Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@H:13]([O:16][C:17]2[C:25](/[CH:26]=C/C)=[CH:24][CH:23]=[C:22]3[C:18]=2[CH:19]=[CH:20][N:21]3[S:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH:14]=C)(=[O:10])=[O:9])=[CH:4][CH:3]=1>ClCCl.C(=[Ru+2])C1C=CC=CC=1.C1(P(C2CCCC2)C2CCCC2)CCCC1.C1(P(C2CCCC2)C2CCCC2)CCCC1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[O:16][C:17]3=[C:18]4[C:22](=[CH:23][CH:24]=[C:25]3[CH:26]=[CH:14]2)[N:21]([S:29]([C:32]2[CH:33]=[CH:34][C:35]([CH3:38])=[CH:36][CH:37]=2)(=[O:30])=[O:31])[CH:20]=[CH:19]4)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: C=C[C@H](COS(=O)(=O)c1ccc(C)cc1)Oc1c(/C=C/C)ccc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Agent: [Ru+2]=Cc1ccccc1
Agent: C1CCC(P(C2CCCC2)C2CCCC2)C1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@H]2C=Cc3ccc4c(ccn4S(=O)(=O)c4ccc(C)cc4)c3O2)cc1

Procedure:
Treatment of (2R)-2-({1-[(4-methylphenyl)sulfonyl]-5-[(1E)-prop-1-enyl]-1H-indol-4-yl}oxy)but-3-enyl 4-methylbenzenesulfonate with bis(tricyclopentyl-phosphine) benzylidene ruthenium (IV) in dichloromethane under the conditions described for Example 1b gives {(2R)-7-[(4-methylphenyl)sulfonyl]-2,7-dihydropyrano[2,3-e]indol-2-yl}methyl 4-methylbenzenesulfonate.
Reaction SMILES: [C@@H:1]1([O:11][CH2:12][CH2:13][N:14]([CH2:34][CH2:35][O:36][C@@H:37]2[O:45][C@@H:44]([CH3:46])[C@@H:42]([OH:43])[C@@H:40]([OH:41])[C@@H:38]2[OH:39])[CH2:15][C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26]CC2C=CC=CC=2)=[O:25])=[O:17])[O:9][C@@H:8]([CH3:10])[C@@H:6]([OH:7])[C@@H:4]([OH:5])[C@@H:2]1[OH:3]>O.[Pd]>[C@@H:37]1([O:36][CH2:35][CH2:34][N:14]([CH2:13][CH2:12][O:11][C@@H:1]2[O:9][C@@H:8]([CH3:10])[C@@H:6]([OH:7])[C@@H:4]([OH:5])[C@@H:2]2[OH:3])[CH2:15][C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[O:17])[O:45][C@@H:44]([CH3:46])[C@@H:42]([OH:43])[C@@H:40]([OH:41])[C@@H:38]1[OH:39]
Reactant: C[C@@H]1O[C@@H](OCCN(CCO[C@@H]2O[C@@H](C)[C@@H](O)[C@@H](O)[C@@H]2O)CC(=O)NCCCCCC(=O)OCc2ccccc2)[C@@H](O)[C@H](O)[C@@H]1O
Agent: [Pd]
Solvent: O
Product: C[C@@H]1O[C@@H](OCCN(CCO[C@@H]2O[C@@H](C)[C@@H](O)[C@@H](O)[C@@H]2O)CC(=O)NCCCCCC(=O)O)[C@@H](O)[C@H](O)[C@@H]1O
Reaction time: 18 h

