Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4].CCN(CC)CC.[Cl:18][CH2:19][C:20](Cl)=[O:21]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:18][CH2:19][C:20]([NH:1][C@@H:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4])=[O:21]
Reactant: N[C@H](CO)c1ccccc1
Reactant: O=C(Cl)CCl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)N[C@H](CO)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 45.2 %

Procedure:
To a solution of (S)-2-amino-2-phenylethanol (0.852 g, 6.21 mmol), Et3N (0.952 mL, 6.83 mmol), DMAP (76 mg, 0.621 mmol) in CH2Cl2 (10 mL) at 0° C. was added 2-chloroacetyl chloride (0519 mL, 6.52 mmol), and the resulting mixture was stirred at 0° C. for 15 min. The reaction mixture was washed with aqueous HCl (1 M, 20 mL), then sat. NaHCO3 (20 mL), dried (Na2SO4), concentrated, further dried under high vacuum and (S)-2-chloro-N-(2-hydroxy-1-phenylethyl)acetamide (0.60 g, 45.2% yield) was obtained as white solid. LCMS (m/z): 214 (MH+), 0.44 min.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)=O.CC(C)=O.C([Li])CCC.[B:27](OC)([O:30]C)[O:28]C>C1COCC1>[C:1]([C:5]1[S:9][C:8]([C:10]2[S:11][C:12]([B:27]([OH:30])[OH:28])=[CH:13][CH:14]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COB(OC)OC
Reactant: CC(C)(C)c1ccc(-c2cccs2)s1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(-c2ccc(B(O)O)s2)s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96 %

Procedure:
In a flame-dried, 500 mL round bottom flask, 5-(t-butyl)-2,2′-bithiophene (from U152-001, 13 g, 58.5 mmol) was dissolved in anhydrous THF (200 mL) and the solution was cooled to −78° C. (dry ice/acetone). n-butyl lithium (2.5 M in hexanes, 25.7 mL, 64.3 mmol) was added dropwise over a period of 10 minutes, and the resulting green solution was allowed to stir for 15 minutes. Trimethyl borate (19.6 mL, 175 mmol) was added dropwise over a period of 10 minutes, and the resulting light yellow solution was stirred for 2 hours at −78° C., then allowed to warm to room temperature and stirred for 1 hour. The reaction was quenched by pouring it into 10% HCl (500 mL). The organic phase was separated and the aqueous phase extracted with ether (250 mL). The combined organics were washed with water (500 mL), dried over MgSO4, filtered and solvent removed by rotary evaporation. The resulting green solid was dried under vacuum to afford 15 g (96% yield), which was used in the next step without further purification.
Reaction SMILES: [CH:1]1([C:4]2[O:5][C:6]3[C:12]([C:13]4[CH:18]=[C:17]([CH3:19])[C:16](=[O:20])[N:15]([CH3:21])[CH:14]=4)=[CH:11][C:10]([NH:22][S:23]([CH2:26][CH3:27])(=[O:25])=[O:24])=[CH:9][C:7]=3[CH:8]=2)[CH2:3][CH2:2]1>CO.[Pd]>[CH3:21][N:15]1[C:16](=[O:20])[C:17]([CH3:19])=[CH:18][C:13]([C:12]2[C:6]3[O:5][CH:4]([CH2:1][CH2:2][CH3:3])[CH2:8][C:7]=3[CH:9]=[C:10]([NH:22][S:23]([CH2:26][CH3:27])(=[O:25])=[O:24])[CH:11]=2)=[CH:14]1
Reactant: CCS(=O)(=O)Nc1cc(-c2cc(C)c(=O)n(C)c2)c2oc(C3CC3)cc2c1
Agent: [Pd]
Solvent: CO
Product: CCCC1Cc2cc(NS(=O)(=O)CC)cc(-c3cc(C)c(=O)n(C)c3)c2O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 14.2 %

