Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Li].[CH2:3]([O:10][C@@H:11]1[CH2:16][CH2:15][CH2:14][C:13]2([O:20][CH2:19][CH2:18][O:17]2)[C@@:12]1([CH3:26])[CH2:21][CH2:22][CH2:23][CH:24]=[O:25])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CCOCC>[CH2:3]([O:10][C@@H:11]1[CH2:16][CH2:15][CH2:14][C:13]2([O:17][CH2:18][CH2:19][O:20]2)[C@@:12]1([CH3:26])[CH2:21][CH2:22][CH2:23][CH:24]([OH:25])[CH3:1])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C[C@]1(CCCC=O)[C@H](OCc2ccccc2)CCCC12OCCO2
Reactant: [Li]C
Solvent: CCOCC
Product: CC(O)CCC[C@@]1(C)[C@H](OCc2ccccc2)CCCC12OCCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
Methyllithium (63.3 ml, 0.0918 l mol, 1.45 M in ether) is added dropwise to a solution of the aldehyde, (2S*,3R*)-3-benzyloxy-1,1-ethylenedioxy-2-methyl-2-(4'-oxobutyl)-cyclohexane (25.4 g, 0.0765 mol) in ether (1000 ) at 0° C. in a nitrogen atmosphere. The cooling bath is removed and the mixture is stirred for 0.5 hours at ambient temperature. The mixture is then poured into a cold saturated sodium chloride solution (500 ml). The ether phase is separated and the aqueous phase is extracted with ether (3×100 ml). The ether phases are combined, dried (MgSO4) and the solvent is removed at reduced pressure. The crude product (27.1 g) is chromatographed on SilicAR CC-7 (300 g, Mallinckrodt) in hexane. Elution with 10% ethyl acetate/hexane gives (2S*,3R*)-3-benzyloxy-1,1-ethylenedioxy-2-methyl-2-(4'-hydroxypentyl)-cyclohexane as a colorless oil (25.8 g, 97%).
Reaction SMILES: [Br-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C[CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])C=CC=CC=1.[CH:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][C:30]=1[CH:39]=O.CC(C)([O-])C.[K+]>CS(C)=O>[CH:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][C:30]=1/[CH:39]=[CH:10]\[CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15]
Reactant: O=Cc1ccc2ccccc2c1
Reactant: O=C(O)CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(O)CCC/C=C\c1ccc2ccccc2c1
Reaction time: 0.5 h

Procedure:
Triphenyl (5-carboxypentyl)phosphonium bromide (937 mg, 2.1 mmole) and 2-napthaldehyde (300 mg, 1.92 mmole) were dissolved in DMSO (50 mL, freshly distilled from CaH2) and potassium t-butoxide (540 mg, 4.8 mmole) was added. After stirring for 30 minutes the reaction was quenched with saturated NH4Cl solution (25 mL) and poured into ether. The ether layer was dried with saturated NaCl and MgSO4 and the solvent was evaporated. The resulting 1:1 mixture E/Z isomers were separated with flash chromatography eluting with ether/hexane/formic acid (10:89:1).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8](=O)[CH2:9]Br)=[C:5]([CH3:7])[N:6]=1.[CH3:12][C:13]([CH3:18])([CH3:17])[C:14](=[S:16])[NH2:15].C(N(CC)CC)C>C(O)C>[C:13]([C:14]1[S:16][CH:9]=[C:8]([C:4]2[S:3][C:2]([NH2:1])=[N:6][C:5]=2[CH3:7])[N:15]=1)([CH3:18])([CH3:17])[CH3:12]
Reactant: Cc1nc(N)sc1C(=O)CBr
Reactant: CC(C)(C)C(N)=S
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1nc(N)sc1-c1csc(C(C)(C)C)n1
Temperature: 25 °C

