Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([C:14]([NH2:16])=[O:15])[CH:9]=1.[Cl:17][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:27]=1[N:26]=[C:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[Cl:34])[C:24]([S:35]([NH2:38])(=[O:37])=[O:36])=[CH:23]2.CC(C1C=C(C(C)C)C(C2C(P(C(C)(C)C)C(C)(C)C)=CC=CC=2)=C(C(C)C)C=1)C.N#N>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.C(Cl)(Cl)Cl.[Pd].[Pd]>[Cl:17][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:27]=1[N:26]=[C:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[Cl:34])[C:24]([S:35]([NH:38][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([C:14]([NH2:16])=[O:15])[CH:9]=1)(=[O:36])=[O:37])=[CH:23]2
Reactant: NS(=O)(=O)c1cc2cccc(Cl)c2nc1-c1ccccc1Cl
Reactant: NC(=O)c1cc(Br)ccn1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: N#N
Solvent: ClC(Cl)Cl
Product: NC(=O)c1cc(NS(=O)(=O)c2cc3cccc(Cl)c3nc2-c2ccccc2Cl)ccn1
Temperature: 100 °C

Procedure:
The flask was charged with tris(dibenzylideneacetone)dipalladium (0) chloroform adduct (53.2 mg, 51.4 μmol), cesium carbonate (402 mg, 1.23 mmol), 4-bromo-picolinamide (103.4 mg, 0.514 mmol), 8-chloro-2-(2-chlorophenyl)quinoline-3-sulfonamide (200 mg, 0.566 mmol), tBuXPhos (37.0 mg, 77.2 μmol) and filled with N2. Then toulene (15.0 ml) was added and N2 was bubbled through the mixture for 10 minutes. The mixture was heated at 100° C. for 16 hours. The mixture was cooled to room temperature, evaporation of the solvent, diluted with CH2Cl2-MeOH (1:1, 25 mL), filtered through a pad of Celite™. The mixture was concentrated, and the residue was diluted with MeOH. The solution was purified by HPLC, 20%-70% of B in 35 min. The collected fractions were concentrated and neutralized by adding aq. NaHCO3. Filtration and rinse with water gave 4-(8-chloro-2-(2-chlorophenyl)quinoline-3-sulfonamido)picolinamide, 1H-NMR (MeOD) δ 9.33 (s, 1H), 8.21 (d, J=8.0 Hz, 1H), 8.09 (d, J=7.8 Hz, 1H), 7.74 (t, J=7.8 Hz, 1H), 7.61 (s, 1H), 7.36-7.50 (m, 6H), 7.08 (d, J=8.0 Hz, 1H). Mass Spectrum (ESI) m/e=472.9 (M+1).
Reaction SMILES: Br[CH2:2][C:3]1([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH:5]([C:6]2[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=2[Cl:13])[O:4]1.[NH:21]1[CH:25]=[CH:24][N:23]=[CH:22]1.C[O-].[Na+]>CN(C)C=O>[N:21]1([CH2:2][C:3]2([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH:5]([C:6]3[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=3[Cl:13])[O:4]2)[CH:25]=[CH:24][N:23]=[CH:22]1
Reactant: Clc1ccc(C2(CBr)OC2c2ccc(Cl)cc2Cl)cc1
Reactant: c1c[nH]cn1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc(C2(Cn3ccnc3)OC2c2ccc(Cl)cc2Cl)cc1
Reaction time: 8 h
Yield: 47.6 %

Procedure:
A solution of 10 g of 2-bromomethyl-2-(4-chlorophenyl)-3-(2,4-dichlorophenyl)-oxirane (isomer A) in 50 mL of N,N-dimethylformamide was added dropwise, at 100° C., to a melt which comprised 15.6 g of imidazole with 1.37 g of sodium methylate and from which the liberated methanol had been distilled off beforehand. After 8 hours, the reaction solution was poured onto water and the mixture was extracted with ethyl acetate. The organic phase was washed with water, dried over sodium sulfate and evaporated down under reduced pressure, and the residue was chromatographed over a silica gel column using methylene chloride/methanol (100:2). The purified fractions were evaporated down, and the residue was crystallized from diisopropyl ether. 