Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][C:4]([CH:7]([O:11][CH3:12])[C:8]([OH:10])=O)=[CH:3][CH:2]=1.[NH2:19][CH2:20][C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1>>[C:1]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:2]=[CH:3][C:4]([CH:7]([O:11][CH3:12])[C:8]([NH:26][CH2:25][C:24]2[CH:27]=[CH:28][C:21]([C:20]#[N:19])=[CH:22][CH:23]=2)=[O:10])=[CH:5][CH:6]=1
Reactant: COC(C(=O)O)c1ccc(-c2ccccc2)cc1
Reactant: N#Cc1ccc(CN)cc1
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1ccc(-c2ccccc2)cc1

Procedure:
(RS)-Biphenyl-4-yl-methoxy-acetic acid was coupled with 4-aminomethyl benzonitrile according to general procedure C to give (RS)-2-biphenyl-4-yl-N-(4-cyano-benzyl)-2-methoxy-acetamide. Light yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:16]=[C:17]([CH:25]3[CH2:28][CH:27]([CH2:29][OH:30])[CH2:26]3)[N:18]3[CH:23]=[CH:22][N:21]=[C:20](Cl)[C:19]=23)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:31]>N.CC(O)C>[NH2:31][C:20]1[C:19]2[N:18]([C:17]([CH:25]3[CH2:28][CH:27]([CH2:29][OH:30])[CH2:26]3)=[N:16][C:15]=2[C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:10]=2)[CH:23]=[CH:22][N:21]=1
Reactant: OCC1CC(c2nc(-c3cccc(OCc4ccccc4)c3)c3c(Cl)nccn23)C1
Reactant: N
Solvent: CC(C)O
Product: Nc1nccn2c(C3CC(CO)C3)nc(-c3cccc(OCc4ccccc4)c3)c12
Temperature: 110 °C

Procedure:
A solution of {3-[1-(3-benzyloxyphenyl)-8-chloro-imidazo[1,5-a]pyrazin-3-yl]cyclobutyl}methanol (40 mg, 0.095 mmol) in 5 mL of 2N NH3/iPrOH was cooled to −78° C. and charged with NH3 gas for 1 min. This sealed tube was equipped with a teflon O-ring, sealed and heated at 110° C. overnight. The mixture was cooled to rt and the cap was removed. The solution was concentrated under reduced pressure and the crude material was purified by silica gel column chromatography (eluting with 100% ethyl acetate→EtOAc:iPrOH=80:20), yielding the title compound as a white solid, a mixture of cis and trans isomers. MS (ES, Pos.): m/z 401 [MH+]. 1H NMR (CDCl3, 400 MHz) δ 2.37-2.44 (m, 2H), 2.61-2.74 (m, 3H), 3.65-3.82 (m, 3H), 5.03 (br s, 2H, NH2), 5.14 (s, 2H), 7.01-7.46 (m, 11H).
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[NH:3]1.[CH2:29]([CH:31]1[CH2:33][O:32]1)[CH3:30].C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C>C(OCC)(=O)C>[OH:32][CH:31]([CH2:29][CH3:30])[CH2:33][N:3]1[C:2](=[O:1])[C:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:13][CH:14]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]12
Reactant: CCC1CO1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2ncnn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC(O)CC)c2ncnn12
Temperature: 100 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
A mixture of 4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.5 g), 2-ethyloxirane (1.17 mL), potassium carbonate (0.38 g) and N,N-dimethylacetamide (10 mL) was stirred in a sealed tube at 100° C. for 8 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.45 g, 75%).
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:28]=[CH:29][CH:30]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=2)[CH:13]=1)=[O:10])([CH3:5])[CH3:4])#[N:2]>O1CCCC1.CO.[C].[Pd]>[NH2:25][C:22]1[CH:23]=[CH:24][C:19]([O:18][C:14]2[CH:13]=[C:12]([NH:11][C:9](=[O:10])[C:8]3[CH:28]=[CH:29][CH:30]=[C:6]([C:3]([C:1]#[N:2])([CH3:5])[CH3:4])[CH:7]=3)[CH:17]=[CH:16][CH:15]=2)=[CH:20][CH:21]=1
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc([N+](=O)[O-])cc3)c2)c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc(N)cc3)c2)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 97.8 %