Procedure:
A mixture of the title compound from Step 4 (70 mg, 0.18 mmol) and 10 mg of Pd/C in 40 mL of MeOH was stirred under a H2 atmosphere at room temperature for 1 h. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title compound (10 mg, 14% yield) as a white solid. 1H NMR (CDCl3, 300 MHz): δ 7.77 (d, J=2.1 Hz, 1H), 7.56 (s, 1H), 7.04 (s, 1H), 7.01 (s, 1H), 6.26 (d, J=2.7 Hz, 1H), 4.88-4.84 (m, 1H), 3.61 (s, 3H), 3.34-3.26 (m, 1H), 3.09 (q, J=7.5 Hz, 2H), 2.90-2.84 (m, 1H), 2.21 (s, 3H), 1.87-1.82 (m, 1H), 1.72-1.63 (m, 1H), 1.56-1.43 (m, 2H), 1.38 (t, J=7.2 Hz, 3H), 0.98 (t, J=7.5 Hz, 3H). LCMS: 391 (M+1)+.
Reaction SMILES: [Cl:1]C1C=C2C(C=CN=C2)=CC=1F.[ClH:13].[NH:14]1[CH2:19][CH2:18][CH:17]([O:20][C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[CH:27]=[N:26][CH:25]=[CH:24]3)[CH2:16][CH2:15]1>>[ClH:1].[Cl:13][C:30]1[CH:29]=[C:28]2[C:23]([CH:24]=[CH:25][N:26]=[CH:27]2)=[CH:22][C:21]=1[O:20][CH:17]1[CH2:18][CH2:19][NH:14][CH2:15][CH2:16]1
Reactant: Fc1cc2ccncc2cc1Cl
Reactant: c1cc2cc(OC3CCNCC3)ccc2cn1
Agent: Cl
Product: Clc1cc2cnccc2cc1OC1CCNCC1

Procedure:
Starting from 7-Chloro-6-fluoro-isoquinoline (150), the title compound was prepared by the same synthetic route as for compound 124. Rt=0.66 min (Method #1), detected mass: 263.1/265.1 (M+H+).
Reaction SMILES: [C:1]1([C:11]([OH:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[N+:14]([O-])([OH:16])=[O:15]>S(=O)(=O)(O)O>[N+:14]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH:4]=[CH:3][N:2]=[C:1]2[C:11]([OH:13])=[O:12])([O-:16])=[O:15]
Reactant: O=C(O)c1nccc2ccccc12
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C(O)c1nccc2c([N+](=O)[O-])cccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
Isoquinoline-1-carboxylic acid (3.98 g, 23.0 mmol) was dissolved in conc. sulfuric acid (16 ml) at 0° C. A mixture of conc. sulfuric acid (5 ml) and fuming nitric acid (5 ml) was added over 10 min. and the reaction stirred for a further 1 h at 0° C., then poured into ice-water (400 ml). The solid was collected by filtration, then washed with water (100 ml), ethanol (100 ml) and ether (100 ml), then dried under vacuum to give the title compound (4.1 g, 82%).
Reaction SMILES: [CH3:1][C:2]1[O:11][C:5]2[N:6]=[CH:7][N:8]=[C:9](Cl)[C:4]=2[CH:3]=1.[CH3:12][S-:13].[Na+]>C(#N)C>[CH3:1][C:2]1[O:11][C:5]2[N:6]=[CH:7][N:8]=[C:9]([S:13][CH3:12])[C:4]=2[CH:3]=1
Reactant: C[S-]
Reactant: Cc1cc2c(Cl)ncnc2o1
Agent: [Na+]
Solvent: CC#N
Product: CSc1ncnc2oc(C)cc12
Yield: 90 %

Procedure:
A solution of 6-methyl-4-chlorofuro[2,3-d]pyrimidine (U.S. Pat. No. 3,577,420, example IG) (219 mg) in acetonitrile (25 mL) was heated under reflux with sodium thiomethoxide (190 mg) for 16 hours. The mixture was filtered and the solids washed with acetonitrile. Evaporation of the solvent afforded the title compound as a white solid (230 mg, 90%);
Reaction SMILES: [SH:1][CH2:2][C:3]([OH:5])=[O:4].[Cl:6][C:7]1[CH:17]=[CH:16][C:10]([CH:11]=[CH:12][C:13]([OH:15])=[O:14])=[CH:9][CH:8]=1.C(N(CC)CC)C.S(=O)(=O)(O)O>O1CCOCC1>[C:3]([CH2:2][S:1][CH:11]([C:10]1[CH:9]=[CH:8][C:7]([Cl:6])=[CH:17][CH:16]=1)[CH2:12][C:13]([OH:15])=[O:14])([OH:5])=[O:4]
Reactant: O=C(O)CS
Reactant: O=C(O)C=Cc1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C(O)CSC(CC(=O)O)c1ccc(Cl)cc1