4.6 g (47.5%) of 2-(1H-imidazol-1-yl-methyl)-2-(4-chlorophenyl)-3-(2,4-dichlorophenyl)-oxirane (isomer A) of melting point 102°-103° C. were obtained (compound 1).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([OH:13])([C:9]([F:12])([F:11])[F:10])[CH2:4][S:5]([O-:8])(=[O:7])=[O:6].[C:16]1([S+:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C.[C:42](Cl)(=[O:47])[C:43]([CH3:46])([CH3:45])[CH3:44]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:44][C:43]([CH3:46])([CH3:45])[C:42]([O:13][C:3]([C:2]([F:1])([F:14])[F:15])([C:9]([F:12])([F:10])[F:11])[CH2:4][S:5]([O-:8])(=[O:7])=[O:6])=[O:47].[C:29]1([S+:22]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=S(=O)([O-])CC(O)(C(F)(F)F)C(F)(F)F
Agent: CN(C)c1ccncc1
Agent: c1ccc([S+](c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)OC(CS(=O)(=O)[O-])(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.2 %

Procedure:
Into a mixture solution of 2.6 g (5 mmoles) of triphenylsulfonium 3,3,3-trifluoro-2-hydroxy-2-trifluoromethylpropane-1-sulfonate prepared in Synthesis Example 1-9, 0.63 g (6 mmoles) of triethylamine, 0.12 g (1 mmole) of 4-dimethylaminopyridine, and 15 g of methylene chloride was added 0.72 g (6 mmoles) of pivaloyl chloride, and they were stirred at room temperature for 8 hours. Thereafter, the reaction was terminated by adding 11 g of 5% hydrochloric acid, and then the organic layer was separated, washed by water, and concentrated under reduced pressure. Into the concentrated solution was added a mixture solution of methyl isobutyl ketone and methylene chloride, and the resulted mixture was concentrated again under reduced pressure to distil the remaining water out. The obtained residue was recrystallized by adding diisopropyl ether, and then the crystals were recovered and dried to obtain the intended triphenylsulfonium 2-(2,2-dimethylpropionyloxy)-3,3,3-trifluoro-2-trifluoromethylpropane-1-sulfonate (1.8 g of white crystals (yield 58%)). The structure of the intended product is shown below.
Reaction SMILES: [C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([C:9]2[C:10]([CH3:21])=[N:11][O:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)[OH:8])[CH:2]=1.[CH2:28]([O:30][C:31]([C:33]1([C:36]2[CH:41]=[CH:40][C:39](B3OC(C)(C)C(C)(C)O3)=[CH:38][CH:37]=2)[CH2:35][CH2:34]1)=[O:32])[CH3:29]>>[CH2:28]([O:30][C:31]([C:33]1([C:36]2[CH:41]=[CH:40][C:39]([C:17]3[CH:16]=[CH:15][C:14]([C:13]4[O:12][N:11]=[C:10]([CH3:21])[C:9]=4[CH:7]([C:3]4[CH:2]=[C:1]([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=5)[CH:6]=[CH:5][CH:4]=4)[OH:8])=[CH:19][CH:18]=3)=[CH:38][CH:37]=2)[CH2:34][CH2:35]1)=[O:32])[CH3:29]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)c1cccc(-c2ccccc2)c1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)c4cccc(-c5ccccc5)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 42, Step 2, using biphenyl-3-yl-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-methanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.C(Cl)(=O)C(Cl)=O.