Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC1C=CC(C2C=C(C)C=CC=2S(C2C=CC(C)=CC=2C2C=CC(N)=C([N+]([O-])=O)C=2)=O)=CC=1[N+]([O-])=O.[NH2:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]2[CH:49]=[C:48]([O:50][CH3:51])[CH:47]=[CH:46][C:45]=2[S:52]([C:54]2[CH:59]=[CH:58][C:57]([O:60][CH3:61])=[CH:56][C:55]=2[C:62]2[CH:67]=[CH:66][C:65]([NH2:68])=[C:64]([N+:69]([O-])=O)[CH:63]=2)=[O:53])=[CH:40][C:39]=1[N+:72]([O-])=O>>[NH2:69][C:64]1[CH:63]=[C:62]([C:55]2[CH:56]=[C:57]([O:60][CH3:61])[CH:58]=[CH:59][C:54]=2[S:52]([C:45]2[CH:46]=[CH:47][C:48]([O:50][CH3:51])=[CH:49][C:44]=2[C:41]2[CH:42]=[CH:43][C:38]([NH2:37])=[C:39]([NH2:72])[CH:40]=2)=[O:53])[CH:67]=[CH:66][C:65]=1[NH2:68]
Reactant: COc1ccc(S(=O)c2ccc(OC)cc2-c2ccc(N)c([N+](=O)[O-])c2)c(-c2ccc(N)c([N+](=O)[O-])c2)c1
Agent: Cc1ccc(S(=O)c2ccc(C)cc2-c2ccc(N)c([N+](=O)[O-])c2)c(-c2ccc(N)c([N+](=O)[O-])c2)c1
Product: COc1ccc(S(=O)c2ccc(OC)cc2-c2ccc(N)c(N)c2)c(-c2ccc(N)c(N)c2)c1
Yield: 90 %

Procedure:
Following the procedure described in Example 2 but using as a starting material instead of (4-amino-3-nitrophenyl)-4-methylphenyl sulfoxide a corresponding amount of (4-amino-3-nitrophenyl)-4-methoxyphenyl sulfoxide, the title compound is obtained.
Reaction SMILES: C([O:4][C:5]1[C:10]2[CH:11]=[C:12]([CH3:14])[O:13][C:9]=2[CH:8]=[C:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:6]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>C(O)C.ClCCl>[OH:4][C:5]1[C:10]2[CH:11]=[C:12]([CH3:14])[O:13][C:9]=2[CH:8]=[C:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:6]=1
Reactant: CCOC(=O)c1cc(OC(C)=O)c2cc(C)oc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)c1cc(O)c2cc(C)oc2c1
Temperature: 60 °C
Yield: 119.3 %

Procedure:
To a stirred solution of ethyl 4-acetoxy-2-methylbenzofuran-6-carboxylate (I-1b: 549.03 g, 1.37 mol) in ethanol (4.00 L) at room temperature was added potassium carbonate (266 g, 1.92 mol) in one portion. The reaction mixture was then heated at 60° C. for 3 hours. Potassium carbonate (100 g, 0.720 mol) was then added in one portion and the reaction mixture was heated at 60° C. for a further 3 hours. After cooling to room temperature the mixture was diluted with dichloromethane (2 L) and the suspension filtered, washing the solids with dichloromethane (2×1 L) (all batches were combined at this point). The combined filtrate and washings were then washed with citric acid (2.5 L of a 1 M aqueous solution), then concentrated in vacuo and the resulting residue purified by dry flash chromatography (hexane then 2:1 hexane:ethyl acetate). All fractions containing the desired product were combined and concentrated in vacuo. The resulting residue, which solidified on standing, was slurried with cold toluene and filtered. The solids were then stirred with hot toluene and decolourising charcoal for 1 hour, followed by filtration of the hot mixture through a pad of celite. The filtrate was allowed to cool and the resulting precipitate isolated by filtration to give desired ethyl 4-hydroxy-2-methylbenzofuran-6-carboxylate (I-1c: 360 g, 90%) as orange powder. 1H NMR (CDCl3, 300 MHz) δ ppm 7.73-7.73 (m, 1H), 7.45 (d, 1H), 6.51-6.50 (m, 1H), 5.85 (s, 1H), 4.39 (q, 2H), 2.48 (d, 3H), 1.40 (t, 3H). LCMS (liquid chromatography mass spectrometry): m/z 221.06 (96.39% purity).
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH2:15][NH2:16].C(N(CC)CC)C.C(O)CCC>CO.O>[NH2:8][C:7]1[C:6]([Cl:9])=[N:5][CH:4]=[N:3][C:2]=1[NH:16][CH2:15][C:14]1[CH:17]=[CH:18][C:19]([O:20][CH3:21])=[C:12]([O:11][CH3:10])[CH:13]=1
Reactant: COc1ccc(CN)cc1OC
Reactant: Nc1c(Cl)ncnc1Cl
Solvent: CO
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(CNc2ncnc(Cl)c2N)cc1OC

