Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH:12]=1)(=O)=O.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[K+].[K+].Br[C:41]1[S:49][C:48]2[C:43](=[N:44][CH:45]=[CH:46][C:47]=2[O:50][C:51]2[CH:56]=[CH:55][C:54]([N+:57]([O-:59])=[O:58])=[CH:53][C:52]=2[F:60])[CH:42]=1.[F-].[Cs+].C([O-])(O)=O.[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:60][C:52]1[CH:53]=[C:54]([N+:57]([O-:59])=[O:58])[CH:55]=[CH:56][C:51]=1[O:50][C:47]1[CH:46]=[CH:45][N:44]=[C:43]2[CH:42]=[C:41]([C:7]3[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH:12]=3)[S:49][C:48]=12
Reactant: CN1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(Br)sc23)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: O=C([O-])O
Solvent: COCCOC
Solvent: O
Product: CN1CC=C(c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)CC1
Yield: 39.1 %

Procedure:
To a mixture of 1-methyl-1,2,3,6-tetrahydropyridin-4-yl trifluoromethanesulfonate 257 (450 mg, 1.84 mmol), bis(pinacolato)diboron (477 mg, 2.02 mmol) and K2CO3 (541 mg, 5.52 mmol) in DME (3.7 mg), Pd(PPh3)4 (106 mg, 0.092 mmol) was added in one portion and the system was heated to reflux for 2 h under N2. The reaction mixture was cooled down and filtered. To the filtrate containing the intermediate 258 were added bromide 50 (435 mg, 1.84 mmol), CsF (838 mg, 5.52 mmol), NaHCO3 (463 mg, 5.52 mmol) and water (0.8 mL), and the mixture was heated to reflux for 2 h more. The reaction mixture was diluted with water and extracted with DCM; the organic phase was extracted with 1N HCl, the aqueous phase basified to pH-11 by addition of 2N aqueous NaOH, extracted with DCM, dried over anhydrous Na2SO4 and concentrated under reduced pressure affording 259 (279 mg, 0.72 mmol, 39% yield) as a brown solid. MS (m/z): (M+1) 385.9 (100%).
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]1[CH:12]=[CH:11][C:10]2[CH:13]=[CH:14][CH:15]=[C:16]([N:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]3)[C:9]1=2.O.N>ClCCl>[O:8]1[CH:12]=[CH:11][C:10]2[CH:13]=[CH:14][CH:15]=[C:16]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[C:9]1=2
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3ccoc23)CC1
Agent: N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: c1cc(N2CCNCC2)c2occc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
Trifluoroacetic acid (5 ml) was added dropwise at 20° C. under nitrogen to a cooled solution of tert-butyl 4-(7-benzo[b]furanyl)piperazine-1-carboxylate (1.66 g) in dichloromethane (5 ml). The solution was stirred at ambient temperature for 1 hour, then poured into cold water (50 ml). The mixture was basified by the addition of aqueous ammonia solution, then the product was extracted into dichloromethane (2×50 ml). The combined organic extracts were washed with brine (100 ml), dried (MgSO4), and the solvent removed in vacuo to give 1-(7-benzo[b]furanyl)piperazine (1.02 g).
Reaction SMILES: [CH3:1][Mg]Cl.[C:4]([N:11]1[CH2:17][CH2:16][CH2:15][C@H:12]1[CH:13]=[O:14])([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]>>[C:4]([N:11]1[CH2:17][CH2:16][CH2:15][C@H:12]1[C:13](=[O:14])[CH3:1])([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Reactant: C[Mg]Cl
Product: CC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C