Procedure:
To a stirred mixture of mercaptoacetic acid (5.04 g, 3.8 ml, 54.7 mmol) and 4-chlorocinnamic acid (10.0 g, 54.7 mmol) in 20 ml of dioxane is added dropwise a solution of triethylamine (6.90 g, 9.53 ml, 68.0 mmol) in 20 ml of dioxane. The mixture is heated under reflux for 5 hours, then cooled and poured into ice, acidified with conc. sulfuric acid and extracted with ether. The combined ether extracts are washed with water and with brine, dried and stripped of the solvent. The residue is washed with chloroform to give 3-carboxymethylthio-3-(4-chlorophenyl)propionic acid, a yellow solid.
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[NH2:8][C:9]1[N:14]=[CH:13][N:12]=[C:11]2[N:15]([CH:19]([C:21]3[C:22]([O:38][CH3:39])=[C:23]([CH2:29][CH2:30][C:31]([O:33]C(C)(C)C)=[O:32])[C:24]([CH3:28])=[C:25]([Cl:27])[CH:26]=3)[CH3:20])[N:16]=[C:17]([CH3:18])[C:10]=12>C(Cl)Cl>[F:4][C:3]([F:6])([F:5])[C:1]([OH:7])=[O:2].[NH2:8][C:9]1[N:14]=[CH:13][N:12]=[C:11]2[N:15]([CH:19]([C:21]3[C:22]([O:38][CH3:39])=[C:23]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])[C:24]([CH3:28])=[C:25]([Cl:27])[CH:26]=3)[CH3:20])[N:16]=[C:17]([CH3:18])[C:10]=12
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1CCC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1CCC(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
TFA (0.3 mL, 4 mmol) was added to a solution of tert-butyl 3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}propanoate (35 mg, 0.076 mmol) in methylene chloride (0.2 mL) and the mixture was stirred at room temperature for 2 h. The solvent was removed and the product was used in the next step without further purification. LCMS calculated for C19H23ClN5O3 (M+H)+: m/z=404.1; Found: 404.0
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH3:32])[C:5]1[CH:10]=[C:9]([C:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]=2)[CH:8]=[C:7]([NH:24][C:25]2[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][N:26]=2)[N:6]=1>CO.[Pd]>[OH:1][CH2:2][CH2:3][N:4]([CH3:32])[C:5]1[CH:10]=[C:9]([CH:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:18])[CH2:15][CH2:16]2)[CH:8]=[C:7]([NH:24][C:25]2[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][N:26]=2)[N:6]=1
Reactant: Cc1ccnc(Nc2cc(C3=CCN(C(=O)OC(C)(C)C)CC3)cc(N(C)CCO)n2)c1
Agent: [Pd]
Solvent: CO
Product: Cc1ccnc(Nc2cc(C3CCN(C(=O)OC(C)(C)C)CC3)cc(N(C)CCO)n2)c1
Yield: 78.1 %

Procedure:
tert-butyl 4-(2-((2-hydroxyethyl)(methyl)amino)-6-(4-methylpyridin-2-ylamino)pyridin-4-yl)-5,6-dihydropyridine-1(2H)-carboxylate (130 mg, 0.29 mmol) was dissolved in MeOH (50 mL). The resulting solution was hydrogenated in H-Cube hydrogenation reactor, with 10% Pd/C cartridge under 40 bar, eluded 1 mL/min at 30° C. for two times. The resulting mixture was again hydrogenated under 50 bar, 1 mL/min at 30° C. for three times. The solution was concentrated in vacuo to give 100 mg (76%) of the title compound as a clear yellow gum. It was carried on as is. 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J=5.2 Hz, 1H), 7.35 (s, 1H), 6.96 (s, 1H), 6.65 (d, J=5.2 Hz, 1H), 6.61 (s, 1H), 5.92 (s, 1H), 4.30 (d, J=53.7 Hz, 2H), 3.87 (t, J=5.0 Hz, 2H), 3.75 (t, J=5.0 Hz, 2H), 3.07 (s, 3H), 2.78 (t, J=12.6 Hz, 2H), 2.59-2.51 (m, 1H), 2.31 (s, 3H), 1.82 (d, J=12.7 Hz, 2H), 1.70-1.56 (m, 2H), 1.49 (s, 9H). LC-MS: m/z=442 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:16])[NH:10][C@@H:11]([CH3:15])[CH2:12][CH2:13][OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])(C)C.N1C=CN=C1>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:8][C:9](=[O:16])[NH:10][C@@H:11]([CH3:15])[CH2:12][CH2:13][O:14][SiH2:17][C:20]([CH3:23])([CH3:22])[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](CCO)NC(=O)OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H](CCO[SiH2]C(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 114.6 %

