Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1.CCCCCC>O1CCCC1>[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([N:15]2[CH2:16][CH2:17][N:12]([C:10]3[S:9][N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:11]=3)[CH2:13][CH2:14]2)=[O:35])=[CH:29][CH:28]=1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: COc1ccc(N=C=O)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: COc1ccc(NC(=O)N2CCN(c3nc(-c4ccccc4)ns3)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.1 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2 ml) was added 4-methoxyphenyl isocyanate (0.158 ml, 1.22 mmol), and the mixture was stirred at room temperature for 2 hours. To the resulting solution was added hexane (4 ml) and the solid was separated by filtration, which was recrystallized from a mixed solvent of tetrahydrofuran and ethyl acetate to give 180 mg (56.1%) of the desired product as a solid.
Reaction SMILES: [F:1][C:2]([CH3:37])([CH3:36])[C@H:3]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=4)[N:19]([CH3:27])[N:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])[CH3:4].FC(F)(F)C(O)=O.C(N)CN>ClCCl>[F:1][C:2]([CH3:36])([CH3:37])[C@H:3]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=4)[N:19]([CH3:27])[N:18]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])[CH3:4]
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)C(C)(C)F
Solvent: O=C(O)C(F)(F)F
Solvent: NCCN
Solvent: ClCCl
Product: C[C@@H](NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)C(C)(C)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.5 %

Procedure:
In a round-bottomed flask, 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-2-fluoro-1,2-dimethyl-propyl)amide (93 mg, 0.176 mmol) was dissolved in dichloromethane (0.9 ml) and trifluoroacetic acid (0.54 ml, 7.0 mmol) was added. The reaction mixture was stirred at room temperature for 2 h then concentrated. The residue was dissolved in dichloromethane (0.9 ml) and ethylenediamine (0.7 ml, 10.5 mmol) was added. The yellow solution was stirred at room temperature for 1 h then quenched with water and extracted with dichloromethane (2×). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was absorbed on silica gel and chromatographed with MeOH/CH2Cl2/0.5% NH4OH (gradient 0-6% MeOH) then triturated with ethyl acetate to afford 34 mg (46%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-2-fluoro-1,2-dimethyl-propyl)-amide as a light yellow powder. MS: (M+H)+=399; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 12.90 (br. s., 1H), 9.12 (s, 1H), 8.45-8.54 (m, 2H), 8.25 (d, J=9.8 Hz, 1H), 7.68 (dd, J=9.8, 2.3 Hz, 1H), 7.09 (td, J=9.1, 2.3 Hz, 1H), 4.30-4.48 (m, 1H), 4.15 (s, 3H), 1.29-1.52 (m, 9H).
Reaction SMILES: [O:1]([CH:9](O)[CH2:10][CH3:11])[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])(C)C.CS(Cl)(=O)=O.S([O-])(=O)(=O)C.[N-:23]=[N+:24]=[N-:25].C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl.C1C=CC=CC=1.C(N(CC)CC)C>[N:23]([CH2:11][CH2:10][CH2:9][O:1][SiH2:2][C:5]([CH3:8])([CH3:7])[CH3:6])=[N+:24]=[N-:25]
Reactant: CCC(O)O[Si](C)(C)C(C)(C)C
Reactant: [N-]=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Solvent: ClCCl
Product: CC(C)(C)[SiH2]OCCCN=[N+]=[N-]

Procedure:
Following the procedure given in example 29, t-butyldimethylsiloxypropanol (prepared according to the method of McDougal et al, J. Org. Chem. 1986, 51, 3388) is first reacted with methanesulfonyl chloride in methylene chloride in the presence of triethylamine, and then the crude mesylate is reacted with tetra-n-butylammonium azide in benzene to afford 1-azido-3-t-butylsiloxypropane.
Reaction SMILES: [CH:1]1([CH2:7][C:8]2[CH:9]=[C:10]([OH:35])[CH:11]=[CH:12][C:13]=2[O:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:25][CH:24]=3)[O:20][C:21]=2[CH3:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:37]([CH3:44])([CH3:43])[C:38]([O:40][CH2:41][CH3:42])=[O:39].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:41]([O:40][C:38](=[O:39])[C:37]([O:35][C:10]1[CH:11]=[CH:12][C:13]([O:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:24]=[CH:25][C:26]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:27][CH:28]=3)[O:20][C:21]=2[CH3:22])=[C:8]([CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:9]=1)([CH3:44])[CH3:43])[CH3:42]
Reactant: Cc1oc(-c2ccc(-c3ccccc3)cc2)nc1CCOc1ccc(O)cc1CC1CCCCC1
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)c(CC2CCCCC2)c1
Temperature: 55 °C