Procedure:
A reaction mixture containing 1.00 g (6.09 mmols) of 4,6-dichloro-5-aminopyrimidine, 1.22 g (7.30 mmols) of 3,4-dimethoxybenzylamine, 1.02 ml (7.30 mmols) of triethylamine and 35 ml of 1-butanol was refluxed overnight for 17 hours. Evaporation of the reaction mixture in vacuo gave a residual oil which was crystallized by trituration with water. The crude yellow solid was recrystallized from methanol-water to give 1.61 g (90.1%), mp 185°-188°, of crystalline product. The analytical sample was obtained by recrystallization from methanol-water; yield, 1.36 g (76.9%); mp 188°-191°.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[CH:29]=3)=[C:20]([C:35]#[N:36])[CH:19]=2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.[OH-].[Na+].[ClH:40].O1CCOCC1>O1CCCC1.O.FC(F)(F)C(O)=O.C(Cl)Cl>[ClH:40].[NH2:7][C:8]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[CH:29]=2)=[C:20]([C:35]#[N:36])[CH:19]=1)([CH2:13][OH:12])[CH2:9][OH:10]
Reactant: Cc1cccc(CCCOc2ccc(CCC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)cc2C#N)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(CCCOc2ccc(CCC(N)(CO)CO)cc2C#N)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Compound 208-2 (0.360 g) was dissolved in a mixed solvent of tetrahydrofuran (4 ml) and water (1 ml), trifluoroacetic acid (1 ml) was added, and the mixture was stirred at room temperature for 4 hr. To the reaction mixture was added 1M aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give a yellow oil. To a solution of the yellow oil in methylene chloride (5 ml) was added hydrogen chloride containing dioxane (4 mol/l, 5 ml), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give a white powder. The white powder was purified by HPLC, the obtained residue was converted to hydrochloride by adding hydrogen chloride containing ether (1 mol/l, 15 ml), and the precipitate was collected by filtration and dried to give the object product (110 mg) as a pale-brown powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[NH:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[CH3:11].[H][H]>[Rh].C(O)C>[CH3:1][O:2][C:3](=[O:12])[NH:4][C@H:5]1[C@@H:10]([CH3:11])[CH2:9][CH2:8][NH:7][CH2:6]1
Reactant: COC(=O)Nc1cnccc1C
Reactant: [H][H]
Agent: [Rh]
Solvent: CCO
Product: COC(=O)N[C@@H]1CNCC[C@@H]1C