Procedure:
A mixture of 1-(2-amino-4-methyl-thiazol-5-yl)-2-bromo-ethanone (7.0 g, prepared as described in WO 2006/125805), 2,2-dimethylpropanethioamide (2.25 g, prepared as described by Boys and Downs in Synthetic Communications 2006, 36, 295-298.), triethylamine (7.2 ml) and ethanol (173 ml) are heated at reflux for 3.5 hours. On cooling to room temperature the reaction mixture is filtered, the filtrate evaporated and then partitioned between aqueous NaHCO3 and CH2Cl2, extracting 3×CH2Cl2. The organic layers are dried and evaporated then triturated 4× with diethyl ether (50 ml), the diethyl ether layers combined and extracted with 1M HCl (100 ml). The HCl layer is then washed 3× diethyl ether, basified with aqueous NaOH and extracted 4× diethyl ether and 2×CH2Cl2. The organic layers dried over Na2SO4 and evaporated to give the title compound as a red solid. Hplc/MS (Method B) RT 1.95 minutes, M+H 253.9.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[CH:14]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:20][C:21]([F:34])([F:33])[O:22][C:23]1[CH:24]=[C:25]([S:29](Cl)(=[O:31])=[O:30])[CH:26]=[CH:27][CH:28]=1.C(N(CC)CC)C>O1CCCC1>[CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([C:13]2[CH:14]=[C:15]([NH:19][S:29]([C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([O:22][C:21]([F:20])([F:33])[F:34])[CH:24]=3)(=[O:31])=[O:30])[CH:16]=[CH:17][CH:18]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc([C@@H]2CCN(Cc3ccccc3)C2)c1
Reactant: O=S(=O)(Cl)c1cccc(OC(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=S(=O)(Nc1cccc([C@@H]2CCN(Cc3ccccc3)C2)c1)c1cccc(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.6 %

Procedure:
(S)-1-Benzyl-3-(3-amino-phenyl)-pyrrolidine (0.4 g, 1.59 mmol) and commercially available 3-trifluoromethoxy-benzene sulfonylchloride (0.39 g, 1.5 mmol) were dissolved in 30 ml tetrahydrofurane. 0.66 ml of triethylamine (3.75 mmol) were added and the mixture was stirred for 16 h at room temperature. The solvent was evaporated under reduced pressure and the residue was treated with water/diethylether. After adjusting the aqueous phase to alkaline pH with 1 N aqueous NaOH, the aqueous layer was extracted with diethylether and the combined organic layers dried over magnesium sulfate, filtered and evaporated. The product was purified via silica gel chromatography using an Isco Companion semi-automated chromatography system to yield 0.512 g of the desired compound.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH:7]2[CH2:13][C@H:12]3[N:14]([CH2:15][CH2:16][C:17]4([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=5[CH3:41])[CH2:22][CH2:21][N:20]([C:23]([C:25]5[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=5)[C:28]([O:30]C)=[O:29])=[O:24])[CH2:19][CH2:18]4)[C@H:9]([CH2:10][CH2:11]3)[CH2:8]2)[C:5]2[CH:42]=[CH:43][CH:44]=[CH:45][C:4]=2[N:3]=1.[OH-].[Na+]>CO>[CH3:1][C:2]1[N:6]([CH:7]2[CH2:13][C@H:12]3[N:14]([CH2:15][CH2:16][C:17]4([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=5[CH3:41])[CH2:22][CH2:21][N:20]([C:23]([C:25]5[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=5)[C:28]([OH:30])=[O:29])=[O:24])[CH2:19][CH2:18]4)[C@H:9]([CH2:10][CH2:11]3)[CH2:8]2)[C:5]2[CH:42]=[CH:43][CH:44]=[CH:45][C:4]=2[N:3]=1
Reactant: COC(=O)c1cccc(C(=O)N2CCC(CCN3[C@@H]4CC[C@H]3CC(n3c(C)nc5ccccc53)C4)(c3ccccc3C)CC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccccc1C1(CCN2[C@@H]3CC[C@H]2CC(n2c(C)nc4ccccc42)C3)CCN(C(=O)c2cccc(C(=O)O)c2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 23.3 %