Procedure:
To a solution of 3-(1-cyano-1-methylethyl)-N-[3-(4-nitrophenoxy)phenyl]benzamide (8.10 g, 20.2 mmol) in tetrahydrofuran (50 mL) and methanol (50 mL) was added 10% palladium-carbon (555 mg), and the mixture was stirred under a hydrogen atmosphere (2.5 atm) at room temperature for 14 hr. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (7.34 g, 98%) as a pale-gray amorphous substance. The obtained compound was used in the next reaction without a further purification.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:26])=[C:11]([NH:13][C:14](=[O:25])[C:15]3[CH:20]=[C:19](F)[CH:18]=[CH:17][C:16]=3[N+:22]([O-:24])=[O:23])[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.[OH:27][CH:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]1.[H-].[Na+].[Cl-].[NH4+]>CN(C=O)C>[CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:26])=[C:11]([NH:13][C:14]([C:15]3[CH:20]=[C:19]([CH:18]=[CH:17][C:16]=3[N+:22]([O-:24])=[O:23])[O:27][CH:28]3[CH2:29][CH2:30][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:32][CH2:33]3)=[O:25])[CH:12]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(F)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 22 h
Yield: 91.6 %

Procedure:
To a solution of N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-fluoro-2-nitrobenzamide (2.0 g) and tert-butyl 4-hydroxy-1-piperidinecarboxylate (1.69 g) in DMF (30 ml) was added sodium hydride (0.896 g of a 60% dispersion in oil) portion-wise (ice bath cooling). The reaction was stirred for 22 hours at room temperature under an atmosphere of argon. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution (200 ml) and the resulting precipitate was collected by filtration, washed with diethyl ether, and air dried to yield tert-butyl 4-{3-[({5-[(cyclopropylamino)carbonyl]-2-methylphenyl}amino)carbonyl]-4-nitrophenoxy}piperidine-1-carboxylate (2.76 g) as a yellow solid; NMR Spectrum: (DMSOd6) 0.60 (m, 2H), 0.70 (m, 2H), 1.40 (s, 9H), 1.60 (m, 2H), 1.97 (m, 2H), 2.30 (s, 3H), 2.84 (m, 1H), 3.23 (m, 2H), 3.66 (m, 2H), 4.88 (m, 1H), 7.29 (m, 2H), 7.31 (s, 1H), 7.60 (d, 1H), 7.95 (s, 1H), 8.17 (d, 1H), 8.38 (d, 1H), 10.10 (s, 1H); Mass Spectrum: M+Na+ 561.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7][CH:8]=2)[N:3]1[CH2:16][C:17]([OH:19])=O.[Br:20][C:21]1[C:22]([C:27]2[NH:31][N:30]=[CH:29][N:28]=2)=[C:23]([NH2:26])[S:24][CH:25]=1>>[Br:20][C:21]1[C:22]([C:27]2[NH:31][N:30]=[CH:29][N:28]=2)=[C:23]([NH:26][C:17](=[O:19])[CH2:16][N:3]2[C:4]3[C:9](=[CH:8][N:7]=[C:6]([C:12]([F:13])([F:14])[F:15])[CH:5]=3)[CH:10]=[CH:11][C:2]2=[O:1])[S:24][CH:25]=1
Reactant: O=C(O)Cn1c(=O)ccc2cnc(C(F)(F)F)cc21
Reactant: Nc1scc(Br)c1-c1ncn[nH]1
Product: O=C(Cn1c(=O)ccc2cnc(C(F)(F)F)cc21)Nc1scc(Br)c1-c1ncn[nH]1

Procedure:
The title compound was prepared from 2-(2-oxo-7-(trifluoromethyl)-1,6-naphthyridin-1(2H)-yl)acetic acid (55 mg, 0.203 mmol) and 4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-amine (25 mg, 0.102 mmol) according to protocol A. Retention time (min)=4.505, method [7], MS (ESI) 499.0 (M+H); 1H NMR (300 MHz, CD3OD) δ 9.06 (s, 1H), 8.31 (s, 1H), 8.24 (d, J=9.4 Hz, 1H), 7.94 (s, 1H), 7.14 (s, 1H), 6.99 (d, J=9.4 Hz, 1H), 5.39 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[F:9].C([Li])CCC.[B:15](OC)([O:18]C)[O:16]C.Cl>CCCCCC.O1CCCC1>[Cl:8][C:4]1[C:3]([F:9])=[C:2]([B:15]([OH:18])[OH:16])[CH:7]=[CH:6][CH:5]=1
Reactant: Fc1c(Cl)cccc1Br
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OB(O)c1cccc(Cl)c1F
Temperature: -80 °C
Reaction time: 1.5 h
Yield: 35.8 %

