamate (Reagent 6, 0.118 g, 0.39 mmol), triethyl amine (2 mL), copper(I)iodide (0.025 g, 0.13 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.075 g, 0.107 mmol) followed by flash column chromatography over silica gel (230-400 mesh), the title compound was obtained (0.058 g, 69%).
Reaction SMILES: C[Mg]I.C([O:6][CH2:7][CH3:8])C.[CH2:9](OCC)C.[Br:14][C:15]1[N:20]=[C:19]([C:21](C)([CH3:27])[C:22](OCC)=O)[CH:18]=[CH:17][CH:16]=1.P(=O)(O)(O)O>O>[Br:14][C:15]1[N:20]=[C:19]([C:21]([CH3:22])([CH3:27])[C:7]([CH3:8])([OH:6])[CH3:9])[CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)C(C)(C)c1cccc(Br)n1
Reactant: CCOCC
Agent: C[Mg]I
Agent: O=P(O)(O)O
Solvent: O
Product: CC(C)(O)C(C)(C)c1cccc(Br)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In a nitrogen atmosphere, 13 mL of 2 M methylmagnesium iodide/diethyl ether solution was added to diethyl ether (20 mL) solution of 2.72 g of ethyl 2-(6-bromopyridin-2-yl)-2-methylpropionate with cooling in an ice bath. The reaction liquid was stirred at room temperature for 3 hours, and then water and aqueous 10% phosphoric acid solution were added thereto, extracted with diethyl ether, washed with aqueous saturated sodium hydrogencarbonate solution and saturated saline water, and then dried with anhydrous magnesium sulfate. After concentrated under reduced pressure, the residue was purified through silica gel column chromatography (hexane/ethyl acetate=9/1 to 8/1) to obtain 1.47 g of the entitled compound as a colorless oily substance.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[F:10].C1C(=O)N([Cl:18])C(=O)C1>C(#N)C>[NH2:1][C:2]1[C:3]([F:10])=[CH:4][C:5]([C:6]#[N:7])=[CH:8][C:9]=1[Cl:18]
Reactant: O=C1CCC(=O)N1Cl
Reactant: N#Cc1ccc(N)c(F)c1
Solvent: CC#N
Product: N#Cc1cc(F)c(N)c(Cl)c1
Reaction time: 1 h

Procedure:
A solution of 4-amino-3-fluorobenzonitrile (25.13 g, 185 mmol) and NCS (24.65 g, 185 mmol) in acetonitrile (500 mL) was stirred at 86° C. (reflux) for 5 h. LCMS showed ˜17% of starting material remained. Additional NCS (0.2 eq) was added and the reaction was stirred for 1 h. The reaction was partly concentrated and the residue was partitioned between 5% NaOH (100 mL) and EtOAc. The aqueous layer was back extracted with EtOAc. The organic extracts were dried over Na2SO4 and concentrated to a pink solid. The NMR spectrum showed some of the succinimate side product still remained. The crude product was washed with H2O and air dried to give the desired product as a beige solid. This product was used in the next step without any further purification. MS (m/z) 171.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:13]([CH2:14][CH2:15][CH:16]=[O:17])=[C:12]([CH:18]([CH3:20])[CH3:19])[O:11][N:10]=1.[BH4-].[Na+].[Cl-].[NH4+]>CO>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[C:13]([CH2:14][CH2:15][CH2:16][OH:17])=[C:12]([CH:18]([CH3:20])[CH3:19])[O:11][N:10]=1
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1CCC=O
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1CCCO
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 92.1 %

Procedure:
To a solution of 3-[3-(2,6-dichlorophenyl)-5-(1-methylethyl) -4-isoxazolyl]propanal (220 mg, 0.705 mmol) in methanol (7 mL) at 0° C. was added sodium borohydride (67 mg, 1.8 mmol). The solution was stirred at 0° C. for approximately 20 minutes and was then poured into aqueous ammonium chloride. The mixture was extracted twice with ether. The combined organic layers were dried over magnesium sulfate and concentrated to afford 3-[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]-1-propanol (204 mg, 92%). 1H-NMR (400 MHz, CDCl3) δ 7.42-7.28 (m, 3H), 3.53 (t, J=6 Hz, 2H), 3.21 (septet, J=7 Hz, 1H), 3.35 (t, J=8 Hz, 2H), 1.57-1.50 (m, 2H), 1.38 (d, J=7 Hz, 6H).