Procedure:
To a solution of benzyl 6-(2-(bis(2-[(α-L-fucopyranosyl)oxy)ethyl)amino)acetamido)hexanoate (40 mg, 0.061 mmol) in water (5 ml), was added Pd/C (30.5 mg, 0.029 mmol). The reaction was stirred under H2 balloon for 18 hr. UPLC indicated formation of desired product. The above solution was diluted with MeOH (5 mL), filtered through a pad of celite, concentrated and lyo to give the titled compound as colorless syrup (20 mg, 6.1%). UPLC Method B: m/e=569.3191 [M+1]; Rt=1.93 min.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:14](=[O:16])[CH3:15])[CH2:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.[C:17](=O)([O:20]C)[O:18][CH3:19].S([O-])(O)(=O)=O.[Na+]>O1CCOCC1>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2([C:14](=[O:16])[CH2:15][C:17]([O:18][CH3:19])=[O:20])[CH2:13][CH2:12][CH2:11]2)=[CH:8][CH:9]=1
Reactant: COC(=O)OC
Reactant: CC(=O)C1(c2ccc(Cl)cc2)CCC1
Agent: O=S(=O)([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)CC(=O)C1(c2ccc(Cl)cc2)CCC1
Yield: 83.4 %

Procedure:
Sodium hydride (1.86 g of a 60% dispersion in mineral oil, 46.5 mmol) was added to a solution of 1-[1-(4-chlorophenyl)cyclobutyl]ethanone (4.18 g, 20.0 mmol) and of dimethyl carbonate (8.4 mL, 99.6 mmol) in of dioxane (20 mL). After the reaction mixture had been refluxed for 4 h, it was chilled in an ice-water bath and treated drop wise with 1 M aqueous sodium hydrogen sulfate solution (50 mL). The mixture containing now a thick precipitate was then partitioned between diethyl ether and water. The organic phase was washed with sat. sodium hydrogen carbonate solution and with brine, dried over magnesium sulfate, and evaporated under reduced pressure. The residual material was purified by chromatography on silica gel using heptane/0-10% ethyl acetate as eluent to afford the title compound (4.45 g, 79%) as pale-yellow oil.
Reaction SMILES: S1C=C[N:3]=[C:2]1[C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[CH2:9][CH:8]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:7]=1>C1C=CC2C(=CC=CC=2O)C=1>[C:2]([C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[CH:9]=[C:8]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:7]=1)#[N:3]
Reactant: CCOC(=O)C1C=C(c2nccs2)c2ccc(OC)cc2C1
Agent: Oc1cccc2ccccc12
Product: CCOC(=O)c1cc(C#N)c2ccc(OC)cc2c1

Procedure:
Following the procedure described in Naphthol 5, Step 6, but substituting the ester from Step 2 for 1-(2-thiazolyl)-3-carbethoxy-6-methoxy-3,4-dihydronaphthalene, the title product was obtained as a white solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:9]2[N:10]=[C:11]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[O:15])[S:12][C:8]=2[C:7]([C:22]2[CH2:23][CH2:24][NH:25][CH2:26][CH:27]=2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:35](OC(=O)C)(=[O:37])[CH3:36].C(=O)(O)[O-].[Na+]>C1COCC1.O>[C:35]([N:25]1[CH2:24][CH:23]=[C:22]([C:7]2[C:8]3[S:12][C:11]([NH:13][C:14]([N:16]4[CH2:17][CH2:18][O:19][CH2:20][CH2:21]4)=[O:15])=[N:10][C:9]=3[C:4]([O:3][CH3:2])=[CH:5][CH:6]=2)[CH2:27][CH2:26]1)(=[O:37])[CH3:36]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(C2=CCNCC2)c2sc(NC(=O)N3CCOCC3)nc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C2=CCN(C(C)=O)CC2)c2sc(NC(=O)N3CCOCC3)nc12
Reaction time: 0.5 h
Yield: 76.7 %