Procedure:
25 ml (75 mmol) 3 M methylmagnesium chloride (diethyl ether) and 8.25 g (41.4 mmol) BOC-L-prolinal were allowed to react at −80° C. for 30 min according to procedure F. Yield of the crude product 9.19 g. The product was purified with a silica column using 33% ethyl acetate in petroleum ether as eluent. Yield 7.54 g (35.0 mmol 85%). The product was oxidized to the corresponding ketone according to procedure G. Yield of crude product 6.91 g. The product was purified with a silica column using 20–25% ethyl acetate in petroleum ether as eluent. Yield 5.61 g (26.3 mmol, 75%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([CH:12]=O)[N:11]=[C:4]2[N:3]=1.[CH:14]1([C:19]2([CH2:27][CH2:28][C:29]3[CH:34]=[C:33]([F:35])[C:32]([OH:36])=[C:31]([CH2:37][CH3:38])[CH:30]=3)[O:24][C:23](=[O:25])[CH2:22][C:21](=[O:26])[CH2:20]2)[CH2:18][CH2:17][CH2:16][CH2:15]1>CO>[CH:14]1([C:19]2([CH2:27][CH2:28][C:29]3[CH:34]=[C:33]([F:35])[C:32]([OH:36])=[C:31]([CH2:37][CH3:38])[CH:30]=3)[O:24][C:23](=[O:25])[C:22]([CH2:12][C:10]3[N:11]=[C:4]4[N:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[N:5]4[N:9]=3)=[C:21]([OH:26])[CH2:20]2)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Cc1cc(C)n2nc(C=O)nc2n1
Reactant: CCc1cc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc(F)c1O
Solvent: CO
Product: CCc1cc(CCC2(C3CCCC3)CC(O)=C(Cc3nc4nc(C)cc(C)n4n3)C(=O)O2)cc(F)c1O
Reaction time: 0.25 h

Procedure:
5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde (0.2 g, 0.57 mmol) was added to a solution of 6-Cyclopentyl-6-[2-(3-ethyl-5-fluoro-4-hydroxy-phenyl)-ethyl]-dihydro-pyran-2,4-dione (0.2 g, 0.53 mmol) in MeOH (6 mL). The reaction mixture was stirred for 15 mins and then treated with borane-dimethylamine complex (50 mg, 0.86 mmoL). After 15 hours the reaction mixture was quenched with 1N HCl and extracted with 10% MeOH in CH2Cl2. The combined organic layers were concentrated and recrystallized from EtOAc to give the product as a white soild (0.15 g, 52%). 1H NMR (400 MHz, DMSO-d6): δ 1.09 (t, J=7.3 Hz, 3H), 1.43-1.72 (br m, 8H), 2.05-2.17 (m, 2H), 2.43 (m, 1H), 2.48-2.58 (m, 10H), 2.66 (d, J=17.4 Hz, 1H), 2.81 (d, J=17.4 Hz, 1H), 3.74 (d, J=16.2 Hz, 1H), 3.85 (d, J=16.2 Hz, 1H), 6.76 (s, 1H), 6.84 (d, J=11.6 Hz, 1H) 7.07 (s, 1H), 9.08 (s, 1H), 11.01 (s, 1H). MS: C28H32N4O4F (M+H+) 509.10.
Reaction SMILES: [O-]CC.[Mg+2].[O-]CC.[C:8]([O:16][CH2:17][CH3:18])(=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].[C:19](Cl)(=[O:22])[CH2:20][CH3:21].Cl.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[C:19]([CH:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:8]([O:16][CH2:17][CH3:18])=[O:15])(=[O:22])[CH2:20][CH3:21]
Reactant: CCC(=O)Cl
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C(=O)CC)C(=O)OCC
Temperature: 50 °C
Reaction time: 2.5 h