Procedure:
(3-Hydroxy-1-(S)-methyl-propyl)-carbamic acid benzyl ester (8.02 g, 35.9 mmol) was taken up in DMF (75 mL). tert-Butyl-dimethylsilyl chloride (8.12 g, 53.9 mmol) was added to the solution followed by imidazole (4.15 g, 61.0 mmol). The reaction was stirred at rt and monitored by TLC. The reaction was determined to be complete at 1 h by TLC. The reaction was taken up in EtOAc (200 mL) and partitioned between 5% LiCl(aq) (200 mL). The aqueous was back extracted with EtOAc. The organics were combined and washed with 3×200 mL 5% LiCl(aq), and dried over Na2SO4. Solids were filtered and solvent removed under reduced pressure. [3-(tert-Butyl-silanoxy)-1-(S)-methyl-propyl]-carbamic acid benzyl ester (12.73 g, 100%) was isolated by silica gel chromatography as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:23])[CH:4]([NH:15]C(OC(C)(C)C)=O)[CH2:5][C:6]1[CH:11]=[C:10]([Br:12])[C:9]([OH:13])=[C:8]([Br:14])[CH:7]=1.Br[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[F:32]>>[NH2:15][CH:4]([CH2:5][C:6]1[CH:7]=[C:8]([Br:14])[C:9]([O:13][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[F:32])=[C:10]([Br:12])[CH:11]=1)[C:3]([OH:2])=[O:23]
Reactant: COC(=O)C(Cc1cc(Br)c(O)c(Br)c1)NC(=O)OC(C)(C)C
Reactant: Fc1ccccc1CBr
Product: NC(Cc1cc(Br)c(OCc2ccccc2F)c(Br)c1)C(=O)O
Yield: 10 %

Procedure:
Methyl-2-tert-butoxycarbonylamino-3-(3,5-dibromo-4-hydroxyphenyl)propionate (0.035 mmol) was coupled with 1-bromomethyl-2-fluorobenzene and hydrolyzed using the method described in “General procedure for the preparation of Examples 8-22”. This gave 10% yield of 2-amino-3-[3,5-dibromo-4-(2-fluorobenzyloxy)phenyl]propionic acid. LC/MS (electrospray): m/z 446 (M−1).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@@H:16]([O:17][C:18]3[N:40]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:21]4=[N:22][C:23]([C:27]5[CH:32]=[CH:31][C:30]([C@H:33]6[CH2:38][CH2:37][C@H:36]([OH:39])[CH2:35][CH2:34]6)=[CH:29][CH:28]=5)=[C:24]([Cl:26])[CH:25]=[C:20]4[N:19]=3)[C@H:12]2[O:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N:49]1([C:55](Cl)=[O:56])[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1>N1C=CC=CC=1>[N:49]1([C:55]([O:39][C@H:36]2[CH2:37][CH2:38][C@H:33]([C:30]3[CH:31]=[CH:32][C:27]([C:23]4[N:22]=[C:21]5[N:40]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:18]([O:17][C@@H:16]6[CH2:15][O:14][C@@H:13]7[C@H:9]([O:8][Si:1]([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2])[CH2:10][O:11][C@H:12]67)=[N:19][C:20]5=[CH:25][C:24]=4[Cl:26])=[CH:28][CH:29]=3)[CH2:34][CH2:35]2)=[O:56])[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1
Reactant: O=C(Cl)N1CCOCC1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2cc(Cl)c(-c3ccc([C@H]4CC[C@H](O)CC4)cc3)nc2n1COCC[Si](C)(C)C
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2cc(Cl)c(-c3ccc([C@H]4CC[C@H](OC(=O)N5CCOCC5)CC4)cc3)nc2n1COCC[Si](C)(C)C
Temperature: 50 °C
Reaction time: 12 h