Procedure:
In a 500-mL three-neck flask was put 16 g (72 mmol) of 1-bromo-3-chloro-2-fluorobenzene, and the air in the flask was replaced with nitrogen; then, 200 mL of tetrahydrofuran was added and the solution was cooled down to −80° C. under a nitrogen stream. To this solution, 48 mL (76 mmol) of n-butyl lithium (a 1.6 mol/L hexane solution) was added dropwise with a syringe, and then the mixture was stirred for 1.5 hours at the same temperature. After stirring, 9.0 mL (80 mmol) of trimethyl borate was added to this mixture. While the temperature was raised to room temperature, the mixture was stirred for about 19 hours. After stirring, about 100 mL of a 1 mol/L hydrochloric acid was added to the resulting solution and the mixture was stirred. The organic layer of this mixture was washed with water and the aqueous layer was subjected to extraction with toluene twice. The solution of the extract and the organic layer were combined and washed with a saturated aqueous solution of sodium chloride. The resulting organic layer was dried over magnesium sulfate, and this mixture was gravity-filtered. The resulting filtrate was concentrated to give 4.5 g of a pale yellow solid of a target substance, in a yield of 35%.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:5]=[CH:6][C:7]([CH3:11])=[C:8]([OH:10])[CH:9]=1)[CH3:2].[CH2:12](Br)[CH3:13].[ClH:15]>C(O)C>[ClH:15].[CH2:1]([N:3]([CH2:12][CH3:13])[C:4]1[CH:5]=[CH:6][C:7]([CH3:11])=[C:8]([OH:10])[CH:9]=1)[CH3:2]
Reactant: CCNc1ccc(C)c(O)c1
Reactant: CCBr
Agent: Cl
Solvent: CCO
Product: CCN(CC)c1ccc(C)c(O)c1

Procedure:
5 gm of 5-(ethylamino)-2-methylphenol were dissolved in 50 ml of ethanol, then alkylated analogously to the procedure described in Example 4 with 5,2 gm ethyl bromide, and worked up. The hydrochloride had a melting point of 192° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:12]=[C:11]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:10]=1[CH2:23][CH2:24][NH2:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]1(=O)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:17])([CH3:16])[CH3:18])[CH:12]=[C:11]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:10]=1[CH2:23][CH2:24][NH:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCCCC1
Reactant: CC(C)(C)c1cc(OCc2ccccc2)c(CCN)c(C(C)(C)C)c1
Product: CC(C)(C)c1cc(OCc2ccccc2)c(CCNC2CCCCC2)c(C(C)(C)C)c1

Procedure:
The product from Step A (0.227 g) was treated with 0.070 g (0.71 mmol) of cyclohexanone according to the procedure described in Example 3. The product was purified on a silica gel flash chromatography column eluted with 5-10% isopropanol in hexane. Evaporation of the purified fractions and drying in vacuo afforded the title compound.
Reaction SMILES: I[CH2:2][I:3].[CH2:4]([O:6][C:7]([C:9]1[N:10]([CH3:17])[CH:11]=[C:12](C#N)[C:13]=1[NH2:14])=[O:8])[CH3:5].C(ON=O)CC(C)C>C(#N)C>[CH2:4]([O:6][C:7]([C:9]1[N:10]([CH3:17])[CH:11]=[C:12]([C:13]#[N:14])[C:2]=1[I:3])=[O:8])[CH3:5]
Reactant: CCOC(=O)c1c(N)c(C#N)cn1C
Reactant: ICI
Agent: CC(C)CCON=O
Solvent: CC#N
Product: CCOC(=O)c1c(I)c(C#N)cn1C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Add diiodomethane (22.15 mL, 274.97 mmol) to 3-amino-4-cyano-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (14.75 g, 76.34 mmol, prepared in preparation 33) in acetonitrile with stirring at room temperature. Next, add isoamylnitrite (25.65 mL, 190.92 mmol) while heating the reaction to 35° C. After complete addition, the reaction is heated to 65° C. After 10 minutes; cool the reaction mixture to room temperature and concentrate under reduced pressure. Purify the residue by filtering over silica gel with methylene chloride and triturating the filtrate with hexane to afford the title compound.
Reaction SMILES: C([NH:14][CH:15]([C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1)[P:16]([OH:18])[OH:17])(C1C=CC=CC=1)C1C=CC=CC=1.C(NC(P(O)O)C(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>>[NH2:14][CH:15]([C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1)[P:16]([OH:17])[OH:18]
Reactant: OP(O)C(NC(c1ccccc1)c1ccccc1)c1c[nH]c2ccccc12
Agent: CC(C)C(NC(c1ccccc1)c1ccccc1)P(O)O
Product: NC(c1c[nH]c2ccccc12)P(O)O