Procedure:
A solution of methyl 3-{[4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-(2-methylphenyl)piperidin-1-yl]carbonyl}benzoate (0.15 g, 0.29 mmol) in methanol (1 mL) was treated with 2N sodium hydroxide solution (1.5 mL) and let stir at rt for 4 h. The mixture was concentrated to remove methanol and acidified by adding 1N hydrochloric acid. The resulting precipitate was collected, washed with water and dried to give 3-{[4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-(2-methylphenyl) piperidin-1-yl]carbonyl}benzoic acid as a pale pink solid (0.04 g, 31%). 1H NMR (400 MHz, CD3OD) δ 8.11 (m, 1H), 8.02 (s, 1H), 7.54 (m, 3H), 7.48 (m, 1H), 7.34 (m, 1H), 7.17-7.28 (m, 5H), 5.08 (m, 1H), 4.07 (m, 1H), 3.87 (m, 2H), 3.54 (m, 2H), 3.30 (m, 1H), 2.71 (m, 2H), 2.39-2.55 (m, 10H), 2.22-2.30 (m, 6H), 2.09 (m, 3H), 1.92 (m, 1H). HRMS C37H42N4O3 m/z 591.3335 (M+H)Cal., 591.3350 (M+H)Obs..
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[C:13]#[N:14])=[CH:5][CH:4]=1.Cl.[NH+]1C=CC=CC=1>>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[C:13]#[N:14])=[CH:5][CH:4]=1
Reactant: COc1ccc2cccc(C#N)c2c1
Agent: Cl
Agent: c1cc[nH+]cc1
Product: N#Cc1cccc2ccc(O)cc12

Procedure:
The title compound was prepared by reacting 7-methoxy-1-naphthonitrile (1.19 g, 6.50 mmol) with pyridinium HCl (9 g) according to method D to yield 0.88 g (80%) of a white solid: mp 184–188° C.; 1H NMR (DMSO-d6): δ 7.25 (1H, dd, J=2.30 Hz, J=8.88 Hz), 7.38 (1H, d, J=2.20 Hz), 7.39–7.44 (1H, m), 7.98 (1H, d, J=8.91 Hz), 8.04 (1H, d, J=7.14 Hz), 8.17 (1H, d, J=8.19 Hz), 10.48 (1H, s); MS (ESI) m/z 170 ([M+H]+); MS (ESI) m/z 168 (M−H)−.
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16](Cl)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1.Cl.[F:26][C:27]1([F:31])[CH2:30][NH:29][CH2:28]1.CCN(C(C)C)C(C)C>C(#N)C>[F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([N:29]4[CH2:30][C:27]([F:31])([F:26])[CH2:28]4)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1
Reactant: FC1(F)CNC1
Reactant: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(Cl)ccc12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(N3CC(F)(F)C3)ccc12
Temperature: 25 °C
Yield: 58.6 %

Procedure:
In a microwave vial 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide (100 mg, 0.27 mmol), 3,3-difluoro-azetidine hydrochloride (347.07 mg, 2.68 mmol) and DIPEA (519.43 mg, 4.02 mmol) in ACN (1.5 mL) was heated at 120° C. for 2 hours under microwave irradiation. After cooling to room temperature, the mixture was concentrated and purified through reverse phase HPLC to provide the desired product (68 mg, 59%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.88 (1H), 6.69 (1H), 4.54 (4H), 3.24 (t, J=6.24 Hz, 2H), 2.04 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 3H), 1.27-1.30 (m, 2H). m/z: 430 [M+H]
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][Si](C)(C)C)[CH:5]=[CH:4][C:3]=1[NH:14][C:15]1[C:27]([F:28])=[C:26]([F:29])[CH:25]=[CH:24][C:16]=1[C:17]([NH:19][O:20][CH2:21][CH2:22][OH:23])=[O:18].C(O)(=O)C.[F-].[Cs+]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[CH:9])[CH:5]=[CH:4][C:3]=1[NH:14][C:15]1[C:27]([F:28])=[C:26]([F:29])[CH:25]=[CH:24][C:16]=1[C:17]([NH:19][O:20][CH2:21][CH2:22][OH:23])=[O:18]
Reactant: C[Si](C)(C)C#Cc1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)c(Cl)c1
Agent: [Cs+]
Agent: [F-]
Solvent: CC(=O)O
Solvent: CO
Product: C#Cc1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)c(Cl)c1
Reaction time: 26 h