Procedure:
To a solution of 0.04 g (0.097 mMol) morpholine-4-carboxylic acid [4-methoxy-7-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzothiazol-2-yl]-amide hydrochloride in 2 ml THF were added 0.016 ml triethyl amine. At 0° C. 0.01 ml (0.11 mMol) acetic anhydride was added dropwise and stirred for 30 min. Then a mixture of 5 ml sat. aqueous sodium bicarbonate and 10 ml water were added. After extracting four times with 15 ml ethyl acetate the combined organic phases were dried over sodium sulfate and concentrated to dryness in vacuo to yield 0.031 g (76%) morpholine-4-carboxylic acid [7-(1-acetyl-1,2,3,6-tetrahydro-pyridin-4-yl)-4-methoxy-benzothiazol-2-yl]-amide as a white solid. ES-MS m/e (%): 417 ([M+H]+, 100).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:3]=1.CN(C(SC1[N+]([O-])=CC=CC=1)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[F:48][C:49]1[CH:50]=[C:51]2[C:55](=[CH:56][CH:57]=1)[N:54]([NH2:58])[CH2:53][C:52]2([CH3:60])[CH3:59]>CN(C=O)C.O.CCOC(C)=O>[F:48][C:49]1[CH:50]=[C:51]2[C:55](=[CH:56][CH:57]=1)[N:54]([NH:58][C:8]([C:7]1[C:2]([CH3:1])=[N:3][C:4]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)=[N:5][CH:6]=1)=[O:10])[CH2:53][C:52]2([CH3:60])[CH3:59]
Reactant: CC1(C)CN(N)c2ccc(F)cc21
Reactant: Cc1nc(-c2cccnc2)ncc1C(=O)O
Agent: CN(C)C(Sc1cccc[n+]1[O-])=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(-c2cccnc2)ncc1C(=O)NN1CC(C)(C)c2cc(F)ccc21
Temperature: 80 °C
Reaction time: 8 h
Yield: 52.6 %

Procedure:
A solution of 4-methyl-2-pyridin-3-yl-pyrimidine-5-carboxylic acid (706 mg, 3.28 mmol), HOTT (1.34 g, 3.6 mmol), and DIPEA (1.65 mL, 9.45 mmol) in DMF (15 mL) is stirred at rt under N2 for 10 min. 5-Fluoro-3,3-dimethyl-2,3-dihydro-indol-1-ylamine (560 mg, 3.11 mmol) is added. The resulting mixture is stirred at 80° C. overnight. The mixture is cooled and portioned between EtOAc and water. The organic phase is separated, washed with saturated aqueous NaHCO3, water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 35% EtOAc in heptane to afford 4-methyl-2-pyridin-3-yl-pyrimidine-5-carboxylic acid (5-fluoro-3,3-dimethyl-2,3-dihydro-indol-1-yl)-amide (617 mg, 53%) as a solid. MS: 378 (M+H). 1H NMR (300 MHz, DMSO-d6): δ 10.44 (s, 1H), 9.55-9.54 (m, 1H), 9.01 (s, 1H), 8.77-8.75 (m, 1H), 8.72-8.68 (m, 1H), 7.60 (dd, 1H), 7.06 (dd, 1H), 6.96-6.88 (m, 1H), 6.76-6.72 (m, 1H), 3.51 (s, 2H), 2.70 (s, 3H), 1.33 (s, 6H).
Reaction SMILES: [CH2:1]([C:8]1[C:13]([O:14]COC)=[CH:12][CH:11]=[CH:10][C:9]=1[O:18]COC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O>CO>[CH2:1]([C:8]1[C:9]([OH:18])=[CH:10][CH:11]=[CH:12][C:13]=1[OH:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCOc1cccc(OCOC)c1Cc1ccccc1
Agent: Cl
Solvent: O
Solvent: CO
Product: Oc1cccc(O)c1Cc1ccccc1
Yield: 100.6 %

Procedure:
A solution of 13 (214 mg, 0.74 mmol) in MeOH (6.20 mL) was treated dropwise with 3 M HCl (0.22 mL, 5.92 mmol), then heated to reflux for one hour. Water (10 mL) was added and the solution was extracted with EtOAc (3×15 mL). Combined organic fractions were washed with saturated aqueous NaCl, dried (Na2SO4), and concentrated to afford 14 as a red amorphous solid (149 mg, 99%). 1H NMR (CDCl3, 400 MHz) 7.31 (d, J=6.6 Hz, 4H), 7.25-7.19 (m, 1H), 7.01 (t, J=8.1 Hz, 1H), 6.44 (d, J=8.1 Hz, 2H), 4.82 (s, 2H), 4.09 (s, 2H).
Reaction SMILES: [CH2:1]([N:3](CC)CC)[CH3:2].Cl.[NH2:9][C@@H:10]([CH2:13][CH:14]1[CH2:19][CH2:18]CCC1)[CH2:11][OH:12]>C(Cl)Cl>[N:9]1[CH:18]=[CH:19][CH:14]=[CH:13][C:10]=1[C:11]1[O:12][CH2:2][CH2:1][N:3]=1
Reactant: CCN(CC)CC
Reactant: N[C@H](CO)CC1CCCCC1
Agent: Cl
Solvent: ClCCl
Product: c1ccc(C2=NCCO2)nc1
Temperature: 50 °C