Procedure:
(trans)-4-(4-(2-((3R,3aR,6R,6aS)-6-(tert-Butyldimethylsilyloxy)hexahydrofuro[3,2-b]-furan-3-yloxy)-6-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-5-yl)phenyl)cyclohexanol (50 mg) is dissolved in pyridine (1 mL), treated with morpholine-4-carbonyl chloride (25 μL) and stirred for 12 hours at 50° C. Morpholine-4-carbonyl chloride (25 μL) is added and the mixture is stirred for 2 hours at 50° C. Then morpholine-4-carbonyl chloride (75 μL) is added and the mixture is stirred for 48 hours at 70° C. The mixture is partitioned between ethylacetate and hydrochloric acid (1 M). The organic phase is dried (MgSO4) and concentrated. The crude product is used directly in the next step.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=2)[CH:4]=1.[CH2:22]([N:29]=[C:30]=[O:31])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>>[CH2:22]([NH:29][C:30](=[O:31])[N:2]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:14]=2)[CH:4]=1)[CH3:1])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCN=C=O
Reactant: CCOC(=O)CCc1ccc(-c2cc(NC)ccn2)cc1
Product: CCCCCCCNC(=O)N(C)c1ccnc(-c2ccc(CCC(=O)OCC)cc2)c1
Yield: 97 %

Procedure:
270 mg (0.63 mmol, 1 eq) of ethyl 3-[4-(4-methylaminopyrid-2-yl)phenyl]propanoate are mixed with 0.6 mL (3.7 mmol, 6 eq) of heptyl isocyanate and then irradiated in a microwave machine for 2 times 30 minutes, while keeping the temperature constant at 100° C. The reaction mixture is chromatographed on silica gel (90/10 heptane/ethyl acetate). 260 mg of ethyl 3-{4-[4-(3-heptyl-1-methylureido)pyrid-2-yl]phenyl}propanoate are obtained. Yield=64%.
Reaction SMILES: FC(F)(F)S(O[Si:7]([CH3:18])([CH3:17])[CH:8]1[C:12]([CH3:13])=[C:11]([CH3:14])[C:10]([CH3:15])=[C:9]1[CH3:16])(=O)=O.[C:21]([C:25]1[CH:30]=[CH:29][C:28]([C-:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:33]=[CH:32]2)=[CH:27][CH:26]=1)([CH3:24])([CH3:23])[CH3:22].[Li+]>CCOCC>[C:21]([C:25]1[CH:26]=[CH:27][C:28]([C:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:33]([Si:7]([CH3:17])([CH3:18])[CH:8]3[C:12]([CH3:13])=[C:11]([CH3:14])[C:10]([CH3:15])=[C:9]3[CH3:16])[CH:32]=2)=[CH:29][CH:30]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CC1=C(C)C([Si](C)(C)OS(=O)(=O)C(F)(F)F)C(C)=C1C
Reactant: CC(C)(C)c1ccc(-[c-]2ccc3ccccc32)cc1
Agent: [Li+]
Solvent: CCOCC
Product: CC1=C(C)C([Si](C)(C)C2C=C(c3ccc(C(C)(C)C)cc3)c3ccccc32)C(C)=C1C
Reaction time: 18 h

Procedure:
To a solution of dimethyl(2,3,4,5-tetramethylcyclopenta-2,4-dien-1-yl)silyl trifluoromethanesulfonate (Compound C, 7.50 g, 22.8 mmol, 1.00 eq.) in ether (25 mL) at −35° C. was added lithium (1-(4-t-butylphenyl)indenide) (6.20 g, 24.4 mmol, 1.07 eq.). The reaction was stirred for 18 hours, and was then evaporated under vacuum. The residue was extracted with pentane (40 mL) and the extract was filtered. The resulting solution was evaporated under vacuum to give a thick oil. Yield 10.11 g (104%). 1H NMR(C6D6): δ 7.83 (d, 1H), 7.67 (d, 2H), 7.50 (d, 1H), 7.41 (d, 2H), 7.26 (m, 2H), 6.64 (s, 1H), 3.71, (s, 1H), 2.95 (br s, 1H), 1.95 (s, 3H), 1.93 (s, 3H), 1.84 (s, 3H), 1.82 (s, 3H), 1.30 (s, 9H), −0.06 (s, 3H), −0.36 (s, 3H).
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4]>[Pt].O>[OH:1][CH2:2][C:3]([C@H:5]([C@H:2]([CH2:3][OH:4])[OH:1])[OH:6])=[O:4]
Reactant: OCC(O)CO
Agent: [Pt]
Solvent: O
Product: O=C(CO)[C@@H](O)[C@@H](O)CO
Reaction time: 48 h