Procedure:
The hydrogenation was carried out by charging 5 grams (1 equiv., 30.1 mmol) (4-methyl-pyridin-3-yl)-carbamic acid methyl ester, 50 ml ethanol (10 volumes), and 2.5 grams rhodium on alumina (0.5 wt. equivs.) to a bomb hydrogenator. The hydrogenation was performed under 100 psi hydrogen at 100° C. for 24 hours to give only cis-(4-methyl-piperidin-3-yl)-carbamic acid methyl ester and its trans isomer (5:1 ratio) in quantitative yield. 1 H NMR: δ5.6 (1 H, d, J=8.4 Hz), 3.66 (1 H, d, J=3.6 Hz), 3.65-3.57 (3 H, brs), 3.1 (2 H, d, J=9.6, minor isomer), 2.91-2.86 (2 H, m), 2.67-2.64 (1 H, m), 2.54-2.43 (1 H, m), 2.2-1.9 (1 H, m, minor isomer), 1.78-1.65 (5 H, brs, minor isomer), 1.65-1.59 (4 H, m, minor isomer), 1.36-1.25 (2 H, m), 1.24-1.13 (2 H, m), 0.92 (3 H, d, J=6.8 Hz, minor isomer), 0.83 (3 H, d, J=7.2).
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]([CH3:18])([CH3:17])[C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15]C)[CH:11]=2)[CH:6]=1.O>Br.C(O)(=O)C>[CH3:17][C:4]([CH3:18])([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:15])[CH:11]=2)[CH:6]=1)[C:3]([OH:19])=[O:2]
Reactant: COC(=O)C(C)(C)c1ccc2cc(OC)ccc2c1
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C(=O)O)c1ccc2cc(O)ccc2c1
Temperature: 25 °C
Yield: 92.6 %

Procedure:
To a solution of (α-methyl-6-methoxy-2-naphthaleneacetic acid methyl ester (12.2 g, 50 mmol) in tetrahydrofuran (100 ml) at -70° C. is added a solution of lithium diisopropylamide in cyclohexane (50 ml, 1.5 equiv). After 20 minutes, methyl iodide (4.0 ml, 1.3 equiv) is added followed by hexamethylphosphoraniide (20 ml). After allowing the reaction mixture to warm to room temperature and stir 16 hours, the reaction is quenched by addition of acetic acid (4.3 ml, 75 mmol). The solvent is then removed and the residue is partitioned between ethyl acetate and water. The organic layer is washed with water 3 times and finally with brine. After drying over magnesium sulfate, the organic extract is evaporated to afford a crude solid. Recrystallization of this solid from hexane affords 8.56 g (66%) of α,α-dimethyl-6-methoxy-2-naphthaleneacetic acid methyl ester as white crystals, m.p. 97°-98° C. A solution of this ester (7.4 g, 28.6 mmol) in 48% HBr (50 ml) and acetic acid (50 ml) is refluxed for 3 hours. After the reaction mixture is cooled to room temperature, 0.8 L of water is added and the reaction mixture is extracted with ethyl acetate 5 times. The combined organic extract is washed sequentially with saturated sodium bicarbonate solution and water. After drying over magnesium sulfate, the organic extract is evaporated to afford 6.1 g (93%) of α,α-dimethyl-6-hydroxy-2-naphthaleneacetic acid as white crystals, m.p. 208°-210° C. The title compound is prepared according to the method of Example 7 using α,α-dimethyl-6-hydroxy-2-naphthaleneacetic acid. A white solid is obtained having a melting point of 207°-209° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH:7]2[CH:8]=[CH:9][CH:4]([C:5]([CH2:10][CH2:11][OH:12])=[CH:6]2)[C:3]1=[O:13].[H][H]>[Pd].C(O)(C)C>[CH3:1][C:2]1([CH3:14])[CH:7]2[CH2:8][CH2:9][CH:4]([CH:5]([CH2:10][CH2:11][OH:12])[CH2:6]2)[C:3]1=[O:13]
Reactant: [H][H]
Reactant: CC1(C)C(=O)C2C=CC1C=C2CCO
Agent: [Pd]
Solvent: CC(C)O
Product: CC1(C)C(=O)C2CCC1CC2CCO
Temperature: 100 °C
Yield: 89.8 %