Procedure:
To a solution of the product of Example 8, Step A, 2-(2-Chloro-4-trimethylsilanylethynyl-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-benzamide (0.704 g, 1.60 mmol) in methanol (21 mL) was added acetic acid (0.1 mL) and cesium fluoride (0.600 g, 3.95 mmol). The resultant solution was stirred at ambient temperature. After 26 hours, the reaction mixture was partitioned between ethyl acetate (100 mL) and water (25 mL) and the organic layer was further washed with water (25 mL) and saturated brine (25 mL). The combined aqueous was extracted with ethyl acetate (50 mL). The combined organics were dried over magnesium sulfate and concentrated to a dark brown oil. Ether (15 mL) was added and crystallization ensued. The cream-colored solid was collected and dried under vacuum at 70° C. to afford 2-(2-chloro-4-ethynyl-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-benzamide (0.290 g): m.p. 155–157° C.; 1H NMR (400 MHz, DMSO-d6) δ 11.94 (br s, 1 H), 8.95 (br s, 1 H), 7.55 (d, J=2.0 Hz, 1 H), 7,48 (m, 1H), 7.34–7.27 (m, 2 H), 6.74 (dd, J=8.4, 6.5 Hz, 1 H), 4.71 (br s, 1 H), 4.13 (s, 1 H), 3.88 (t, J=4.6 Hz, 2 H), 3.58 (t, J=4.7 Hz, 2 H); MS (APCI+)=367.0; MS (APCI−)=365.0; Anal. Calcd/found for C17H13ClF2N2O3: C, 55.67/55.54; H, 3.57/3.23; N, 7.64/7.31. Concentration of the mother liquor afforded an additional crop of product (0.209 g, 85% total yield).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)(=[O:21])=[O:20])=[CH:15][C:14]=2[C:29]([OH:31])=[O:30])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:28][C:24]1[CH:23]=[C:22]([S:19]([C:16]2[CH:17]=[CH:18][C:13]([CH:10]3[CH2:11][CH2:12][NH:8][CH2:9]3)=[C:14]([CH:15]=2)[C:29]([OH:31])=[O:30])(=[O:21])=[O:20])[CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(S(=O)(=O)c3cccc(F)c3)cc2C(=O)O)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1cc(S(=O)(=O)c2cccc(F)c2)ccc1C1CCNC1
Reaction time: 4 h
Yield: 101.1 %