Procedure:
To a stirred suspension of magnesium ethoxide (3.56 g, 31.2 mmol) in anhydrous toluene (10 ml) at RT is added a solution of diethyl malonate (5 g, 31.2 mmol) in toluene (40 ml). The mixture is stirred at 50° C. for 2.5 hrs (until all the solid dissolved) then cooled to 8-10° C. (note: solidification occurs at 5° C.). To this solution is added slowly propionyl chloride (2.7 ml, 31.2 mmol). The reaction mixture is warmed to ambient temperature and stirring continues for 2 hrs. The reaction mixture is cooled to 5-10° C. and treated with 1M HCl (approx. 35 ml, 1.1 equiv.) to adjust the pH to approx. 1-3. The mixture is allowed to warm to RT and treated with sat. aq. NaHCO3 to give a pH of 6-7. The layers are separated and the organic layer is washed with brine, dried (Na2SO3) and concentrated in vacuo to afford the title compound as a viscous orange oil; 1H NMR (400 MHz, CDCl3) δ [13.45 (s) and 4.47 (s) combined 1H], 4.15-4.30 (4H, m), [2.66 (q, J 7.2) and 2.48 (q, J 7.5) combined 2H], 1.30 (6H, m), [1.21 (t, J 7.5) and 1.12 (t, J 7.2) combined 3H].
Reaction SMILES: [CH:1]1([CH2:7]/[CH:8]=[CH:9]/[CH2:10][OH:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:12](OC(=O)C)(=[O:14])[CH3:13].C(N(CC)CC)C>C(OCC)C.CN(C)C1C=CN=CC=1>[C:12]([O:11][CH2:10]/[CH:9]=[CH:8]/[CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)(=[O:14])[CH3:13]
Reactant: OC/C=C/CC1CCCCC1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(=O)OC/C=C/CC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
A solution of 7.54 g of (E)-4-cyclohexyl-2-butenol in 200 ml of diethyl ether was treated with 9.99 g of acetic anhydride and 7.42 g of triethylamine and stirred overnight at room temperature. The mixture was then treated with 0.005 g of 4-dimethylaminopyridine and stirred for a further 0.5 hours. The mixture was washed with 5% aqueous sodium hydrogen carbonate, water and brine, then dried over anhydrous magnesium sulphate and evaporated. The residue was dried under vacuum to give 9.50 g of (E)-4-cyclohexyl-2-butenol acetate in the form of a pale yellow oil.
Reaction SMILES: C1C([N+]([O-])=O)=CC=C([O:10][C@@H:11]2[O:16][C@H:15]([CH2:17][OH:18])[C@@H:14]([OH:19])[C@H:13]([OH:20])[C@H:12]2[OH:21])C=1.C(O)[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O.[OH-].[Na+]>C([O-])(=O)C.[Na+]>[O:10]=[CH:11][C@@H:12]([C@H:13]([C@@H:14]([C@@H:15]([CH2:17][OH:18])[OH:16])[OH:19])[OH:20])[OH:21]
Reactant: O=[N+]([O-])c1ccc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Agent: CC(=O)[O-]
Agent: OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Agent: [Na+]
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reaction time: 0.5 h

Procedure:
Activity on cellobiose and 4-nitrophenyl-beta-D-glucopyranoside: Cellobiose was dissolved in 50 mM sodium acetate-0.01% TWEEN® 20 pH 5 buffer to 2 g/L. Enzyme was diluted at various concentrations using the same buffer. To 50 μl of the enzyme dilutions (0.04-5 μg/ml), 100 μl of the cellobiose solution (2 g/L buffer) was added. The reaction was incubated at 50° C. for 30 minutes before the reaction was stopped with 50 μl of 0.5 M sodium hydroxide. Glucose produced was measured using the Glucose Oxidase reagent (Pointe Scientific, Inc., Canton, Mich., USA) according to the manufacturer.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=O)[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][CH2:18][CH:17]([O:21][CH3:22])[CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:29].[Na+].O1CCCC1>CO.C(#N)C>[Cl:1][C:2]1[CH:11]=[C:10]([CH:12]([NH2:29])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][CH2:18][CH:17]([O:21][CH3:22])[CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: COC1CCCN(c2c(C(C)=O)cc(Cl)c3cccnc23)C1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC#N
Product: COC1CCCN(c2c(C(C)N)cc(Cl)c3cccnc23)C1
Temperature: 65 °C

Procedure:
A mixture of 1-[5-chloro-8-(3-methoxypiperidin-1-yl)quinolin-7-yl]ethanone (0.0373 g, 0.117 mmol) and ammonium acetate (0.0902 g, 1.17 mmol) in methanol (0.5 mL) and acetonitrile (0.5 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, to the resulting mixture was added 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.29 mL, 0.29 mmol). The reaction was heated at 65° C. overnight. The mixture was cooled to room temperature, quenched with sat. NaHCO3 solution and extracted with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated to give the desired product. LCMS calculated for C17H23ClN3O (M+H)+: m/z=320.2; Found: 320.1.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]([N+:17]([O-:19])=[O:18])([CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH2:7][CH2:8][C:9]([OH:11])=[O:10])([OH:3])=[O:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(#N)C>[CH2:26]([O:10][C:9]([CH2:8][CH2:7][C:6]([CH2:5][CH2:4][C:1]([O:3][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:2])([N+:17]([O-:19])=[O:18])[CH2:12][CH2:13][C:14]([O:16][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:15])=[O:11])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)CCC(CCC(=O)O)(CCC(=O)O)[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=C(CCC(CCC(=O)OCc1ccccc1)(CCC(=O)OCc1ccccc1)[N+](=O)[O-])OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.2 %