Procedure:
A mixture of 60 g of 3,3-dimethyl-6-(2-hydroxyethyl)-bicyclo(2.2.2)-octa-5,7-diene-2-one produced according to Example I, 300 ml of isopropyl alcohol and 5 g of 5% palladium on charcoal catalyst is placed in an autoclave. The autoclave is pressurized with hydrogen and heated to 100° C. for six hours. The resulting reaction mixture is filtered and the solvent is removed by vacuum stripping. Distillation of the residue through a 3" microvigreaux column yields 55 g of 3,3-dimethyl-6-(2-hydroxyethyl)-bicyclo(2.2.2)-octanone having the structure: ##STR32##
Reaction SMILES: C([O:3][C:4](=[O:42])[C:5](C(OCC)=O)([CH2:10][C:11]1[CH:16]=[C:15]([Cl:17])[C:14]([S:18][C:19]2[CH:24]=[CH:23][C:22]([O:25]C)=[C:21]([CH2:27][C:28]3[CH:29]=[N:30][C:31]([O:34]C)=[CH:32][CH:33]=3)[CH:20]=2)=[C:13]([Cl:36])[CH:12]=1)[NH:6]C(=O)C)C.B(Br)(Br)Br>ClCCl>[OH:25][C:22]1[CH:23]=[CH:24][C:19]([S:18][C:14]2[C:15]([Cl:17])=[CH:16][C:11]([CH2:10][C@@H:5]([C:4]([OH:42])=[O:3])[NH2:6])=[CH:12][C:13]=2[Cl:36])=[CH:20][C:21]=1[CH2:27][C:28]1[CH:33]=[CH:32][C:31](=[O:34])[NH:30][CH:29]=1
Reactant: CCOC(=O)C(Cc1cc(Cl)c(Sc2ccc(OC)c(Cc3ccc(OC)nc3)c2)c(Cl)c1)(NC(C)=O)C(=O)OCC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: N[C@@H](Cc1cc(Cl)c(Sc2ccc(O)c(Cc3ccc(=O)[nH]c3)c2)c(Cl)c1)C(=O)O
Temperature: 25 °C
Yield: 101.6 %

Procedure:
To a cooled (-74°) solution of N-acetyl-3,5-dichloro-4-(4'-methoxy-3'-(6-methoxy-3-pyridylmethyl)phenylthio) -α-carbethoxy-phenylalanine ethyl ester (0.39 g) in dry dichloromethane (10 ml) was added boron tribromide (0.58 ml) with stirring. The mixture was stirred whilst warming to room temperature and stirred for 5 hours. The reaction mixture was worked up and refluxed with concentrated hydrochloric in glacial acetic acid in a manner similar to that as described in Example 1 to afford DL-4-(4'-Hydroxy-3'-(6-oxo-3(1H)-pyridylmethyl) phenylthio)-3,5-dichlorophenylalanine as a cream solid (0.29 g, 70%), m.p. 261-264°.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([CH:12]2[CH2:14][CH2:13]2)([CH:9]2[CH2:11][CH2:10]2)[OH:8])=[N:4][CH:3]=1.[N+:15]([C:18]1[CH:19]=[C:20]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[CH:21]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:23]=1)([O-:17])=[O:16].C([O-])([O-])=O.[Na+].[Na+].ClCCl>COCCOC.C(OCC)(=O)C.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]>[CH:9]1([C:7]([CH:12]2[CH2:14][CH2:13]2)([C:5]2[S:6][C:2]([C:22]3[CH:23]=[C:18]([N+:15]([O-:17])=[O:16])[CH:19]=[C:20]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)[CH:21]=3)=[CH:3][N:4]=2)[OH:8])[CH2:11][CH2:10]1
Reactant: CC1(C)OB(c2cc(N3CCOCC3)cc([N+](=O)[O-])c2)OC1(C)C
Reactant: OC(c1ncc(Br)s1)(C1CC1)C1CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc(-c2cnc(C(O)(C3CC3)C3CC3)s2)cc(N2CCOCC2)c1
Yield: 68.2 %