Procedure:
Methyl-6-phenylpyridyl-2-imidate (0.160 g, 0.754 mmol) was dissolved in CH2Cl2 (3 mL). Triethylamine (0.12 mL, 0.83 mmol) was added followed by 2-(S)-amino-3-cyclohexylpropanol hydrochloride (0.161 g, 0.829 mmol). The reaction vessel was sealed and heated on a heating block (50° C.) for 16 hours and the resultant solution was then filtered to remove the insoluble salts. The filtrate was loaded onto the top of a Biotage cartridge (silica gel, 40S) and the product was eluted using a stepped gradient of 0 to 30% ethyl acetate in hexanes as the eluent. The product was obtained after evaporation of the eluent as a slightly yellow solid (0.181 g, 75%).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[C:9]2[N:25]([CH3:26])[N:24]=[CH:23][C:10]=2[N:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)[N:13]=1>C1COCC1.[Pd]>[CH3:26][N:25]1[C:9]2[C:8]([N:3]3[CH2:4][CH2:5][O:6][CH2:7][C@@H:2]3[CH3:1])=[N:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=3)=[N:11][C:10]=2[CH:23]=[N:24]1
Reactant: C[C@H]1COCCN1c1nc(-c2ccc([N+](=O)[O-])cc2)nc2cnn(C)c12
Agent: [Pd]
Solvent: C1CCOC1
Product: C[C@H]1COCCN1c1nc(-c2ccc(N)cc2)nc2cnn(C)c12
Yield: 82.2 %

Procedure:
A solution of (S)-3-methyl-4-(1-methyl-5-(4-nitrophenyl)-1H-pyrazolo[4,3-d]pyrimidin-7-yl)morpholine (122.4 mg, 0.345 mmol) dissolved in anhydrous THF (15 mL) was subjected to a continuous flow hydrogenated apparatus (H-Cube: 10% Pd/C cartridge, 1.0 mL/min flow). The crude was concentrated in vacuo and purified by column chromotagraphy (Si-PPC, gradient 0 to 100% EtOAc in heptane) to give the desired product as a yellow foam (92.0 mg, 82.1%). LC-MS m/z (method A)=325.4 [M+H]+, RT=1.34 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[C:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[C:22]1([S:28](Cl)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>N1C=CC=CC=1>[F:21][C:18]1[CH:17]=[CH:16][C:15]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:9]2[CH2:14][CH2:13][N:12]([S:28]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:30])=[O:29])[CH2:11][CH2:10]2)=[CH:20][CH:19]=1
Reactant: Fc1ccc(C(=C2CCNCC2)c2ccc(F)cc2)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Product: O=S(=O)(c1ccccc1)N1CCC(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Yield: 49.3 %

