Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@H:10]([O:12][C:13]1[C:14]([NH2:28])=[N:15][CH:16]=[C:17](B2OC(C)(C)C(C)(C)O2)[CH:18]=1)[CH3:11].[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH:39]([N:42]2[CH:46]=[C:45](Br)[CH:44]=[N:43]2)[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:29]([O:33][C:34]([N:36]1[CH2:37][CH2:38][CH:39]([N:42]2[CH:46]=[C:45]([C:17]3[CH:16]=[N:15][C:14]([NH2:28])=[C:13]([O:12][C@@H:10]([C:3]4[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=4[Cl:1])[CH3:11])[CH:18]=3)[CH:44]=[N:43]2)[CH2:40][CH2:41]1)=[O:35])([CH3:32])([CH3:30])[CH3:31]
Reactant: C[C@@H](Oc1cc(B2OC(C)(C)C(C)(C)O2)cnc1N)c1c(Cl)ccc(F)c1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(Br)cn2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: C[C@@H](Oc1cc(-c2cnn(C3CCN(C(=O)OC(C)(C)C)CC3)c2)cnc1N)c1c(Cl)ccc(F)c1Cl
Temperature: 87 °C
Reaction time: 16 h
Yield: 62.1 %

Procedure:
To a stirred solution of 3-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine (4.2711 g, 10.0 mmol) and 4-(4-bromo-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (see procedure 11) (3.9628 g, 12.0 mmol) in DME (40 mL) was added a solution of Na2CO3 (3.1787 g, 30.0 mmol) in water (10 mL). The solution was degassed and charged with nitrogen three times. To the solution was added Pd(PPh3)2Cl2 (351 mg, 0.50 mmol). The reaction solution was degassed and charged with nitrogen again three times. The reaction solution was stirred at 87° C. oil bath for about 16 hours (or until consumption of the borane pinacol ester), cooled to ambient temperature and diluted with EtOAc (200 mL). The reaction mixture was filtered through a pad of celite and washed with EtOAc. The EtOAc solution was washed with brine, dried over Na2SO4, and concentrated. The crude product was purified on a silica gel column eluting with EtOAc/hexane system (0% EtOAc to 100% EtOAc) to afford 4-(4-{6-amino-5-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (3.4167 g, 65% yield, ˜95% purity) with a Rf of 0.15 (50% EtOAc/Hexanes). MS m/e 550 (M+1)+.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][CH2:7]2.F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1.O>CN(C=O)C>[C:9]1(=[O:13])[C:10]2[C:6](=[CH:5][C:4]([O:3][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=3)=[CH:12][CH:11]=2)[CH2:7][NH:8]1
Reactant: O=C1NCc2cc(O)ccc21
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1NCc2cc(Oc3ccc([N+](=O)[O-])cc3)ccc21
Temperature: 70 °C
Reaction time: 0.75 h
Yield: 89 %

Procedure:
To a slurry of NaH (0.39 g, 16.1 mmol) in DMF at 0° C. was added 5-hydroxyisoindolin-1-one (2.0 g, 13.4 mmol) in portions. The resulting slurry was allowed to warm to room temp. and was stirred for 45 min., then 4-fluoro-1-nitrobenzene was added and then mixture was heated at 70° C. for 3 h. The mixture was cooled to 0° C. and treated with water dropwise until a precipitate formed. The resulting solids were collected to give 4-(1-isoindolinon-5-yloxy)-1-nitrobenzene as a dark yellow solid (3.23 g, 89%): TLC (100% EtOAc) Rf 0.35. Step 3. Synthesis of 4-(1-oxoisoindolin-5-yloxy)aniline
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[OH-].[K+].[CH2:12](Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C>[CH2:12]([O:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: ClCc1ccccc1
Reactant: N#Cc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: N#Cc1ccc(OCc2ccccc2)cc1
Temperature: 80 °C
Yield: 58 %