Procedure:
One hundred ml aliquots of a nutrient culture medium, consisting of 2 w/v % trypton soya broth, one w/v % glycerol and deionized water, were distributed to ten 500-ml shaking flasks, followed by autoclaving the flasks at 120° C. for 20 min. Thereafter, the flasks were cooled and inoculated with a seed culture of Gluconobacter frateurii (IFO 3254) using a platinum loop, followed by incubation at 30° C. for 2 days under shaking conditions. After completion of the culture, the cells were collected by centrifugation, and about 10 g wet alive cells was mixed with 100 ml of 0.05 M Tris-HCl buffer (pH 7.0) containing 5 w/v % ribitol. The mixture solution in a volume of 100 ml was placed in a 500-ml shaking flask, and incubated at 30° C. for 20 hours under shaking conditions to convert ribitol into L-ribulose. Thereafter, the culture was centrifuged to remove cells, and the resulting supernatant was in a conventional manner decolored with activated charcoal, desalted with “DIAION SK1B (H-form)” and “DIAION WA30 (OH-form)”, both of which are cation exchangers of Mitsubishi Chemical Corporation, Tokyo, Japan, and concentrated in vacuo to obtain a transparent syrup with a concentration of about 60 w/w %. The syrup was fractionated by column chromatography using “DOWEX 50W-X4”, a cation exchanger in Ca++-form commercialized by The Dow Chemical Co., Midland, Mich., USA, to obtain high L-ribulose content fractions which were then concentrated into an about 70 w/w % syrup. High-performance liquid chromatographic (HPLC) analysis using a column, 8×300 mm, packed with “MCIGEL CK-08EC”, a gel in Ca++-form commercialized by Mitsubishi Chemical Corporation, Tokyo, Japan, revealed that the product contained at least 97 w/w % L-ribulose, d.s.b. The yield of L-ribulose to the material ribitol was about 90%, d.s.b.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[CH:15]=[C:14]([CH:16]3[CH2:18][CH2:17]3)[NH:13][C:12]1=[O:19])[CH2:8]2.Br[CH2:21][CH:22]1[CH2:24][CH2:23]1>>[CH:1]12[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH:2]1[N:11]1[CH:15]=[C:14]([CH:16]3[CH2:17][CH2:18]3)[N:13]([CH2:21][CH:22]3[CH2:24][CH2:23]3)[C:12]1=[O:19])[CH2:10]2
Reactant: O=c1[nH]c(C2CC2)cn1C1C2CC3CC(C2)CC1C3
Reactant: BrCC1CC1
Product: O=c1n(C2C3CC4CC(C3)CC2C4)cc(C2CC2)n1CC1CC1

Procedure:
This material was obtained in analogy to the procedure outlined in example 23 from 1-adamantan-2-yl-4-cyclopropyl-1,3-dihydro-imidazol-2-one (obtained in example 15, 100 mg) by alkylation with bromomethylcyclopropane (57 mg). 1-Adamantan-2-yl-4-cyclopropyl-3-cyclopropylmethyl-1,3-dihydro-imidazol-2-one was obtained as a light yellow oil (11 mg). MS (EI): 312.3 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.[Cl:10][C:11]([F:16])([F:15])[C:12](O)=O>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:12]([C:11]([Cl:10])([F:16])[F:15])=[N:9][C:4]=2[CH:3]=1
Reactant: O=C(O)C(F)(F)Cl
Reactant: Nc1ccc(Br)cc1N
Solvent: O
Product: FC(F)(Cl)c1nc2cc(Br)ccc2[nH]1
Yield: 41.8 %