Procedure:
A solution of 15.18 g (0.0529 mole) of 4-[bis(4-flurophenyl)methylene]piperidine and 10,89 g (0.0617 mole) of benzenesulfonyl chloride in 350 ml of pyridine was stirred at room temperature for 16 hr. The solvent was removed in vacuo, and the residue was partitioned between methylene chloride and dilute sulfuric acid. The methylene chloride solution was extracted with dilute sodium hydroxide, and the methylene chloride solution was dried over sodium sulfate. The solvent was removed in vacuo, and the residue was dissolved in 200 ml of methanol. A precipitate was collected. This was recrystallized from methylene chloride - methanol to give 11.14 g (49.3%) of the title compound as a white solid: mp 180-184° C.
Reaction SMILES: O[N:2]1[C:6]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[C:5]([CH3:13])[N:4]=[C:3]1[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=1[O:21][CH3:22].P(Cl)(Cl)Cl.O.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:22][O:21][C:15]1[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:14]=1[C:3]1[NH:2][C:6]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[C:5]([CH3:13])[N:4]=1
Reactant: COc1cc(C)ccc1-c1nc(C)c(-c2cccnc2)n1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClP(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C)ccc1-c1nc(C)c(-c2cccnc2)[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.9 %

Procedure:
To a solution of 1-hydroxy-2-(2-methoxy-4-methylphenyl)-4-methyl-5-(3-pyridyl)imidazole (1.40 g) in N,N-dimethylformamide (28 ml), was added phosphorus trichloride (0.83 ml), and the mixture was stirred for 2 hours at ambient temperature. Then, the solution was poured into water (150 ml), and stirred for an hour at ambient temperature. After neutrallized with aqueous sodium bicarbonate, resulting precipitates were collected by filtration. The precipitates were dried, dissolved in chloroform, and chromatographed on silica gel eluting with a mixture of chloroform and methanol. The fractions were collected, evaporated and triturated in diisopropyl ether to give 2-(2-methoxy-4-methylphenyl)-4-methyl-5-(3-pyridyl)imidazole (0.82 g)
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=4[O:31][CH2:32][CH:33]4[CH2:35][CH2:34]4)[C:15]=3[NH:14][C:13]=2[CH3:36])=[O:11])[CH2:5][CH2:4]1.C([O:40][CH2:41][C:42](Cl)=[O:43])(=O)C>>[CH:33]1([CH2:32][O:31][C:22]2[CH:23]=[CH:24][C:25]([C:27]([F:30])([F:29])[F:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:36])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:41](=[O:40])[CH2:42][OH:43])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:35]1
Reactant: Cc1[nH]c2c(-c3cc(C(F)(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@@H](N)CC1
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Product: Cc1[nH]c2c(-c3cc(C(F)(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@@H](NC(=O)CO)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-(trifluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f33) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: CS(C)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[OH:18][CH:19]1[CH:24]([OH:25])[CH2:23][CH2:22][N:21]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:20]1.C(N(CC)CC)C>ClCCl>[O:18]=[C:19]1[C:24](=[O:25])[CH2:23][CH2:22][N:21]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)C(O)C1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(=O)C(=O)C1
Temperature: -60 °C
Reaction time: 1.5 h

Procedure:
In a dried flask, a solution of 8.8 mL (9.7 g, 125 mmol) of anhydrous dimethyl sulfoxide in 400 mL of anhydrous dichloromethane was stirred under nitrogen at −60° C. as 15.9 mL (23.6 g, 113 mmol) of trifluoroacetic anhydride was added dropwise. The resultant solution was stirred at −60° C. for 20 min, at which time a solution of 8.5 g (39.1 mmol) of tert-butyl 3,4-dihydroxypiperidine-1-carboxylate from Step B in 100 mL of anhydrous dichloromethane was added via cannula. The solution was stirred at −60° C. for 1.5 h, during which time some precipitation occurred. Then 36.2 mL (26.3 g, 260 mmol) of triethylamine was added, and stirring was continued at −60° C. for an additional 30 min. The reaction mixture was concentrated in vacuo, and the residue was purified by flash chromatography (silica gel, 0-30% ethyl acetate/hexanes) to yield the title compound, which may exist as a mixture of tautomers. 1H NMR (500 MHz, CDCl3) δ 7.8-7.6 (br m, <1H), 5.3 (br apparent s, ≦1H), 4.00 (m, 2H), 2.69 (t, J=7.5 Hz, 2H), 1.57 (s, 9H). LC/MS: 214 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=1[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:18]=[CH:17][C:16]=1[OH:28].[CH:29]1([CH2:35]Br)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+]>[Cu].CN(C=O)C>[CH:29]1([CH2:35][O:1][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=2[C:15]2[CH:20]=[C:19]([CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:18]=[CH:17][C:16]=2[O:28][CH2:15][CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7][CH2:2]2)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: BrCC1CCCCC1
Reactant: COC(=O)CCCc1ccc(O)c(-c2cc(CCCC(=O)OC)ccc2O)c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CCCc1ccc(OCC2CCCCC2)c(-c2cc(CCCC(=O)OC)ccc2OCC2CCCCC2)c1
Yield: 119.7 %