Procedure:
Treated a solution of 4-hydroxybenzonitrile (5.0 g, 42 mmol) in DMF (20 mL) with 2M KOH (21 mL, 42 mmol) followed by benzyl chloride (3.46 mL, 42 mmol). Heated in an oil bath at 80° C. for 2 h. Cooled to room temperature and poured onto water (100 mL). Filtered the resulting solid, washed with water (2×25 mL) and dried to obtain 4-benzyloxy-benzonitrile (5.1 g) as a solid.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[F:7][C:8]1[CH:13]=[C:12]([OH:14])[C:11]([OH:15])=[C:10]([N+:16]([O-:18])=[O:17])[CH:9]=1.Br[CH2:20][CH2:21]Br>CN(C=O)C.C(OCC)(=O)C>[F:7][C:8]1[CH:9]=[C:10]([N+:16]([O-:18])=[O:17])[C:11]2[O:15][CH2:21][CH2:20][O:14][C:12]=2[CH:13]=1
Reactant: BrCCBr
Reactant: O=[N+]([O-])c1cc(F)cc(O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(F)cc2c1OCCO2
Reaction time: 2 h

Procedure:
K2CO3 (15.27 g, 110.6 mmol) was added to a solution of 5-fluoro-3-nitrobenzene-1,2-diol (5 g, 28.9 mmol) in DMF (35 mL) followed by the addition of 1,2-Dibromoethane (13.63 g, 6.25 mL, 72.5 mmol) and stirring was continued at 80° C. for 2 h. Reaction mixture was diluted with ethyl acetate, washed with cold water, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the crude, which was purified by MPLC (silica gel, Mobile Phase: ethyl acetate in n-Hexane 0 to 5% as eluant) to afford 7-fluoro-5-nitro-2,3-dihydrobenzo[b][1,4]dioxine (Int-51) as pale yellow solid. 1H NMR (300 MHz, CDCl3) δ ppm 7.3-7.2 (1H, dd), 6.9-6.8 (1H, dd), 4.4 (4H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13]C)=O)=[CH:4][CH:3]=1.[Cl-].[NH4+:16].N>CO>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([NH2:16])=[O:13])=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: COC(=O)CCCc1ccc(N)cc1
Agent: N
Agent: [Cl-]
Solvent: CO
Product: NC(=O)CCCc1ccc(N)cc1
Temperature: 100 °C
Reaction time: 20 h
Yield: 35.1 %

Procedure:
A 100-mL vial was charged with methyl 4-(4-aminophenyl)butanoate (2.07 g, 10.7 mmol), ammonium chloride (0.76 g, 14.2 mmol) in methanol (10 mL). To this mixture was added NH3 (10 mL, 7N in methanol, 70.0 mmol, 6.5 eq.). The vial was sealed and the resulting mixture was stirred at 100° C. for 20 h. After this time, the crude reaction solution was concentrated under reduced pressure. The residue was absorbed on silica (10 g) then purified by chromatography on silica using dichloromethane/methanol (10:0 to 9:1) as eluent to afford the title compound (0.67 g, 35%) as a white solid. MW=178.23. 1H NMR (DMSO-d6, 500 MHz) δ 7.20 (br s, 1H), 6.83-6.80 (m, 2H), 6.66 (br s, 1H), 6.49-6.46 (m, 2H), 2.37 (t, J=7.5 Hz, 2H), 2.01 (t, J=7.5 Hz, 2H), 1.68 (quin, J=7.5 Hz, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])/[CH:5]=[C:6](\[C:13]1[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=1)/[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].[CH3:21][N:22]([CH3:26])[CH2:23][C:24]#[CH:25]>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I.ClCCl>[CH2:1]([O:3][C:4](=[O:20])/[CH:5]=[C:6](\[C:13]1[CH:18]=[CH:17][C:16]([C:25]#[C:24][CH2:23][N:22]([CH3:26])[CH3:21])=[CH:15][CH:14]=1)/[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2]
Reactant: C#CCN(C)C
Reactant: CCOC(=O)/C=C(/c1ccccc1)c1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)/C=C(/c1ccccc1)c1ccc(C#CCN(C)C)cc1