Procedure:
To a mixture of [3-(2-carboxyethyl)]-3-nitropentane-1,5-dicarboxylic acid (2.8 g, 0.01 mole) (prepared as described by James K. Young et al., Macromolecules, 1994, 27, 3464-34-71) and cesium carbonate (3.25 g, 0.025 mol) in acetonitrile (20.0 mL) was added benzylbromide (8.55 g, 6.0 mL, 0.05 mole) and the mixture stirred at RT for 24 h. Inorganic salts were filtered and the salts washed with acetonitrile. The filtrate and the washings were combined and evaporated to obtain an oil. Purification by chromatography over silica gel (hexane:ethyl acetate, 7:3) afforded the benzyl ester (40) as colorless viscous oil (4.5 g, yield: 82%). Mass Spectrum (M+H)+=548.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][CH:12]2[CH2:17][CH2:16][C:15]3([CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:14][CH2:13]2)=[CH:6][CH:5]=1.[CH3:24][S:25][C:26]1[CH:27]=[C:28]([N:32]=[C:33]=[O:34])[CH:29]=[CH:30][CH:31]=1>C(#N)C>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:5]=[CH:6][C:7]([CH2:10][N:11]([CH:12]2[CH2:17][CH2:16][C:15]3([CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:14][CH2:13]2)[C:33]([NH:32][C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([S:25][CH3:24])[CH:27]=2)=[O:34])=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(CNC2CCC3(CCCCC3)CC2)cc1
Reactant: CSc1cccc(N=C=O)c1
Solvent: CC#N
Product: COC(=O)c1ccc(CN(C(=O)Nc2cccc(SC)c2)C2CCC3(CCCCC3)CC2)cc1
Reaction time: 48 h
Yield: 44.2 %

Procedure:
The above 4-(spiro[5.5]undec-3-ylaminomethyl)benzoic acid methyl ester (1.02 g, 3.2 mmol) was added acetonitrile (50 mL) and 3-(methylthio)phenylisocyanate (668 mg, 4 mmol). Upon stirring for 2 days, the reaction appeared incomplete as shown by HPLC, so another portion of 3-(methylthio)phenylisocyanate (240 mg) was added. After stirring for 2 hours the solvent was evaporated. The residue was taken up in dichloromethane (2 mL) and purified by chromatography on silica using dichloromethane as eluent affording 4-[3-(3-methylsulfanyl-phenyl)-1-spiro[5.5]undec-3-yl-ureidomethyl]benzoic acid methyl ester (680 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]3[N:22]=[CH:23][C:24]([C:25]([OH:27])=O)=[C:14]3[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[NH2:28][C:29]1[N:34]=[CH:33][C:32]([C:35]([NH:37]O)=[NH:36])=[CH:31][N:30]=1>>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([C:18]([F:20])([F:21])[F:19])[N:15]3[N:22]=[CH:23][C:24]([C:25]4[O:27][N:37]=[C:35]([C:32]5[CH:31]=[N:30][C:29]([NH2:28])=[N:34][CH:33]=5)[N:36]=4)=[C:14]3[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9]
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)c(F)c3)nc12
Reactant: N=C(NO)c1cnc(N)nc1
Product: Nc1ncc(-c2noc(-c3cnn4c(C(F)(F)F)cc(-c5ccc(C(F)(F)F)c(F)c5)nc34)n2)cn1