[C:28]([NH:32][S:33]([C:36]1[C:37]([C:42]2[CH:47]=[CH:46][C:45]([NH2:48])=[C:44]([F:49])[CH:43]=2)=[CH:38][CH:39]=[CH:40][CH:41]=1)(=[O:35])=[O:34])([CH3:31])([CH3:30])[CH3:29]>C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:15])[NH:48][C:45]1[CH:46]=[CH:47][C:42]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[S:33](=[O:35])(=[O:34])[NH:32][C:28]([CH3:29])([CH3:30])[CH3:31])=[CH:43][C:44]=1[F:49])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(N)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(NC(=O)C2CCCN2C(=O)OC(C)(C)C)c(F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (1.6 g, 7.4 mmol) was dissolved in 40 mL dry diethyl ether under Ar, cooled in an ice water bath, added dry pyridine (3 mL, 37.2 mmol) followed by the dropwise addition of oxalyl chloride (1.6 mL, 18.6 mmol). A precipitate forms immediately. The reaction was stirred vigorously at 0° C. for one hour, then at ambient temperature for one hour. Added 50 mL diethyl ether, filtered off solids washing with diethyl ether. Concentrated the filtrates to an off-white oil. Redissolved oil in 40 mL dry DCM under Ar, cooled to 0° C., added 3 mL pyridine followed by 4′-amino-3′-fluoro-biphenyl-2-sulfonic acid tert-butylamide (2 g, 6.2 mmol). The reaction was allowed to warm to ambient temperature, stirred for 3 hours then concentrated. Redissolved in 250 mL EtOAc, washed with 10% citric acid (2×100 mL), water (3×100 mL), brine (100 mL), dried with MgSO4, filtered and concentrated. Purified on a silica gel column eluted with 30% moving to 50% EtOAc in hexanes. Combined and concentrated pure fractions to yield title compound as a white solid. (1.4 g, 42%) APCI (AP−): 518.2 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].P(O)(O)O.[H][H]>[Ti].[Pt].O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[Cl:8])[NH2:9]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Agent: [Pt]
Agent: [Ti]
Agent: OP(O)O
Solvent: O
Product: Nc1ccc(Cl)c(Cl)c1
Temperature: 90 °C
Reaction time: 0.38 h
Yield: 90 %

Procedure:
A titanium autoclave equipped with a jacket for heating, coils for circulating temperature controlled water and an efficient agitator was charged with 300 parts of 3,4-dichloronitrobenzene, 0.30 part of phosphorous acid and 0.006 part of platinum (the actual charge consisting of an aqueous paste of platinum deposited on a carbon support, the quantity of platinum on the support being 5.0 weight % on a dry basis). Air in the autoclave and lines was displaced by pressuring with nitrogen and releasing the pressure through a vent system. The nitrogen was then displaced by pressurizing with hydrogen to 300 p.s.i.g. and releasing the pressure as before. The temperature of the mixture was then raised to 90° C., the agitator was started and the hydrogen pressure was increased to about 500 p.s.i.g. Absorption of hydrogen was rapid with evolution of heat; the temperature of the reaction mass was held at 115° ± 5° C. by circulating low pressure steam through the coils. The autoclave was repressured with hydrogen to 500 p.s.i.g. after each 100 lb. drop in pressure. When no further hydrogen absorption occurred, the mass was held at the operating temperature and 500 p.s.i.g. hydrogen pressure for 15-30 minutes. The total hydrogenation time was 1.25-1.50 hours. The hot reduction mass was cooled to below 100° C., removed from the autoclave, treated with ammonium hydroxide (to a pH above 7.0) and then filtered. The filtrate was allowed to settle at 70°-85° C. and the layers were separated. Analysis of the organic layer by gas chromatography showed the presence of 0.04 mole % of dechlorination products. If desired, the dichloroaniline product can be distilled in the presence of 2 weight % soda ash and 0.25 weight % tetraethylenepentamine, for example, as described in U.S. Pat. No. 2,911,340, to give 3,4-dichloroaniline of greater than 98% purity in greater than 90% yield.