Procedure:
The procedure described in Example 36B was repeated using DL-1-benzhydrylamino-1-(indol-3-yl)-methanephosphonous acid instead of DL-1-benzhydrylamino-2-methylpropanephosphonous acid to give DL-1-amino-1-(indol-3-yl)-methanephosphonous acid.
Reaction SMILES: [OH-].[Na+:2].CO.[CH2:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[N:18]=[CH:17][C:16]([C:19]([O:21]C)=[O:20])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)[CH3:6]>O>[CH2:5]([N:7]1[CH2:8][CH2:9][N:10]([C:13]2[N:18]=[CH:17][C:16]([C:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)[CH2:11][CH2:12]1)[CH3:6].[Na+:2]
Reactant: CCN1CCN(c2ccc(C(=O)OC)cn2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCN1CCN(c2ccc(C(=O)[O-])cn2)CC1
Yield: 111.1 %

Procedure:
A solution of 3.1 g of sodium hydroxide in 15 ml of water was added to 75 ml of methanol. 15 g of methyl 6-(4-ethyl-1-piperazinyl)pyridine-3-carboxylate was added and the mixture was heated under reflux for 1.5 hours. The solvent was distilled off under reduced pressure, to the resulting residue was added hot acetone and the crystal thus precipitated out was recovered by filtration. It was again washed with hot acetone to afford 17.2 g of the title compound as a crystal.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[Br:10]C1C=C(C)C=CC=1F>>[Br:10][C:7]1[C:2]([Br:1])=[C:3]([CH3:9])[CH:4]=[CH:5][C:6]=1[F:8]
Reactant: Cc1ccc(F)c(Br)c1
Reactant: Cc1ccc(F)cc1Br
Product: Cc1ccc(F)c(Br)c1Br
Yield: 9 %

Procedure:
11 g of iron powder were added to a solution of 110 g (1 mole) of 4-fluorotoluene in 165 ml of carbon tetrachloride. 160 g (1 mole) of bromine were added dropwise to this mixture at room temperature, the mixture was subsequently stirred for 24 hours, the solvent was distilled off under normal pressure and the residue was fractionated under normal pressure over a 10 cm Vigreux column. 26.4 g of unreacted 4-fluorotoluene were obtained as the first fraction at a boiling point of 114° to 117° C., and 78 g of a mixture consisting of 66% of 2-bromo-4-fluorotoluene, 24% of 3-bromo-4-fluorotoluene and 9% of dibromo-4-fluorotoluene were obtained as the second fraction at a boiling point of 175° to 185° C. Relative to the 4-fluorotoluene reacted, the yield of 2-bromo-4-fluorotoluene plus 3-bromo-4-fluorotoluene was 48% and that of 3-bromo-4-fluorotoluene was 11.4%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:11]([CH3:20])([CH3:19])[CH2:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.[N:21]1[CH:26]=[C:25](B(O)O)[CH:24]=[N:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>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.CO.COCCOC.CN(C=O)C>[F:15][C:14]([F:17])([F:16])[C:13](=[O:18])[CH2:12][C:11]([CH3:20])([C:4]1[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=[C:2]([C:25]2[CH:26]=[N:21][CH:22]=[N:23][CH:24]=2)[CH:3]=1)[CH3:19]
Reactant: CC(C)(CC(=O)C(F)(F)F)c1cc(Br)cc2c1OCC2
Reactant: OB(O)c1cncnc1
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: CO
Solvent: COCCOC
Solvent: CN(C)C=O
Product: CC(C)(CC(=O)C(F)(F)F)c1cc(-c2cncnc2)cc2c1OCC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 63.2 %