Procedure:
A solution of (Z)-3-(4-bromo-phenyl)-3-phenyl-acrylic acid ethyl ester (1.200 g, 3.6 mmol), dimethyl-prop-2-ynyl-amine (0.9 ml, 10.88 mmol), bis(triphenylphosphine) palladium(II) chloride (0.102 g, 0.144 mmol), copper(I) iodide (2.06 mg, 0.0108 mmol) in dry triethyllamine (10 ml) were heated to 100° C. by microwave irradiation for 20 min. The cooled reaction mixture was added dichloromethane (20 ml) and silica gel Fluka 60 (10 g) and evaporated in vacuo. The resulting residue was purified by ISCO combiflash 16 (silica gel, hexane/ethyl acetate 85:15) giving (Z)-3-[4-(3-Dimethylamino-prop-1-ynyl)-phenyl]-3-phenyl-acrylic acid ethyl ester as an oil.
Reaction SMILES: [C:1]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[O:8][C:9]([CH3:25])=[C:10]([CH2:12][CH2:13][O:14]S(C3C=CC(C)=CC=3)(=O)=O)[N:11]=2)[CH:2]=1.[CH2:32]([O:34][C:35](=[O:47])[C:36]([O:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42](O)[CH:41]=1)([CH3:38])[CH3:37])[CH3:33].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:32]([O:34][C:35](=[O:47])[C:36]([O:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([O:14][CH2:13][CH2:12][C:10]2[N:11]=[C:7]([C:3]3[CH:2]=[C:1]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:6]=[CH:5][CH:4]=3)[O:8][C:9]=2[CH3:25])[CH:41]=1)([CH3:38])[CH3:37])[CH3:33]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccc(-c4ccccc4)c3)oc2C)cc1
Reactant: CCOC(=O)C(C)(C)Oc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1cccc(OCCc2nc(-c3cccc(-c4ccccc4)c3)oc2C)c1

Procedure:
A mixture of the toluene-4-sulfonic acid 2-(2-biphenyl-3-yl-5-methyloxazol-4-yl)ethyl ester (66.9 mmol) and 2-(3-hydroxyphenoxy)-2-methylpropanoic acid ethyl ester (Columbia University WO 9731530) (12.5 g, 55.71 mmol) and Cs2CO3 (22.7 g, 69.6 mmol) was heated at 55° C. in DMF (45 mL) for 18 h. The reaction was partitioned between ethyl acetate (160 mL) and H2O (180 mL), and the aqueous phase extracted with ethyl acetate (150 mL). The combined organic phases were dried (MgSO4) and concentrated under reduced pressure to an oil which was purified by column chromatography (1500 mL SiO2, 10% ethyl acetate/hexanes to 20% ethyl acetate/hexanes) to provide 2-{3-[2-(2-biphenyl-3-yl-5-methyloxazol-4-yl)ethoxy]phenoxy}-2-methylpropionic acid ethyl ester. Rf=0.50 in 20% ethyl acetate/hexanes; 1H NMR (400 MHz, CDCl3) δ8.18 (s, 1H), 7.95 (d, 1H), 7.65-7.59 (m, 3H), 7.44-7.39 (m, 3H), 7.36 (t, 1H), 7.08 (t, 1H), 6.55 (d, 1H), 6.41 (s, 1H), 6.37 (d, 1H), 4.20-4.14 (m, 4H), 2.97 (t, 2H), 2.38 (s, 3H), 1.57 (s, 6H), 1.20 (t, 3H); MS (EI) 508.2 (M+Na)+, 486.2 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][N:8]1[S:13]([C:16]1[CH:21]=[C:20]([CH3:22])[C:19]([Cl:23])=[CH:18][C:17]=1[CH3:24])(=[O:15])=[O:14])C.[OH-].[Li+]>CO.O>[Cl:23][C:19]1[C:20]([CH3:22])=[CH:21][C:16]([S:13]([N:8]2[CH2:9][CH2:10][CH2:11][CH2:12][CH:7]2[CH2:6][CH2:5][C:4]([OH:25])=[O:3])(=[O:14])=[O:15])=[C:17]([CH3:24])[CH:18]=1
Reactant: CCOC(=O)CCC1CCCCN1S(=O)(=O)c1cc(C)c(Cl)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(S(=O)(=O)N2CCCCC2CCC(=O)O)c(C)cc1Cl
Temperature: 0 °C
Reaction time: 16 h
Yield: 89 %