Procedure:
The title compound was prepared from 5-(3-fluoro-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C. 18) (197 mg, 0.5 mmol) and 2-amino-N-hydroxy-pyrimidine-5-carboxamidine (example B.5) (115 mg, 0.75 mmol) according to general procedure II. Obtained after flash chromatography on silica gel (ethyl acetate/heptane) and further purification by crystallization (dichloromethane/hexane) as a yellow solid (130 mg, 51%). MS (EI) 510.1 [(M)+]; mp 270° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([C:14]2[O:15][C:16]([CH2:19][OH:20])=[CH:17][CH:18]=2)[CH:3]=1.[Na].O.[CH:23](=O)[CH2:24][CH:25]=O.FC(F)(F)C(O)=O>O1CCOCC1>[CH2:7]([N:6]1[C:2]2=[N:1][CH:23]=[CH:24][CH:25]=[C:3]2[C:4]([C:14]2[O:15][C:16]([CH2:19][OH:20])=[CH:17][CH:18]=2)=[N:5]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Nc1cc(-c2ccc(CO)o2)nn1Cc1ccccc1
Reactant: O=CCC=O
Agent: [Na]
Solvent: O
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: OCc1ccc(-c2nn(Cc3ccccc3)c3ncccc23)o1

Procedure:
2.69 g (10 mmol) of 5-amino-1-benzyl-3-(5-hydroxymethyl-2-furyl)pyrazole and 1.4 g of malonaldehyde hydrate sodium salt are stirred at 100° C. for 30 min in 100 ml of dioxane and slowly treated with 1.9 ml of trifluoroacetic acid during the course of 5.5 hours. The mixture is evaporated in vacuo, the residue is taken up in ethyl acetate, the mixture is extracted by shaking with K2HPO4 solution, and the organic phase is dried using Na2SO4 and concentrated in vacuo in a rotary evaporator. The residue is chromatographed on silica gel. 200 mg (6.6% of theory) of crystals having a melting point of 104° C. are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[P:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.N1C=CC=CC=1.Cl[C:42]([O:44][CH3:45])=[O:43].[Cl-].[NH4+]>C(Cl)Cl>[CH3:45][O:44][C:42]([NH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[P:22]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:43]
Reactant: COC(=O)Cl
Reactant: Nc1ccc2ccccc2c1-c1c(P(c2ccccc2)c2ccccc2)ccc2ccccc12
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)Nc1ccc2ccccc2c1-c1c(P(c2ccccc2)c2ccccc2)ccc2ccccc12
Temperature: 25 °C
Reaction time: 21 h
Yield: 92.2 %

Procedure:
1.20 gram (2.65 mmol) of (−)-2-amino-2′-diphenylphosphino-1,1′-binaphthyl (1-1a) was dissolved in 53 ml of methylene chloride, followed by the addition of 0.26 ml (3.18 mmol) of pyridine and 0.23 ml (2.91 mmol) of methyl chloroformate under 0° C. The reaction mixture was stirred at room temperature for 21 hours. To the reaction solution, 40 ml of saturated aqueous solution of ammonium chloride was added and extracted with 100 ml of methylene chloride. The extract was washed with 80 ml of brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure. The residue was purified using a silica gel column chromatography (eluent: 1:4 mixture of ethyl acetate and hexane) to obtain 1.25 gram of the titled compound.
Reaction SMILES: [F:1][CH:2]([F:32])[O:3][C:4]1[C:9]2[O:10][C:11]3[CH:16]=[CH:15][C:14]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[CH:13][C:12]=3[C:8]=2[C:7]([C:22]2[O:23][CH:24]=[C:25]([C:27]([O:29]CC)=[O:28])[N:26]=2)=[CH:6][CH:5]=1.[OH-].[K+]>C(O)C.O1CCCC1.O>[F:32][CH:2]([F:1])[O:3][C:4]1[C:9]2[O:10][C:11]3[CH:16]=[CH:15][C:14]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[CH:13][C:12]=3[C:8]=2[C:7]([C:22]2[O:23][CH:24]=[C:25]([C:27]([OH:29])=[O:28])[N:26]=2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)c1coc(-c2ccc(OC(F)F)c3oc4ccc(NS(C)(=O)=O)cc4c23)n1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CS(=O)(=O)Nc1ccc2oc3c(OC(F)F)ccc(-c4nc(C(=O)O)co4)c3c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.4 %