Procedure:
To a mixture of 4-(5-bromo-2,3-dihydrobenzofuran-7-yl)-1, 1,1-trifluoro-4-methylpentan-2-one (1.00 g, 2.8 mmol), pyrimidine-5-boronic acid (529 mg, 4.3 mmol) and potassium carbonate (787 mg) in a sealed tube was added 20 mL of MeOH-DME-DMF (3:2:1). After stirring at room temperature for 10 minutes, tetrakis(triphenylphosphine)palladium(0) (329 mg) was added and the reaction mixture was heated at 120° C. for 40 minutes. After cooling to room temperature, the crude mixture was filtered through a cotton plug with the aid of ethyl acetate. The filtrate was concentrated in vacuo to remove most of the methanol, redissolved in 160 mL of ethyl acetate, and washed with 80 mL of aqueous 1 N sodium hydroxide solution, 80 mL of water, and 80 mL of brine respectively. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Purification by column chromatography with 20% to 30% ethyl acetate-hexanes afforded 620 mg (62% yield) of the title compound.
Reaction SMILES: C([O:3][C:4](=[S:17])[CH2:5][CH2:6][CH2:7][CH2:8][CH:9]([S:13]C(=O)C)[CH2:10][CH2:11][CH3:12])C.[OH-].[K+]>CO.O>[SH:13][CH:9]([CH2:10][CH2:11][CH3:12])[CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:3])=[S:17]
Reactant: CCCC(CCCCC(=S)OCC)SC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCC(S)CCCCC(O)=S
Yield: 84.5 %

Procedure:
11.9 grams (40.7 mmoles) of 6-acetylthio-8-methylthiooctanoic acid ethyl ester (XI) were added to a solution of 7.5 grams (133.7 mmoles) of potassium hydroxide in 100 ml of methanol and 5 ml of water and the mixture heated at reflux for 10 hours under a cover of nitrogen. After a further 10 hours at room temperature the solvent was removed in a vacuum, the residue taken up in 100 ml of 3N hydrochloric acid and extracted three times, each time with 100 ml of ethyl acetate. After drying the combined extracts with magnesium sulfate the solvent was removed in a vacuum. The short path distillation of the residue gave 7.1 grams (78% of theory) of 6-mercapto-8-methylthiooctanoic acid as a pale yellow oil having a boiling point of 150° C. to 170° C. at 0.5 mbar.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[C:7](=[O:12])[N:6]([CH2:13][CH:14]1[O:23][CH2:22][CH2:21][C:16]3(OCC[O:17]3)[CH2:15]1)[C:5]2=[O:24].Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[C:7](=[O:12])[N:6]([CH2:13][CH:14]1[CH2:15][C:16](=[O:17])[CH2:21][CH2:22][O:23]1)[C:5]2=[O:24]
Reactant: O=C1c2cc(Cl)c(Cl)cc2C(=O)N1CC1CC2(CCO1)OCCO2
Agent: Cl
Solvent: C1CCOC1
Product: O=C1CCOC(CN2C(=O)c3cc(Cl)c(Cl)cc3C2=O)C1
Temperature: 75 °C
Yield: 82.3 %