Procedure:
Methanol/H2O (3:1, 90 ml) was added to 3-(1-(4-chloro-2,5-dimethylphenylsulfonyl)piperidin-2-yl)propionic acid ethyl ester (3.48 g, 9 mmol) at 25° C., the mixture was cooled to 0° C., lithium hydroxide (0.75 g, 18 mmol) was added, and the mixture was stirred for 16 h at 25° C. The solvent was removed under vacuum, the residue taken up in water and washed with dichloromethane. The aqueous phase was carefully acidified with hydrogen chloride solution (1 mol/l) and extracted with ethyl acetate. This organic phase was washed with water and saturated sodium chloride solution, dried over sodium sulfate and concentrated to small volume under vacuum. Yield: 89%
Reaction SMILES: [CH2:1]([C:7]([OH:9])=[O:8])[C@@H:2]([OH:6])[C:3]([OH:5])=[O:4].CO[C:12](OC)([CH3:14])[CH3:13].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[CH3:13][C:12]1([CH3:14])[O:6][C@H:2]([CH2:1][C:7]([OH:9])=[O:8])[C:3](=[O:5])[O:4]1
Reactant: O=C(O)C[C@@H](O)C(=O)O
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CC1(C)OC(=O)[C@@H](CC(=O)O)O1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a suspension of D-(+)-malic acid (10 g, 75 mmol) in CH2Cl2 (100 mL) was added 2,2-dimethoxypropane (23 g, 225 mmol) and p-toluenesulfonic acid (0.129 g, 0.75 mmol). The reaction mixture was stirred at rt for 4 h, filtered through silica gel (50% EtOAc/hexane) and concentrated to give the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[NH:5][CH:6]=[N:7]2.C(=O)([O-])[O-].[K+].[K+].[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:21]=1[CH2:22]Cl>CN(C)C(=O)C>[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:21]=1[CH2:22][N:7]1[CH:6]=[N:5][C:4]2[C:8]1=[N:9][CH:10]=[N:11][C:3]=2[N:2]([CH3:12])[CH3:1]
Reactant: Fc1cccc(Cl)c1CCl
Reactant: CN(C)c1ncnc2nc[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CN(C)c1ncnc2c1ncn2Cc1c(F)cccc1Cl
Yield: 62.2 %

Procedure:
In a procedure analogous to that of Example 9, by using 1.63 g of 6-dimethylaminopurine, 1.38 g of potassium carbonate, 50 ml of N,N-dimethylacetamide and 3.58 g of 2-chloro-6-fluorobenzyl chloride, there was obtained 1.9 g of 9-(2-chloro-6-fluorobenzyl)-6-dimethylaminopurine as colorless needles (yield: 62%); m.p. 134°-135° C.
Reaction SMILES: [CH2:1]([SH:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[N+:18]([C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1)([O-:20])=[O:19]>C(#N)C>[N+:18]([C:21]1[CH:22]=[CH:23][C:24]([NH:27][C:28](=[O:29])[S:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:25][CH:26]=1)([O-:20])=[O:19]
Reactant: CCCCCCCCCCCCCCCCS
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Solvent: CC#N
Product: CCCCCCCCCCCCCCCCSC(=O)Nc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97.1 %