Procedure:
To 5 ml of a DMF solution containing 250 mg (0.6477 mmol) of 2,2'-dihydroxy-5,5'-bis(3-methoxycarbonylpropyl) biphenyl and 0.920 ml (6.477 mmol) of cyclohexylmethyl bromide, there was added 360 ml (2.5907 mmol) of anhydrous potassium carbonate and a small amount of copper powder and the resulting mixture was agitated overnight at 100° C. The reaction mixture was filtered by suction through Celite to remove the solid matter, which was washed with ethyl acetate. After the solvent in the filtrate had been evaporated off under reduced pressure, the evaporated residue was dissolved in chloroform. This solution was washed with dilute hydrochloric acid, dilute aqueous sodium bicarbonate, water and saline solution in this sequence and was dried over anhydrous sodium sulfate. The residue obtained after the solvent had been evaporated off was purified by silica gel column chromatography (with 12 g of WAKO-gel C-200, eluent: hexane and hexane/ethyl acetate of 25/1) to obtain 224 mg (0.3877 mmol, 60%) of 2,2'-dicyclohexylmethoxy-5,5'-bis(3-methoxycarbonylpropyl) biphenyl as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:11]3([CH2:16][CH2:15][S:14][C:13]([NH:17]C(=O)OC(C)(C)C)=[N:12]3)[CH2:10][CH:9]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:8][C:5]2=[CH:6][CH:7]=1.[C:31]([C:33]1C=C(B(O)O)[CH:36]=[CH:37][CH:38]=1)#[N:32].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.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:25]1([CH:9]2[CH2:10][C:11]3([CH2:16][CH2:15][S:14][C:13]([NH2:17])=[N:12]3)[C:4]3[C:5](=[CH:6][CH:7]=[C:2]([C:37]4[CH:36]=[N:32][CH:31]=[CH:33][CH:38]=4)[CH:3]=3)[O:8]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)NC1=NC2(CCS1)CC(c1ccccc1)Oc1ccc(Br)cc12
Reactant: N#Cc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: NC1=NC2(CCS1)CC(c1ccccc1)Oc1ccc(-c3cccnc3)cc12
Temperature: 110 °C
Yield: 5.5 %

Procedure:
To a solution of t-butyl 6-bromo-2-phenyl-5′,6′-dihydrospiro[chroman-4,4′-[1,3]thiazine]-2′-ylcarbamate (39 mg, 0.08 mmol), 3-cyanophenylboronic acid (19.7 mg, 0.16 mmol), and Cs2CO3 (120 mg) in 1,4-dioxane (4 mL) and H2O (0.5 mL) charged in a 10 mL CEM microwave test tube is added PdCl2(PPh3)2 (20 mg). The system is degassed by sweeping with N2. The tube is capped and heated to 110° C. for 30 min in a CEM microwave reactor. Solvent is removed in vacuo and the residue is purified by preparative HPLC to give 2-phenyl-6-(pyridin-3-yl)-5′,6′-dihydrospiro[chroman-4,4′-[1,3]thiazin]-2′-amine (1.7 mg) as a TFA salt. MS ESI +ve m/z 389 (M+H)+.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([C:15]([OH:17])=[O:16])=[C:8]([C:12]([OH:14])=O)[C:9]([NH:11][C:4]2=[CH:3][CH:2]=1)=[O:10].P(Cl)(Cl)(Cl)=O>C(Cl)(Cl)Cl>[C:15]1(=[O:16])[C:7]2[C:5]3[CH:6]=[CH:1][CH:2]=[CH:3][C:4]=3[NH:11][C:9](=[O:10])[C:8]=2[C:12](=[O:14])[O:17]1
Reactant: O=C(O)c1c(C(=O)O)c2ccccc2[nH]c1=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=C1OC(=O)c2c1c(=O)[nH]c1ccccc21