Reaction SMILES: [OH:1][C:2]([C:5]1[N:6]=[C:7]([CH2:15][CH2:16][CH3:17])[NH:8][C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])([CH3:4])[CH3:3].[O-]CC.[Na+].Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1.[Cl-].[Na+]>C1(C)C=CC=CC=1.CN(C)C(=O)C>[C:36]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[C:27]1[CH:26]=[CH:25][C:24]([CH2:23][N:8]2[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:5]([C:2]([OH:1])([CH3:4])[CH3:3])[N:6]=[C:7]2[CH2:15][CH2:16][CH3:17])=[CH:29][CH:28]=1)#[N:37]
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)OCC)[nH]1
Agent: CC[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: Cc1ccccc1
Product: CCCc1nc(C(C)(C)O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
Ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1H-imidazole-5-carboxylate (8.09 g) obtained in Example 6 was dissolved in a mixture of toluene (28.3 ml) and N,N-dimethylacetamide (18 ml) under a nitrogen atmosphere, and to the reaction solution, sodium ethoxide (2.43 g) was added. After the reaction solution was stirred at room temperature for 1 hour, 4′-(bromomethyl)biphenyl-2-carbonitrile (9.70 g) was added, and the reaction solution was stirred at 40° C. for 4 hours. After the reaction solution was cooled to room temperature, it was poured into aqueous sodium chloride solution (5.4 wt %), and the aqueous layer was extracted with toluene. The organic layers were combined and concentrated under reduced pressure to approximately half the volume, subsequently Isopar E was added, then the mixture was stirred at room temperature for 16 hours, followed by further stirring for 1 hour under ice cooling. The precipitated crystals were collected by filtration, and subsequently dried under reduced pressure to afford the title compound (13.1 g) as white crystals.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]3[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)[N:9]=[C:10]([I:11])[C:3]=12.[ClH:25]>CC(C)=O>[ClH:25].[ClH:25].[I:11][C:10]1[C:3]2[C:4](=[N:5][CH:6]=[N:7][C:2]=2[NH2:1])[N:8]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[N:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2nc(I)c3c(N)ncnc32)CC1
Agent: Cl
Solvent: CC(C)=O
Product: Nc1ncnc2c1c(I)nn2C1CCNCC1
Temperature: 45 °C
Reaction time: 1.5 h

Procedure:
The crude tert-butyl 4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-piperidinecarboxylate (69.4 g, 156.30 mmol) was dissolved in acetone (900 mL) and 6N aqueous hydrochloric acid (300 mL) was slowly added dropwise. The reaction was then heated at 45° C. which yielded a precipitate. After 1.5 hours, the precipitate was collected by vacuum filtration, washed with minimal acetone and dried on the lyophilizer to yield 3-iodo-1-(4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride salt as a yellow solid (16.61 g, 39.8 mmol). HPLC-RT: 6.16 min. (flow rate: 1 mL/min λ=254 nm Gradient: 5% to 85% acetonitrile/0.1M aqueous ammonium acetate gradient over 20 min.; Deltapak C18, 300 A, 5 μm, 150×3.9 mm column); m/z (MH+)=345.0.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:9]=[N:10][C:11]([Cl:14])=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.[I:21]I.O>C1COCC1>[C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:9]=[N:10][C:11]([Cl:14])=[CH:12][C:13]=1[I:21])([CH3:4])([CH3:2])[CH3:3]
Reactant: II
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)nc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cnc(Cl)cc1I
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 32.2 %

Procedure:
To the solution of tert-butyl(6-chloropyridin-3-yl)carbamate (160 g, 0.7 mol) in 1 L of anhydrous THF was added n-BuLi (600 mL, 1.5 mol) at −78° C. under N2 atmosphere. After the addition was finished, the solution was stirred at −78° C. for 30 min, and the solution of I2 (177.68 g, 0.7 mol) in 800 mL of anhydrous THF was added. Then the solution was stirred at −78° C. for 4 hrs. TLC indicated the reaction was over. Water was added for quench, and EtOAc was added to extract twice. The combined organic phases were washed with brine, dried over Na2SO4, filtered and purified by flash chromatography to afford 80 g of tert-butyl(6-chloro-4-iodopyridin-3-yl)carbamate as a yellow solid (32.3%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH2:12](O)[CH3:13].O=S(Cl)Cl>C(OCC)(=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: CCO
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1ccc(O)cc1

Procedure:
A mixture of 4-hydroxyphenylacetic acid (9.12 g, 0.06 mol), absolute ethanol (50 mL) and SOCl2 (2 mL, 0.028 mol) was refluxed for 3 hours. The residue was cooled, diluted with ethyl acetate (200 mL), washed first with dilute aqueous sodium bicarbonate (100 mL) and then twice with water (100 mL), then was dried over anhydrous MgSO4, filtered and evaporated in vacuo. Ethyl 4-hydroxyphenylacetate was obtained as an oil.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:15]([OH:17])=[O:16])[CH2:13]Cl)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C(=O)([O-])[O-].[Na+].[Na+].[C:24]1([SH:30])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl>O>[C:1]([NH:11][C@H:12]([C:15]([OH:17])=[O:16])[CH2:13][S:30][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: O=C(N[C@@H](CCl)C(=O)O)OCc1ccccc1
Reactant: Sc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(N[C@@H](CSc1ccccc1)C(=O)O)OCc1ccccc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
N-Carbobenzyloxy-β-chloro-L-alanine (0.108 g, 0.42 mmol) was dissolved in 0.5 ml of water and, then, 0.097 g (0.92 mmol) of sodium carbonate was added. Thereafter, 0.054 g (0.50 mmol) of thiophenol was added dropwise at room temperature in a nitrogen gas atmosphere. After 2 hours of stirring at 60° C., the reaction mixture was cooled with ice and acidified with 1 N hydrochloric acid, and then extracted with ethyl acetate. The solvent was distilled off and the residue was purified by column chromatography to give 0.112 g (0.34 mmol, 81%) of N-carbobenzyloxy-S-phenyl-L-cysteine. The compound obtained had an optical purity of not less than 98% e.e. The optical purity was determined by HPLC. The analytical conditions are shown below.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][N:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1>[C:1]([O:5][C:6]([C:8]1[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[CH:10][N:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(C(=O)OC(C)(C)C)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc(C(=O)O)cn1
Temperature: 0 °C
Yield: 75.3 %

Procedure:
A mixture of methyl 6-tert-butoxycarbonylnicotinate (1.2 g, 5.06 mmol) in THF (15 ml) and 0.25 N NaOH (40 ml, 10 mol) at an ambient temperature for 0.5 hr. The mixture was poured into ice-1N HCl (10 ml). The solid was collected, washed with water and air-died. The crude solid was recrystallized from CHCl3—EtOH—IPE to afford 6-tert-butoxycarbonylnicotinic acid (850 mg, 76%) as needles. IR (KBr) m/n 3095, 1728, 1705 cm−1; 1H-NMR (DMAO-d6) δ1.63 (s, 9 H), 8.09 (m, 1 H), 8.17 (m, 1 H), 8.42 (dt, J=2.4 and 8.3 Hz, 1 H), 9.21 (t, J=2.4 and 8.8 Hz, 1 H); MS (FAB) m/z 224 (M++1); Anal. Calcd. for C29H33N3O6: C, 36.18; H,3.18; N, 3.84. Found: C, 36.85; H, 3.35; N, 3.79.