Procedure:
In a three necked flask equipped with a dropping funnel, a thermometer and reflux condenser, n-hexadecanethiol (165 g) was dissolved in acetonitrile (1000 ml) in a nitrogen atmosphere. To the solution, p-nitrophenyl isocyanate (100 g) was gradually added, stirred at room temperature for 10 minutes, and then heat-refluxed for 30 minutes. The reaction liquid was cooled to room temperature to allow crystals to precipitate. The crystals were collected by filtering and washed with acetonitrile, to obtain S-n-hexadecyl p-nitrophenylthiocarbamate (250 g) at a yield of 97%.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.S(=O)(=O)(O)O.[CH2:17](O)[CH3:18]>>[NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([O:9][CH2:17][CH3:18])=[O:8])=[CH:10][CH:11]=1
Reactant: CCO
Reactant: NCc1ccc(C(=O)O)cc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(CN)cc1

Procedure:
A mixture of 4-aminomethylbenzoic acid (25 g) and concentrated sulphuric acid (25 ml) in ethanol (250 ml) was heated at reflux for 18 hours. The volume of solvent was reduced to a third by evaporation. The residue was poured onto ice (500 g) and basified with concentrated aqueous ammonia. The product was extracted with ethyl acetate (3×200 ml) and the extracts dried and evaporated to give ethyl 4-aminomethylbenzoate.
Reaction SMILES: O[N:2]1[C:10]2[C:5](=[C:6]([I:11])[CH:7]=[CH:8][CH:9]=2)[CH2:4][C:3]1=[O:12].C(N(S(F)(F)[F:19])CC)C>ClCCl>[F:19][C:7]1[C:6]([I:11])=[C:5]2[C:10](=[CH:9][CH:8]=1)[NH:2][C:3](=[O:12])[CH2:4]2
Reactant: CCN(CC)S(F)(F)F
Reactant: O=C1Cc2c(I)cccc2N1O
Solvent: ClCCl
Product: O=C1Cc2c(ccc(F)c2I)N1
Temperature: -25 °C
Reaction time: 0.5 h
Yield: 43 %

Procedure:
A suspension of 1,3-dihydro-1-hydroxy-4-iodo-2H-indol-2-one (2.43 g, 9 mmol) (prepared according to Kende et al., Synth. Commun. 20(14, 2133-2138 (1990)) in dry dichloromethane (500 mL) was cooled to −25° C. under an argon atmosphere with magnetic stirring. A solution of diethylaminosulfur trifluoride (DAST, 1.35 mL) (Aldrich) in dry dichloromethane (40 mL) was added dropwise at such a rate that the reaction temperature did not rise above −25° C. (about 15 min.) After stirring for an additional 30 min. at −25° C., the reaction was quenched by the addition of saturated aqueous sodium bicarbonate solution (180 mL) and allowed to warm to room temperature. The mixture was then filtered through Celite® (Fisher) and the layers separated. The aqueous layer was extracted with dichloromethane (2×300 mL). The dichloromethane layers were washed with saturated aqueous sodium chloride solution (200 mL), combined, dried (magnesium sulfate) and concentrated. The resulting residue was purified by flash chromatography on silics gel using ethyl acetate—dichloromethane (1:7, V/V) as solvent to give 1,3-dihydro-5-fluoro-4-iodo-2H-indol-2-one (Yield 1.08 g, 43%).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:3]=1N.[BrH:12].[N+]([O-])([O-])=O.[Na+]>O>[Br:12][C:3]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:6][CH:7]=[CH:8][C:2]=1[CH3:1]
Reactant: Br
Reactant: Cc1cccc([N+](=O)[O-])c1N
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cccc([N+](=O)[O-])c1Br
Temperature: 15 °C
Reaction time: 16 h