Procedure:
3-[2-Carboxy-4-(3-fluoro-benzenesulfonyl)-phenyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (75 mg, 0.167 mmol) was dissolved in 3 ml of CH2Cl2. TFA (0.5 ml) was added and the mixture was stirred for 4 hours. The solution was concentrated under reduced pressure. The residue was crystallized from MeOH to give 59 mgs (quantitative) of 5-(3-Fluoro-benzenesulfonyl)-2-pyrrolidin-3-yl-benzoic acid as a white powder, MS (M+H)=350.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:20]=[CH:19][C:18]2[CH2:17][CH2:16][C:15](=[O:21])[NH:14][C:13]=2[N:12]=1)(=O)=O.[Na+].[I-].Cl.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]1[CH2:39][CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.C([O-])([O-])=O.[K+].[K+]>CC#N.O>[CH3:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]1[CH2:39][CH2:38][CH2:37][N:36]([CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]2[N:12]=[C:13]3[C:18]([CH2:17][CH2:16][C:15](=[O:21])[NH:14]3)=[CH:19][CH:20]=2)[CH2:35][CH2:34]1
Reactant: COc1ccccc1N1CCCNCC1
Reactant: CS(=O)(=O)OCCCCOc1ccc2c(n1)NC(=O)CC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Solvent: O
Product: COc1ccccc1N1CCCN(CCCCOc2ccc3c(n2)NC(=O)CC3)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
A mixture of intermediate 12 (150 mg, 0.48 mmol) and NaI (141 mg, 0.94 mmol) in CH3CN was heated to reflux for 30 min and then cooled to rt. Intermediate 29 (114 mg, 0.47 mmol) and anhydrous K2CO3 (260 mg, 1.88 mmol) were added to the mixture. The resulting mixture was heated to reflux and stirred overnight. The reaction solution was diluted with water and extracted with EtOAc. The combined EtOAc layers were washed with brine, dried over anhydrous Na2SO4, concentrated in vacuo and purified by flash chromatography on silica gel column (elution with DCM/MeOH=30:1) to give 7-(4-(4-(2-methoxyphenyl)-1,4-diazepan-1-yl)butoxy)-3,4-dihydro-1,8-naphthyridin-2(1H)-one (compound 11) (40 mg, 17%). HPLC: 95%, RT 2.400 min. MS (EST) m/z 422.2 [M+H]+.
Reaction SMILES: I[C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][CH2:15][N:16]3[C:20]([CH3:22])([CH3:21])[C:19](=[O:23])[NH:18][C:17]3=[O:24])[N:8]=2)=[CH:4][CH:3]=1.[CH2:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[SH:33])[CH3:26].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(O[K])(C)(C)C>C1(C)C=CC=CC=1.C(O)(C)(C)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][CH2:15][N:16]3[C:20]([CH3:22])([CH3:21])[C:19](=[O:23])[NH:18][C:17]3=[O:24])[N:8]=2)=[CH:4][CH:3]=1)[CH3:26]
Reactant: CC1(C)C(=O)NC(=O)N1CCNc1nccc(-c2ccc(I)s2)n1
Reactant: CCc1ccccc1S
Agent: [Pd]
Agent: CC(C)(C)O[K]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1
Product: CCc1ccccc1Sc1ccc(-c2ccnc(NCCN3C(=O)NC(=O)C3(C)C)n2)s1
Temperature: 110 °C

Procedure:
A solution of 1-{2-[4-(5-iodothiophen-2-yl)pyrimidin-2-ylamino]ethyl}-5,5-dimethyl-imidazolidine-2,4-dione (50 mg, 0.109 mmol) and 0.060 mL (0.44 mmol) of 2-ethylthiophenol in 2 mL toluene was treated with 3 mg of Pd2dba3 (0.003 mmol), 3 mg of Xantphos (0.005 mmol) and 0.22 mL of a 1 M solution of tBuOK in t-butanol. The reaction vial was sealed and heated at 110° C. in a microwave for 10 min. The crude solution was concentrated onto 5 g of silica gel and then purified by flash chromatography to give the title compound. MS (M+H)+ 468.
Reaction SMILES: [Br:1]Br.[CH:3]1([C:6]([CH:13]2[CH2:15][CH2:14]2)([C:8]2[S:9][CH:10]=[CH:11][N:12]=2)[OH:7])[CH2:5][CH2:4]1.CC([O-])=O.[Na+]>C(O)(=O)C>[Br:1][C:10]1[S:9][C:8]([C:6]([CH:3]2[CH2:5][CH2:4]2)([CH:13]2[CH2:14][CH2:15]2)[OH:7])=[N:12][CH:11]=1
Reactant: BrBr
Reactant: OC(c1nccs1)(C1CC1)C1CC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: OC(c1ncc(Br)s1)(C1CC1)C1CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 57.1 %

Procedure:
Bromine (0.271 mL, 5.26 mmol) was added dropwise to a stirred mixture of the product of Step 1 (411 mg, 2.10 mmol) and NaOAc (863 mg; 10.5 mmol) in acetic acid (9.17 mL) and the mixture was stirred at room temperature for 4 h. The reaction was quenched with brine and the aqueous layer was extracted with ethyl acetate (3×). The combined organics were washed with brine, dried (sodium sulfate), filtered, and concentrated. The residue was purified by chromatography on silica gel (0-100% ethyl acetate in hexanes) to give (5-bromo-1,3-thiazol-2-yl)(dicyclopropyl)methanol (329 mg, 1.20 mmol, 57% yield) as an off-white solid. MS APCI: [M-OH]+ m/z 255.9
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([NH2:7])=[N:4][CH:3]=1.[C:8]1([CH:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15](Cl)=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[CH3:1][C:2]1[O:6][C:5]([NH:7][C:15](=[O:16])[CH:14]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:4][CH:3]=1
Reactant: Cc1cnc(N)o1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Product: Cc1cnc(NC(=O)C(c2ccccc2)c2ccccc2)o1