Procedure:
A mixture of 2(1H)-Oxo-quinoline-3,4-dicarboxylic acid (2 g), phosphorous oxychloride (4 g) and dry chloroform (30 mL) was heated at reflux for 2 h. The solvent and excess reagents are removed in vacuo and the residue was treated with ice water to afford Furo[3,4-c]quinoline-1,3,4(5H)-trione as a yellow solid.
Reaction SMILES: [C:1]1([C:7]2[C:8]([CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])=[CH:9][N:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[N:22]=[C:23]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=5)[S:24][CH:25]=4)=[CH:15][CH:14]=3)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[C:1]1([C:7]2[C:8]([CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[CH:9][N:10]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]4[N:22]=[C:23]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=5)[S:24][CH:25]=4)=[CH:17][CH:18]=3)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3csc(-c4ccccn4)n3)cc2)cc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)CCc1cn(Cc2ccc(OCc3csc(-c4ccccn4)n3)cc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.5 %

Procedure:
A mixture of ethyl 3-[4-phenyl-1-[4-[2-(2-pyridyl)-4-thiazolylmethoxy)benzyl]-3-pyrrolyl]propionate (471 mg), 1N aqueous sodium hydroxide solution (2 ml), tetrahydrofuran (5 ml), and ethanol (5 ml) was stirred at room temperature overnight, and 1N hydrochloric acid (2 ml) was added to the mixture, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The colorless crystals obtained were collected by filtration to yield 3-[4-phenyl-1-[4-[2-(2-pyridyl)-4-thiazolylmethoxy)benzyl]-3-pyrrolyl]propionic acid (408 mg, yield: 91%). This was recrystallized from ethanol-hexane. Melting point: 117–118° C.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[F:6][C:7]([F:24])([F:23])[CH:8]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][C:11]2[CH:19]=[CH:20][CH:21]=[CH:22][C:10]=2[O:9]1>>[Cl:1][S:2]([C:20]1[CH:21]=[CH:22][C:10]2[O:9][CH:8]([C:7]([F:24])([F:23])[F:6])[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][C:11]=2[CH:19]=1)(=[O:5])=[O:3]
Reactant: CCOC(=O)C1=Cc2ccccc2OC1C(F)(F)F
Reactant: O=S(=O)(O)Cl
Product: CCOC(=O)C1=Cc2cc(S(=O)(=O)Cl)ccc2OC1C(F)(F)F
Temperature: -15 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
Chlorosulfonic acid (50.0 mL) was cooled to 15° C. and ethyl 2-trifluoromethyl-2H-1-benzopyran-3-carboxylate (Example 10, Step 2) (6.21 g, 22.83 mmol) was added. After stirring at −15° C. for 1 hour, the solution was warmed to room temperature and stirred for 16 hours. The solution was added dropwise onto ice (500 mL) with vigorous stirring and extracted with diethyl ether (2×250 mL). The ether layers were combined, washed with water (2×250 mL), saturated sodium bicarbonate (2×250 mL), and brine (2×250 mL). Hexanes (50 mL) were added and the solution was dried over sodium sulfate. The solvent was removed in vacuo to afford the ester as a yellow solid (7.41 g, 87%): mp 97.2–98.4° C. 1H NMR (CDCl3, 300 MHz) 7.97 (dd, 1H, J=8.6, 2.2. Hz), 7.92 (d, 1H, J=2.2 Hz), 7.73 (s, 1H), 7.17 (d, 1H, J=2.2 Hz), 5.82 (qH-F, 1H, J=7.2 Hz), 4.28–4.39 (m, 2H), 1.35 (t, 3H, J=7.0 Hz). FABLRMS m/z 376 (M+Li+).