Procedure:
5,6-Dichloro-2-(1,4,8-trioxa-spiro[4.5]dec-7-ylmethyl)-isoindole-1,3-dione (87 mg, 0.23 mmol) was dissolved in tetrahydrofuran (2.5 ml). 1.0 N hydrochloric acid (1.0 ml) was added to the solution and the mixture was heated at 75° C. for 20 h. The heterogeneous mixture was evaporated to dryness in vacuo and the resulting solid was dissolved in dichloromethane (10 ml) and washed with water (3×2 ml). The organic layer was dried (MgSO4), filtered and the solvent evaporated in vacuo affording 62.1 mg (81%) of 5,6-dichloro-2-(4-oxo-tetrahydro-pyran-2-ylmethyl)-isoindole-1,3-dione as a solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:24]1[O:26][C@@H:25]1[CH2:27][OH:28].[Cl-].[NH4+]>CN(C)C=O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:24][C@H:25]([OH:26])[CH2:27][OH:28])=[CH:15][CH:16]=2)([CH3:10])[CH3:9])=[CH:6][CH:7]=1
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: OC[C@@H]1CO1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(c1ccc(O)cc1)c1ccc(OC[C@H](O)CO)cc1
Reaction time: 0.33 h
Yield: 28.4 %

Procedure:
To a stirred solution of bisphenol A (10 g, 43.84 mmol, 1.0 equiv) in anhydrous dimethyl formamide (35 mL) at rt was added K2CO3 (9.1 g, 65.76 mmol, 1.5 equiv), and the mixture was stirred for 20 min under argon atmosphere. R(+) glycidol (3.8 mL, 56.99 mmol, 1.3 equiv) was added and the mixture was stirred for 5 h at 70-80° C. A saturated solution of ammonium chloride (10 mL) was added to the resulting orange-brown solution at room temperature. The mixture was extracted with ethyl acetate (3×15 mL). The organic layer was washed with deionized water (10 mL), was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (eluent: 40% to 90% ethyl acetate in hexane) to provide the title compound (3.77 g, 28%) as a clear foam.
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:25][CH2:26][CH2:27][O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[C:10]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:5]=2[O:4][CH2:3]1.[NH:35]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:37]([CH:44]=O)=[N:36]1.N1CCCCC1>CO>[NH:35]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:37](/[CH:44]=[C:3]2\[O:4][C:5]3[C:10]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]4)=[C:9]([O:25][CH2:26][CH2:27][O:28][C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:8]=[CH:7][C:6]=3[C:2]\2=[O:1])=[N:36]1
Reactant: O=Cc1n[nH]c2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(OCCOc3ccccc3)ccc3c2OCC3=O)CC1
Solvent: C1CCNCC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(OCCOc3ccccc3)ccc3c2O/C(=C\c2n[nH]c4ccccc24)C3=O)CC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 43.5 %

Procedure:
A solution of tert-butyl 4-[(3-oxo-6-(2-phenoxyethoxy)-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.0720 g, 0.154 mmol) in methanol (1 mL) was added with 1H-indazole-3-carboxaldehyde (0.0225 g, 0.154 mmol) and piperidine (0.00131 g, 0.0154 mmol), and the mixture was stirred at 60° C. for 3 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol) to obtain tert-butyl (Z)-4-({2-[(1H-indazol-3-yl)methylene]-3-oxo-6-(2-phenoxyethoxy)-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.0400 g, 43%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([S:13]([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[NH:10][CH:11]=O.P(Cl)(Cl)(Cl)=O>COCCOC>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([N+:10]#[C-:11])[S:13]([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:14])=[O:15]
Reactant: Cc1ccc(S(=O)(=O)C(NC=O)c2ccc(F)cc2F)cc1
Solvent: COCCOC
Solvent: O=P(Cl)(Cl)Cl
Product: [C-]#[N+]C(c1ccc(F)cc1F)S(=O)(=O)c1ccc(C)cc1
Temperature: -5 °C
Reaction time: 3 h
Yield: 20 %

Procedure:
To a solution of N-((2,4-difluorophenyl)(tosyl)methyl)formamide (7.31 g, 22.5 mmol) in DME (100 mL) at about −10° C. was added phosphorus oxychloride (Fluka, 6.28 mL, 67.4 mmol) followed by dropwise addition of TEA (15.7 mL, 112 mmol) in DME (10 mL). The reaction mixture was stirred at about −5° C. for about 3 h. The reaction mixture was poured into ice-cold water (250 mL) and extracted with EtOAc (3×50 mL). The organic layer was dried with MgSO4, filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography using heptane/EtOAc (gradient; 1:0 to 1:1) to give the title compound (1.38 g, 20.0%), as a yellow solid. LC/MS (Table 1, Method a) Rt=2.96 min; MS m/z: 306.1 (M−H)−.