Procedure:
A stirred solution of 75.0 grams (0.493 mole) of 2-methyl-6-nitroaniline and 40 ml of aqueous 48% hydrobromic acid in 135 ml of water was cooled to 0° C. and a solution of 36.2 grams (0.510 mole) of sodium nitrate in 60 ml of water was added dropwise during a one hour period. Upon complete addition the mixture was filtered through glass wool into a large dropping funnel. This solution was added dropwise to a second solution of 77.8 grams (0.542 mole) of cuprous bromide in 165 ml of aqueous 48% hydrobromic acid that was being stirred at 15° C. Upon complete addition the reaction mixture was stirred at 15° C. for a few minutes then was allowed to warm to ambient temperature where it stirred for one hour. The reaction mixture stood for 16 hours then was heated to 60° C. where it stirred for two hours. The reaction mixture was subjected to steam distillation. The distillate was extracted with three portions of 150 ml each of methylene chloride. The combined extracts were washed with two portions of 150 ml each of aqueous 2 N sodium hydroxide and five portions of 200 ml each of an aqueous solution saturated with sodium chloride (until the wash was pH-7). The organic layer was dried with magnesium sulfate while being slurried with decolorizing carbon. The mixture was filtered and the filtrate concentrated under reduced pressure to give 6.6 grams of 2-bromo-3-nitrotoluene; mp 36°-41° C. The nmr spectrum was consistent with the proposed structure. The pot residue from the steam distillation was extracted with 400 ml of methylene chloride. The extract was washed with aqueous 2 N sodium hydroxide then with an aqueous solution saturated with sodium chloride (until the salt wash was pH-7). The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give 18.0 grams of 2-bromo-3-nitrotoluene, which was combined with the 6.6 grams of above to give a total yield of 24.6 grams.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)O[C:2]2=[O:3].[CH3:13][NH2:14]>O1CCCC1.CO>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:14][CH3:13])=[O:3]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: CN
Solvent: CO
Solvent: C1CCOC1
Product: CNC(=O)c1ccccc1N
Yield: 97.8 %

Procedure:
Isatoic anhydride (10 g, 61.3 mmol) was suspended in tetrahydrofuran (200 ml) and treated dropwise with methylamine in methanol (40%, 10 mL) with stirring. After stirring at room temperature for 16 hours, the solvent was distilled off under reduced pressure to afford the product 2-amino-N-methylbenzamide (9 g, yield 97.8%). 1H NMR (400 MHz, CDCl3) δ ppm 7.14-7.32 (m, 2H), 6.60-6.72 (m, 2H), 6.05 (br s, 1H), 2.97 (d, 3H, J=5.0 Hz).
Reaction SMILES: F[C:2](F)(F)[C:3]([O:5][C:6]([CH3:10])([CH3:9])[C:7]#[CH:8])=O.[C:13]([C:15]1[CH:20]=CC(O)=[CH:17][CH:16]=1)#[N:14]>O>[CH3:9][C:6]([O:5][C:3]1[CH:17]=[CH:16][C:15]([C:13]#[N:14])=[CH:20][CH:2]=1)([CH3:10])[C:7]#[CH:8]
Reactant: N#Cc1ccc(O)cc1
Reactant: C#CC(C)(C)OC(=O)C(F)(F)F
Solvent: O
Product: C#CC(C)(C)Oc1ccc(C#N)cc1