Procedure:
A mixture of 4-bromo-phenylene-diamine (1.00 g, 5.35 mmol), chlorodifluoroacetic acid (3.0 mL, 35.4 mmol), and a drop of water was heated to 80° C. for 14 hours. The crude product was purified by chromatography (silica, hexanes: EtOAc, 4:1) to afford the title compound as a colorless oil (0.63 g, 42%).
Reaction SMILES: C(Cl)(=O)C(C)(C)C.[CH3:8][O:9][C:10]([C:12]1[CH:13]=[C:14]([CH:20]=[CH:21][CH:22]=1)[O:15][CH2:16][C:17]([OH:19])=O)=[O:11].C(N(CC)CC)C.[CH3:30][O:31][C:32]1[CH:37]=[C:36]([O:38][C:39]2[CH:40]=[C:41]([NH:46][CH3:47])[C:42]([NH2:45])=[CH:43][CH:44]=2)[CH:35]=[CH:34][N:33]=1>ClCCl>[CH3:30][O:31][C:32]1[CH:37]=[C:36]([O:38][C:39]2[CH:44]=[CH:43][C:42]([NH:45][C:17](=[O:19])[CH2:16][O:15][C:14]3[CH:13]=[C:12]([CH:22]=[CH:21][CH:20]=3)[C:10]([O:9][CH3:8])=[O:11])=[C:41]([NH:46][CH3:47])[CH:40]=2)[CH:35]=[CH:34][N:33]=1
Reactant: COC(=O)c1cccc(OCC(=O)O)c1
Reactant: CNc1cc(Oc2ccnc(OC)c2)ccc1N
Agent: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNc1cc(Oc2ccnc(OC)c2)ccc1NC(=O)COc1cccc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.4 %

Procedure:
Pivaloyl chloride (1.74 mL, 14.2 mmol) was added dropwise to a solution of [3-(methoxycarbonyl)phenoxy]acetic acid produced in Example (1c) (3.27 g, 15.6 mmol) and triethylamine (1.97 mL, 14.2 mmol) in dichloromethane (40 mL) in a nitrogen atmosphere at 0° C. After one hour, a solution of 4-[(2-methoxypyridin-4-yl)oxy]-N2-methylbenzene-1,2-diamine produced in Example (16d) (3.46 g, 14.2 mmol) and triethylamine (1.97 mL, 14.2 mmol) in dichloromethane (40 mL) was added dropwise at 0° C., and the mixture was stirred at room temperature for two hours. The reaction mixture was concentrated under reduced pressure. Then, the residue was purified by silica gel chromatography (ethyl acetate) to obtain the title compound (4.81 g, 78%) as a pale brown oil.
Reaction SMILES: [F:1][CH:2]([F:12])[O:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([CH2:10]O)[CH:5]=1.C(Br)(Br)(Br)[Br:14].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[Br:14][CH2:10][C:6]1[CH:5]=[C:4]([O:3][CH:2]([F:12])[F:1])[CH:9]=[CH:8][N:7]=1
Reactant: OCc1cc(OC(F)F)ccn1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: FC(F)Oc1ccnc(CBr)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (4-(difluoromethoxy)pyridin-2-yl)methanol (250 mg; 1.42 mmol) in anh. DCM (12 ml) was treated at rt with CBr4 (473 mg; 1.42 mmol), and with PPh3 (374 mg; 1.42 mmol). The resulting mixture was further stirred at rt, under nitrogen, for 1 h. Concentration to dryness under reduced pressure, and subsequent purification by FC (DCM) afforded 2-(bromomethyl)-4-(difluoromethoxy)pyridine as a yellow oil which was directly used for the next reaction. LC-MS (conditions A): tR=0.56 min.; [M+H]+: 237.92 g/mol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][CH:12]=1)[C:5]#[N:6].C(=O)([O-])[O-:20].[K+].[K+].OO>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][CH:12]=1)[C:5]([NH2:6])=[O:20]
Reactant: N#Cc1ccc(Oc2ccc(C=O)cc2)c(Cl)c1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)c1ccc(Oc2ccc(C=O)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 166.5 %

Procedure:
Cool a solution of 3-chloro-4-(4-formyl-phenoxy)-benzonitrile (1.57 g, 6.10 mmol) in dimethylsulfoxide (50 mL) to 0° C. Add potassium carbonate (0.42 g, 3.05 mmol) followed by 30% aqueous hydrogen peroxide (1.83 mL, 6.10 mmol). Remove the cooling bath and let stir at rt for 3 hrs. Pour into water (100 mL) and after trituration, filter the solid formed to obtain the product (1.40 g, 84%). 1H NMR (DMSO-d6) 9.93 (s, 1H), 8.12 (d, J=1.2 Hz, 1H), 8.10 (bs, 1H), 7.95-7.90 (m, 3H), 7.53 (bs, 1H), 7.34 (d, J=8.6 Hz, 1H), 7.13 (d, J=8.6 Hz, 2H).