Procedure:
To a slurry of ethyl 2-(4-(difluoromethoxy)-8-(methylsulfonamido)dibenzo[b,d]furan-1-yl)1,3-oxazole-4-carboxylate (0.2 g, 0.429 mmol) in ethanol (5 mL) and tetrahydrofuran (3 mL) was added potassium hydroxide (0.256 g, 4.562 mmol) in water (0.5 mL). Then it was stirred at room temperature for 16 hours. The solvent was removed in vacuum. The residue was diluted with water and acidified with 1N HCl until the solid separates out. The solid was filtered and washed with hexane. Yield—98.4%. 1H-NMR (DMSO-d6) δ: 3.09 (s, 3H), 7.40 (s, 1H), 7.48-7.51 (m, 1H), 7.59-7.63 (m, 2H), 7.87 (d, 1H), 8.06 (d, 1H), 8.97-8.99 (m, 2H), 9.81 (s, 1H); HPLC (purity): 99.1%; Mass calculated for C18K2F2N2O7S-438.4, observed—437.0; Rf—0.2 (Dichloromethane:Methanol (8:2)).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Br:13][C:14]1[CH:19]=[C:18]([Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[C:17]([F:27])=[CH:16][N:15]=1.CN(C)[C:30](=[O:32])[CH3:31].Cl>C1COCC1.[Cl-].[Na+].O.O>[Br:13][C:14]1[N:15]=[C:16]([C:30](=[O:32])[CH3:31])[C:17]([F:27])=[C:18]([Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[CH:19]=1
Reactant: CC(=O)N(C)C
Reactant: CC[Si](CC)(CC)c1cc(Br)ncc1F
Agent: Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)c1cc(Br)nc(C(C)=O)c1F
Temperature: -40 °C
Reaction time: 1.17 h
Yield: 91.2 %

Procedure:
A solution of diisopropylamine (25.4 g, 250 mmol) in 500 ml THF was cooled to −75° C. BuLi (100 ml, 250 mmol, 2.5 M in hexanes) was added dropwise while maintaining the temperature below −50° C. After the reaction temperature had reached −75° C. again, a solution of 2-bromo-5-fluoro-4-triethylsilanyl-pyridine (56.04 g, 193 mmol) in 60 ml THF was added dropwise. The mixture was stirred in a dry ice bath for 70 minutes. N,N-dimethylacetamide (21.87 g, 250 mmol) was added quickly, the reaction temperature rose to −57° C. The reaction mixture was stirred in a dry ice bath for 15 min and then allowed to warm to −40° C. It was poured on a mixture of 2M aq. HCl (250 ml, 500 mmol), 250 ml water and 100 ml brine. The mixture was extracted with TBME, washed with brine, dried over MgSO4.H2O, filtered and evaporated to give a yellow oil which was purified on a silica gel column by eluting with hexane/0-5% TBME to yield 58.5 g of the title compound as a yellow liquid. TLC (Hex/TBME 99/1): Rf=0.25; HPLC: RtH11=1.921 min; ESIMS: 332, 334 [(M+H)+, 1Br]; 1H-NMR (400 MHz, CDCl3): 7.57 (d, 1H), 2.68 (s, 3H), 1.00-0.84 (m, 15H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12]([O:14][CH3:15])=[O:13])[CH2:10][CH2:9][C:8]([C:16]([O:18][CH3:19])=[O:17])=[CH:7][C:6]=2[CH:20]=1.B([O-])([O-])O[C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH3:15][O:14][C:12]([N:11]1[C:5]2[CH:4]=[CH:3][C:2]([C:23]3[CH:24]=[CH:25][C:26]([N:29]4[CH2:30][CH2:31][O:32][CH2:33][CH2:34]4)=[CH:27][CH:28]=3)=[CH:20][C:6]=2[CH:7]=[C:8]([C:16]([O:18][CH3:19])=[O:17])[CH2:9][CH2:10]1)=[O:13]
Reactant: COC(=O)C1=Cc2cc(Br)ccc2N(C(=O)OC)CC1
Reactant: [O-]B([O-])Oc1ccc(N2CCOCC2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)C1=Cc2cc(-c3ccc(N4CCOCC4)cc3)ccc2N(C(=O)OC)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.2 %

Procedure:
A mixture of methyl 7-bromo-1-methoxycarbonyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.3 g), 4-morpholinophenyl borate (0.22 g), 1M potassium carbonate solution (2.5 ml), ethanol (2.5 ml) and toluene (25 ml) was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakis(triphenylphosphine)palladium (0.04 g), and the mixture was refluxed overnight under argon atmosphere and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give methyl 1-methoxycarbonyl-7-(4-morpholinophenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.31 g) as pale yellow crystals.