Procedure:
A solution of the product of Step 2 (239 mg, 0.872 mmol), crude product of Step 3 (320 mg, ˜0.96 mmol), Pd(dppf)Cl2 (31.9 mg, 0.044 mmol) and Na2CO3 (aq) (2.0 M, 1.3 mL, 2.6 mmol) in DME (4.4 mL) was irradiated to 130° C. in the microwave for 35 minutes. The reaction mixture was filtered through a celite pad with dichloromethane and the filtrate was concentrated. The residue was purified twice by chromatography on silica gel (0-100% ethyl acetate in hexanes then 0-60% dichloromethane in ethyl acetate) to give the desired dicyclopropyl{5-[3-(morpholin-4-yl)-5-nitrophenyl]-1,3-thiazol-2-yl}methanol (239 mg, 0.595 mmol, 68% yield) as a yellow solid. MS APCI: [M-OH]+ m/z 385.1.
Reaction SMILES: Br.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]#[C:9][CH2:10]Br.[F:12][C:13]1[CH:14]=[C:15]([OH:28])[CH:16]=[C:17]([C:19]2([O:26][CH3:27])[CH2:23][CH2:22][CH2:21][CH:20]2[O:24][CH3:25])[CH:18]=1>>[F:12][C:13]1[CH:14]=[C:15]([O:28][CH2:10][C:9]#[C:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=2)[CH:16]=[C:17]([C:19]2([O:26][CH3:27])[CH2:23][CH2:22][CH2:21][CH:20]2[O:24][CH3:25])[CH:18]=1
Reactant: BrCC#Cc1ccccn1
Reactant: COC1CCCC1(OC)c1cc(O)cc(F)c1
Agent: Br
Product: COC1CCCC1(OC)c1cc(F)cc(OCC#Cc2ccccn2)c1
Yield: 83 %

Procedure:
Using the procedure described in Example 1, 3-(2-pyridyl)prop-2-yn-1-yl bromide hydrobromide was reacted with (1RS,2SR)-1-(5-fluoro-3-hydroxyphenyl)-1,2-dimethoxycyclopentane to give (1RS,2SR)-1-[5-fluoro-3-(3-(2-pyridyl)prop-2-yn-1-yloxy)phenyl]-1,2-dimethoxycyclopentane in 83% yield, as an oil.
Reaction SMILES: [O:1]=[S:2]1(=[O:19])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]12[CH2:15][CH:11]3[CH2:12][CH:13]([CH2:14]1)[C:9](C(O)=O)([CH2:10]3)[CH2:8]2.OS(O)(=O)=O.[N-:25]=[N+]=[N-].[Na+]>C(Cl)(Cl)Cl.O>[O:1]=[S:2]1(=[O:19])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]12[CH2:15][CH:11]3[CH2:12][CH:13]([CH2:14]1)[C:9]([NH2:25])([CH2:10]3)[CH2:8]2
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O)C12CC3CC1CC(N1CCCS1(=O)=O)(C3)C2
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: NC12CC3CC1CC(N1CCCS1(=O)=O)(C3)C2
Temperature: 45 °C
Reaction time: 2 h
Yield: 66.3 %

Procedure:
To a stirred solution of the acid obtained in step II (0.29 g, 1.0 mmol) in CHCl3 (5 mL) at room temperature was added conc. H2SO4 (0.53 mL, 10 mmol) followed by the addition NaN3 (0.2 g, 3.0 mmol) in portions over a period of 30 min; while maintaining the temperature below 40° C. The reaction mixture was warmed to 45° C. and stirred for 2 h. The reaction mixture was cooled to ice bath temperature, diluted with water and extracted with EtOAc. The aqueous layer was basified by adding a 50% NaOH solution and extracted with CHCl3. The combined organic layer was washed with brine, dried over Na2SO4 and the solvent was removed under reduced pressure to obtain 1-(1,1-dioxidoisothiazolidin-2-yl)tricyclo[3.3.1.03,7]nonan-3-amine as a viscous liquid (0.17 g) in 66% yield. m/z (M+1) 257; 1H NMR (CDCl3) 300 MHz δ 3.36 (t, J=6.6 Hz, 2H), 3.15 (t, J=7.5 Hz, 2H), 2.40-2.24 (m, 4H), 2.18 (dd, J=3.0, 10.4 Hz, 1H), 2.13-1.83 (m, 6H), 1.76 (dd, (J=2.4, 10.8 Hz, 1H), 1.65-1.58 (m, 1H), 1.48 (dd, J=2.4, 10.8 Hz, 1H).
Reaction SMILES: [Cl-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[CH3:9][O:10][C:11]([C:13]1[S:14][C:15]([C:35]#[C:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:16][C:17]=1[N:18]([C:26]([C@@H:28]1[CH2:33][CH2:32][C:31]([CH3:34])=[CH:30][CH2:29]1)=[O:27])[CH:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1)=[O:12].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CS(C)=O.C1COCC1>[CH3:9][O:10][C:11]([C:13]1[S:14][C:15]([C:35]#[C:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:16][C:17]=1[N:18]([C:26]([C@@H:28]1[CH2:33][CH2:32][C:31]([CH3:34])=[CH:30][CH2:29]1)=[O:27])[CH:19]1[CH2:20][CH2:21][C:22]2([O:25][CH2:2]2)[CH2:23][CH2:24]1)=[O:12]
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC=C(C)CC1)C1CCC(=O)CC1
Reactant: C[S+](C)(C)=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Cl-]
Agent: [H-]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC=C(C)CC1)C1CCC2(CC1)CO2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70 %