Reaction SMILES: Cl.[CH2:2]([CH2:4][NH2:5])[OH:3].CCN(CC)CC.[C:13](Cl)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)Cl.CC#N.C(Cl)Cl>[C:13]([NH:5][CH2:4][CH2:2][OH:3])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: NCCO
Agent: Cl
Solvent: ClCCl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: OCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
Ethanolamine hydrochloride (9.9 g; 100 mmol) is partially dissolved in CH2Cl2 /CH3CN (200 ml/100 ml) and Et3N (23 ml; 170 mmol) is then added. Tritylchloride (18.9 g; 67.6 mmol) is added portionwise over 30 minutes. After the addition is complete the reaction mixture is allowed to stir an additional 30 minutes, diluted with CH2Cl2, washed with H2O 2x and brine, dried (MgSO4), concentrated in vacuo and purified by column chromatography with silica/CH2Cl2 to give N-tritylethanolamine as an oil which is used directly in Step B.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:15])=[O:13])=[CH:8][CH:7]=1.[C:25]([C:27]1[CH:28]=[C:29]([CH:44]=[CH:45][CH:46]=1)[O:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([O:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:32]=1)#[CH:26].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CCCCCC.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>[O:37]([C:33]1[CH:32]=[C:31]([CH:36]=[CH:35][CH:34]=1)[O:30][C:29]1[CH:28]=[C:27]([C:25]#[C:26][C:2]2[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=2)[O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:15])=[O:13])=[CH:8][CH:7]=2)[CH:46]=[CH:45][CH:44]=1)[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: O=C(C(=O)c1ccc(Oc2cccc(Br)c2)cc1)c1ccccc1
Reactant: C#Cc1cccc(Oc2cccc(Oc3ccccc3)c2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: O=C(C(=O)c1ccc(Oc2cccc(C#Cc3cccc(Oc4cccc(Oc5ccccc5)c4)c3)c2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 44.1 %

Procedure:
To a 250 ml flask fitted with a reflux condenser, nitrogen inlet and thermometer were added 4(3-bromophenoxy)benzil (11.08 g, 29.08 mmol), 1-(3-ethynylphenoxy)-3-phenoxybenzene (21.64 g, 75.66 mmol), triethylamine (150 ml), and triphenylphosphine (0.40 g). After stirring at room temperature under a nitrogen atmosphere for 10 minutes, cuprous iodide (Alfa 98%, 0.20 g) and dichlorobis(triphenylphosphine)palladium (II) (0.20 g) were added. The flask was heated to an internal temperature of 90° C. and maintained by oil bath heating under nitrogen until TLC indicated reaction completion (4 hr). The triethylamine was distilled from the residue and the residue was suspended in toluene. The toluene was washed with 15% HCl (560 ml) twice and separated. The organic layer was washed with ethylenediamine (20 ml) by adding the ethylenediamine at room temperature, heating to 60° C. for 0.5 h and cooling. Water (250 ml) was added and the toluene was separated from the aqueous layer. The ethylenediamine wash was repeated once more. After washing with water (3×500 ml), the organic layer was dried over anhydrous magnesium sulfate (3.00 g) and the toluene distilled by rotary evaporation at reduced pressure to give a dark brown oil. The oil was dissolved in 4:1 hexane:methylene chloride and chromatographed on a silica gel column (Woelm DCC, 230 g, 5 cm dia×25 cm H) using 4:1 hexane:methylene chloride as the eluent. The product was dried in a 70° C. oven under reduced pressure to afford a light brown tacky oil (7.52 g, 44%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([F:18])=[C:12]([I:17])[CH:13]=2)[N:8]([C@H:19]([CH2:23][OH:24])[CH:20]([CH3:22])[CH3:21])[CH:7]=1)=[O:5])[CH3:2].N1C=CN=C1.[Si:30](Cl)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([F:18])=[C:12]([I:17])[CH:13]=2)[N:8]([C@H:19]([CH2:23][O:24][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH:20]([CH3:21])[CH3:22])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)c1cn([C@H](CO)C(C)C)c2cc(F)c(I)cc2c1=O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn([C@H](CO[Si](C)(C)C(C)(C)C)C(C)C)c2cc(F)c(I)cc2c1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.8 %

Procedure:
The compound (22 g, 48 mmol) obtained in Step 3 was dissolved in dimethylformamide (60 ml), imidazole (3.9 g, 57.7 mmol) and tert-butyldimethylsilyl chloride (8.0 g, 53.0 mmol) were added, and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was dissolved in ethyl acetate (200 ml), washed successively with water (twice) and saturated brine, and dried over sodium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate:hexane=3:7 to 4:6) to give 1-((S)-1-tert-butyldimethylsilyloxymethyl-2-methylpropyl)-7-fluoro-6-iodo-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (25 g, yield 92%) as a white wax.