Procedure:
The 1,1-dimethyl-2-propynyl trifluoroacetate solution, maintained at 0° C., was added to the 4-cyanophenol solution over a 35 minute period while keeping the temperature at ~0° C. The resulting mixture was stirred at ~0° C. (ice bath). After stirring for 90 minutes, water (10 mL) was added and the resulting mixture was concentrated at reduced pressure. The residue was partitioned between water (50 mL) and toluene (300 mL). The organic fraction was washed with 1N HCl (3×50 mL), 1N NaOH (2×50 mL), 1N NaHCO3, and brine. After drying (magnesium sulfate), the solvent was removed at reduced pressure to give crude title compound as a yellow oil. Distillation of the crude material (bulb to bulb) afforded the title compound as a colorless, low melting solid (8.93 g).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[CH:21]1[CH2:24][N:23]([C:25]([C:27]2[O:28][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[N:30][N:31]=2)=[O:26])[CH2:22]1)(=O)=O>CN(C=O)C>[C:32]1([C:29]2[O:28][C:27]([C:25]([N:23]3[CH2:24][CH:21]([O:1][C:2]4[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=4)[CH2:22]3)=[O:26])=[N:31][N:30]=2)[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CS(=O)(=O)OC1CN(C(=O)c2nnc(-c3ccccc3)o2)C1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OC2CN(C(=O)c3nnc(-c4ccccc4)o3)C2)cc1
Temperature: 110 °C
Reaction time: 18 h
Yield: 67.4 %

Procedure:
4-Hydroxybenzaldehyde (1.10 g, 9.17 mmol), cesium carbonate (3.49 g, 10.70 mmol) and 53B (2.70 g, 7.64 mmol) were mixed with DMF (80 mL). The mixture was stirred at 110° C. for 18 h and then cooled to RT. The solids were filtered off and the filtrate was evaporated. The residue was treated with methanol and the formed solid was collected by filtration. Drying under vacuum afforded 1.8 g (62%) of 68A as a beige solid. 1H NMR (500 MHz, DMSO-d6): δ 3.85 (s, 3H), 4.13 (dd, 1H), 4.57 (dd, 1H), 4.65 (dd, 1H), 5.12 (dd, 1H), 5.29 (m, 1H), 7.10 (d, 2H), 7.16 (d, 2H), 7.90 (d, 2H), 8.00 (d, 2H), 9.90 (s, 1H), MS (APCI+) m/z 380 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1([CH2:7][OH:8])[CH2:6][O:5][CH2:4]1)[CH3:2].[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1>N1C=CC=CC=1>[S:15]([O:8][CH2:7][C:3]1([CH2:1][CH3:2])[CH2:6][O:5][CH2:4]1)([C:12]1[CH:13]=[CH:14][C:9]([CH3:19])=[CH:10][CH:11]=1)(=[O:17])=[O:16]
Reactant: CCC1(CO)COC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CCC1(COS(=O)(=O)c2ccc(C)cc2)COC1
Temperature: 0 °C
Yield: 90.2 %

Procedure:
116 g of 3-ethyl-3-hydroxymethyloxetane (Toa Gosei's trade name, OXT-101) was added to 500 ml of pyridine, and cooled to 0° C. with stirring. 190 g of p-toluenesulfonyl chloride divided into a few portions was added to it intermittently. Kept at 0° C., this was stirred for 5 hours, and then 1 L of ice-water was poured into the reaction mixture. This was extracted with 500 ml of diethyl ether. The diethyl ether layer was washed with 3% hydrochloric acid until its pH became acidic, and then washed with saturated sodium carbonate solution and water in this order, and thereafter dried with anhydrous magnesium sulfate. The solvent was evaporated away, and 243 g of 3-[(tosyloxy)methyl]-3-ethyloxetane was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15]O)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18].S(Cl)([Cl:23])=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][Cl:23])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18]
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Product: FC(F)(F)c1cc(Oc2ccc(CCl)cc2)ccc1Cl
Yield: 94.2 %

Procedure:
A solution of (4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)methanol (200 mg, 0.661 mmol) in thionyl chloride (0.5 mL, 6.85 mmol) was stirred at rt for 1 h. Then the excess thionyl chloride was removed under vacuum to afford the title product (200 mg) as a yellow oil, which was used in the next reaction without purification. LC-MS (ESI): m/z 285 [M−Cl]+; 4.17 min (ret time).