Procedure:
Trimethylsulfoxonium chloride (79 mg, 0.62 mmol) in DMSO (1.5 mL) was treated with sodium hydride (21 mg, 60% oil dispersion, 0.53 mmol) and stirred at ambient temperature for 10 min. 5-(3,3-Dimethyl-but-1-ynyl)-3-[((1R)-4-methyl-cyclohex-3-enecarbonyl)-(4-oxo-cyclohexyl)-amino]-thiophene-2-carboxylic acid methyl ester 507 in THF (1 mL+0.5 mL) was added dropwise and the reaction mixture was stirred for 45 min. The orange solution was treated with 5% citric acid until pH 3 and partitioned between water and ethyl acetate. The organic layer was separated and the aqueous was extracted again with ethyl acetate. The combined organics were washed with 5% LiCl, water and brine, and dried over sodium sulfate. After filtration and concentration, the residue was purified by flash chromatography (20-75% EtOAc:hexanes) to afford 0.134 g (70% yield) of 5-(3,3-dimethyl-but-1-ynyl)-3-[((1R)-4-methyl-cyclohex-3-enecarbonyl)-(1-oxa-spiro[2.5]oct-6-yl)-amino]-thiophene-2-carboxylic acid methyl ester 508 as a white powder.
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30]([OH:32])=O)[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:63]([NH2:67])([CH3:66])([CH3:65])[CH3:64]>C(Cl)Cl>[CH2:37]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30]([NH:67][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:32])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=3[F:25])[C:12]=2[N:13]=1)[CH3:38]
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: CC(C)(C)N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCN(CC)CCCNc1nc(-c2cc(C(=O)NC(C)(C)C)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.4 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (40 mg, 0.074 mmol) in methylene chloride (2 mL) were added HBTU (30 mg, 0.079 mmol) and t-butylamine (0.040 mL, 0.37 mmol). The mixture was stirred at rt overnight. Solvent was removed by rotovap. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (39 mg, 88%). LC-MS m/z 577 (M+H)+.
Reaction SMILES: CS(O)(=O)=O.[NH2:6][C:7]1[N:11]([S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[C:10]2[CH:18]=[C:19]([C:22]([C:25]3[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=3[F:32])([CH3:24])O)[CH:20]=[CH:21][C:9]=2[N:8]=1.C(=O)(O)[O-].[Na+].[OH-].[Na+]>C(Cl)Cl>[CH:15]([S:12]([N:11]1[C:10]2[CH:18]=[C:19]([C:22]([C:25]3[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=3[F:32])=[CH2:24])[CH:20]=[CH:21][C:9]=2[N:8]=[C:7]1[NH2:6])(=[O:13])=[O:14])([CH3:17])[CH3:16]
Reactant: CC(C)S(=O)(=O)n1c(N)nc2ccc(C(C)(O)c3cc(F)ccc3F)cc21
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C=C(c1ccc2nc(N)n(S(=O)(=O)C(C)C)c2c1)c1cc(F)ccc1F
Temperature: 25 °C
Yield: 91.9 %