Procedure:
The title compound, off-white solid, m.p. 166-168° C. and MS: m/e=292.2 (M+) was prepared in accordance with the general method of example 44a from 5-methyl-oxazol-2-ylamine and 2,2-diphenylacetic acid chloride.
Reaction SMILES: C([O:8][C:9]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:19](=[O:21])[NH2:20])[NH:13]2)C1C=CC=CC=1.C(O)CO.COC.[H][H]>[Pd].CO>[OH:8][C:9]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:19](=[O:21])[NH2:20])[NH:13]2
Reactant: Cc1cc(OCc2ccccc2)c2cc(C(N)=O)[nH]c2c1
Reactant: [H][H]
Agent: [Pd]
Agent: COC
Solvent: OCCO
Solvent: CO
Product: Cc1cc(O)c2cc(C(N)=O)[nH]c2c1
Yield: 93 %

Procedure:
8.5 g of the thus obtained 4-benzyloxy-2-carbamoyl-6-methyl indole are hydrogenated in a composition of 100 ml methanol and 50 ml ethylene glycol-dimethyl ether during addition of 1.0 g 10% Pd/C up to the absorption of the theoretical amount of hydrogen. The catalyst is aspirated and the filtrate is evaporated in vacuum. There is obtained 5.4 (~93% of theory) 4-hydroxy-2-carbamoyl-6-methyl indole as a light yellow syrup.
Reaction SMILES: [Br:1][C:2]1[CH:30]=[CH:29][C:5]2[N:6]([C:16]([C:18]3[CH:19]=[CH:20][C:21]4[O:26][CH2:25][C:24](=[O:27])[NH:23][C:22]=4[CH:28]=3)=[O:17])[C@@H:7]([CH2:10][C:11]([O:13]CC)=[O:12])[CH2:8][O:9][C:4]=2[CH:3]=1.[OH-].[Li+].CCOC(C)=O>C1COCC1.O>[Br:1][C:2]1[CH:30]=[CH:29][C:5]2[N:6]([C:16]([C:18]3[CH:19]=[CH:20][C:21]4[O:26][CH2:25][C:24](=[O:27])[NH:23][C:22]=4[CH:28]=3)=[O:17])[C@@H:7]([CH2:10][C:11]([OH:13])=[O:12])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: CCOC(=O)C[C@H]1COc2cc(Br)ccc2N1C(=O)c1ccc2c(c1)NC(=O)CO2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)C[C@H]1COc2cc(Br)ccc2N1C(=O)c1ccc2c(c1)NC(=O)CO2
Yield: 96.7 %

Procedure:
Ethyl 2-[(3S)-7-bromo-4-(3-oxo-4H-1,4-benzoxazine-6-carbonyl)-2,3-dihydro-1,4-benzoxazin-3-yl]acetate (Intermediate 28a, 173 mg, 0.37 mmol) was dissolved in THF (1.5 mL). Lithium hydroxide (52.5 mg, 2.19 mmol) dissolved in water (1.50 mL) was added. The reaction was stirred at rt for 2 h before addition of EtOAc (50 mL). The organic layer was washed with HCl (1M, 30 mL) and brine (30 mL). Dried through a phase separator and evaporated under reduced pressure. The title compound (160 mg, 98%) was obtained crude and used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[OH:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15](O)[CH:16]=2)[CH:11]=1.S(=O)(O)[O-].[Na+]>O>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:15]2[CH:16]=[C:17]3[C:12](=[CH:13][CH:14]=2)[CH:11]=[C:10]([OH:9])[CH:19]=[CH:18]3)=[CH:3][CH:4]=1
Reactant: Nc1ccc(O)cc1
Reactant: Oc1ccc2cc(O)ccc2c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Product: Oc1ccc(Nc2ccc3cc(O)ccc3c2)cc1
Yield: 31.1 %