Procedure:
Methanesulfonic acid (33.0 g, 344 mmol) was added to a solution of 2-amino-α-(2,5-difluorophenyl)-α-methyl-1-[(1-methylethyl)sulfonyl]benzimidazole-6-methanol (53.4 g, 97% purity, 115 mmol) in methylene chloride (500 mL) and the solution turned from beige to brown. The solution was heated at reflux for 1.5 hours until the reaction was complete. After cooling to room temperature, a saturated aqueous solution of sodium bicarbonate (200 mL) was added to neutralize the acid. However, the pH remained at 1 and extensive foaming occurred. The reaction mixture was then neutralized to pH 7-8 with 1N sodium hydroxide (about 90 mL) while keeping the temperature at 20° C. The phases were separated and the organic phase extracted with methylene chloride (100 mL). The combined organic fractions were washed with brine (100 mL) and dried over sodium sulfate. The hazy mixture was filtered to give a clear burnt-orange solution which was concentrated by rotary evaporation at 40-70° C. to give 39.9 g of the title compound as a beige powder (98.5% purity, 91% yield), mp 161.0-164.5° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:33]=[CH:32][C:18]2[C:19]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:20]([C:22](OC)=[O:23])[O:21][C:17]=2[CH:16]=1.O1CCCC1.[H-].C([Al+]CC(C)C)C(C)C.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C(OCC)(=O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:33]=[CH:32][C:18]2[C:19]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:20]([CH2:22][OH:23])[O:21][C:17]=2[CH:16]=1
Reactant: COC(=O)c1oc2cc(OCc3nc(-c4ccccc4)oc3C)ccc2c1-c1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc2c(-c3ccccc3)c(CO)oc2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 90.8 %

Procedure:
To a mixture of methyl 6-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]-3-phenyl-1-benzofuran-2-carboxylate (32.70 g) and tetrahydrofuran (500 mL) was added dropwise diisobutylaluminum hydride (0.95M hexane solution, 235 mL) at 0° C. The reaction mixture was stirred at 0° C. for 2 hrs, sodium sulfate decahydrate (71.85 g) was added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate and the precipitate was filtered off. The filtrate was concentrated to give {6-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]-3-phenyl-1-benzofuran-2-yl}methanol as colorless crystals (27.80 g, yield 91%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 152-153° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[NH2:13].C[Al](C)C.[CH3:18][S:19]([C:22]1[CH:23]=[CH:24][C:25]([C:28](OC)=[O:29])=[N:26][CH:27]=1)(=[O:21])=[O:20].Cl>C1(C)C=CC=CC=1.ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:11])([F:12])[F:10])[CH:5]=[CH:4][C:3]=1[NH:13][C:28]([C:25]1[CH:24]=[CH:23][C:22]([S:19]([CH3:18])(=[O:21])=[O:20])=[CH:27][N:26]=1)=[O:29]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)cn1
Reactant: Nc1ccc(OC(F)(F)F)cc1Cl
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(=O)Nc2ccc(OC(F)(F)F)cc2Cl)nc1
Temperature: 85 °C
Reaction time: 0.5 h

Procedure:
2-Chloro-4-trifluoromethoxy-phenylamine (2.0 g, 9.29 mmol) in toluene (50 mL) was added to trimethylaluminum (2.0 M 4.65 mL) then methyl 5-(methylsulfonyl)picolinate 6 (1.0 g, 4.65 mol) was added and the mixture was heated to 80-90° C. for 2 h. The reaction was cooled down and 1N HCl solution (10 mL) was added to be acidic. Dichloromethane (100 mL) was then added and the organic phase was further washed with water (100 mL) and dried over sodium sulfate. The solvent was removed and the residue was mixed with ether (50 mL) and stirred for 0.5 h. The solid was filtered and dried to give 5-methanesulfonyl-pyridine-2-carboxylic acid (2-chloro-4-trifluoromethoxy-phenyl)-amide 7 as a light yellow solid. Yield: 1.26 g, 65%.