Procedure:
A mixture of 300 mg (2.75 mmol, Aldrich) of 4-aminophenol, 1.5 g (90%, 8.4 mmol, Aldrich) of 2,6-dihydroxynaphthalene and 1.0 g (9.6 mmol, Aldrich), of sodium bisulfite in 30 ml of H2O was refluxed for 18 hours. The reaction mixture was cooled, added to 30 ml of H2O and extracted with two 25 ml portions of ethyl acetate. The organic extracts were combined, dried (MgSO4), and concentrated in vacuo to give a solid. The crude solid was purified by flash chromatography (15×5.0 cm, 1:2 EtOAc/pet ether) followed by recrystallization (EtOAc/pet ether) to afford 215 mg (31%) of title compound as pale pink crystals, m.p. 195°-196°.
Reaction SMILES: NC(CCO)CCO.N1ON=C2C=C(C(Cl)=O)C=CC=12.C(=O)([O-])[O-].[K+].[K+].[OH:27][CH2:28][CH2:29][CH:30]([NH:34][C:35]([C:37]1[CH:45]=[CH:44][C:40]2=[N:41][O:42][N:43]=[C:39]2[CH:38]=1)=[O:36])[CH2:31][CH2:32][OH:33].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl.C(Cl)(Cl)Cl.CO.C(N(CC)CC)C>[OH:27][CH:28]1[CH2:29][CH:30]([NH:34][C:35]([C:37]2[CH:45]=[CH:44][C:40]3=[N:41][O:42][N:43]=[C:39]3[CH:38]=2)=[O:36])[CH2:31][CH2:32][O:33]1
Reactant: O=C(NC(CCO)CCO)c1ccc2nonc2c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: NC(CCO)CCO
Agent: O=C(Cl)c1ccc2nonc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: O=C(NC1CCOC(O)C1)c1ccc2nonc2c1
Temperature: 45 °C
Reaction time: 3 h
Yield: 24 %

Procedure:
To a solution of 3-aminopentane-1,5-diol (2.38 g, 20 mmol) (Helv. Chim. Acta 1964, 47(8), 2145-2153) and triethylamine (4 ml), in dichloromethane (30 ml), was slowly added, at 0° C., a solution of [2,1,3]-benzoxadiazole-5-carboxylic acid chloride (1.82 g, 10 mmol), in dichloromethane (20 ml), and the mixture stirred for 1 h. A mixture of methanol (30 ml) and 4N potassium carbonate solution (20 ml) was added and stirred for 3 h. The mixture was evaporated onto silica gel and purified by silica gel chromatography eluting with ethyl acetate/chloroform/methanol (60:30:10) to give, after crystallization from dichloromethane/ethyl acetate/diethyl ether, N-(1,5-dihydroxypentan-3-yl)-[2,1,3]-benzoxadiazole-5-carboxamide as a white solid (Mp: 87-88° C.). N-(1,5-Dihydroxypentan-3-yl)-[2,1,3]-benzoxadiazole-5-carboxamide (0.5 g, 1.9 mmol), suspended in chloroform (20 ml), was warmed to 45° C. and periodinane (Dess Martin reagent; 1.6 g) added and stirred for 1 h. The reaction mixture was evaporated onto silica gel and purified by chromatography, eluting with ethyl acetate/chloroform (60:40) to give N-(2-hydroxytetrahydro-2H-pyran-4-yl)-[2,1,3]-benzoxadiazole-5-carboxamide (0.12 g) as a white solid after trituration with diethyl ether and as the less polar of two components (Rf: 0.55). Mp=91-92° C., 1H NMR (300 MHz, CDCl3) δ 8.22 (s, 1H); 7.96-7.81 (m, 2H); 7.10-7.00 and 6.40-6.05 (m, 2H); 4.65-4.40 (m, 1H); 4.15-3.70 (m, 2H) and 2.15-0.60 ppm (m, 4H).