Procedure:
A mixture of 3-cyclohexylmethyl-4-[2-(5-methyl-2-biphenyl-4-yl-oxazole-4-yl)ethoxy]phenol (0.90 mmol), ethyl 2-bromo-2-methylpropanoate (2.25 mmol) and cesium carbonate (0.45 g, 1.38 mmol) in anhydrous DMF (4 mL) was heated for 24 h at 55° C. The mixture was concentrated in vacuo, and the residue was partitioned between ethyl acetate (50 mL) and water (40 mL), washed with brine, dried (Na2SO4), and removed in vacuo to give a crude oil which was purified using radial chromatography eluting with 2% ethyl acetate/dichloromethane to give 2-{4-[2-(2-biphenyl-4-yl-5-methyloxazol-4-yl)ethoxy]-3-cyclohexylmethylphenoxy}-2-methylpropionic acid ethyl ester. 1H NMR (400 MHz, CDCl3) δ 8.04 (d, J=8.8 Hz, 2H), 7.65 (q, J=8.3 Hz, 4H), 7.46 (t, J=7.6 Hz, 2H), 7.37 (t, J=7.3 Hz, 1H), 6.72-6.64 (m, 3H), 4.25-4.18 (m, 4H), 2.96 (t, J=6.4 Hz, 2H), 2.40 (s, 3H), 2.38 (t, J=7.3 Hz, 2H), 1.59-1.55 (m, 11H), 1.47-1.42 (m, 1H), 1.27 (t, J=7.1 Hz, 3H), 1.13-1.05 (m, 3H), 0.88-0.75 (m, 2H), MS (ES) m/e 582 (M+1).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([O:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH2:4][CH2:3]1.C(Cl)(Cl)Cl.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>CC(O)=O.CCOCC>[O:1]=[C:2]1[CH2:3][CH2:4][CH:5]([O:8][S:9]([C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=2)(=[O:11])=[O:10])[CH2:6][CH2:7]1
Reactant: Cc1ccc(S(=O)(=O)OC2CCC(O)CC2)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)(=O)OC2CCC(=O)CC2)cc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 59.8 %

Procedure:
step 2—To a solution of 76 (2.23 g, 8.22 mmol) and CHCl3 (30 mL) was added PCC (1.77 g, 8.22 mmol) and CHCl3 (20 mL). One drop of HOAc was added and the mixture was stirred at RT for 2.5 days. An additional 1.77 g (8.22 mmol) of PCC was added and stirring continued at RT for an additional 6 h. The reaction was diluted with Et2O and filtered through a bed of SiO2. The cake was washed with Et2O and the filtrate was passed through a second plug of SiO2 while washing the cake with Et2O. The filtrate was stripped in vacuo and the crude material was purified by SiO2 chromatography eluting with a DCM/MeOH gradient (0 to 4% MeOH). The recovered material was re-purified by SiO2 chromatography eluting with a gradient of hexane/acetone (15 to 25% acetone) to afford 1.32 g (58%) of toluene-4-sulfonic acid 4-oxo-cyclohexyl ester (78) as a colorless oil: 1H NMR (CDCl3, 300 MHz): δ 7.83 (d, 2H), 7.37 (d, 2H), 4.92-4.86 (m, 1H), 2.78-2.53 (m, 2H), 2.46 (s, 3H), 2.34-2.13 (m, 4H), 2.03-1.83 (m, 2H).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[OH:12][C:13]([CH3:34])([CH3:33])[CH2:14][N:15]1[C:27]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:20]=[CH:19][C:18]=2[N:17]=[C:16]1[NH:28][C:29](=[O:32])[O:30][CH3:31]>ClCCl>[OH:12][C:13]([CH3:34])([CH3:33])[CH2:14][N:15]1[C:27]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N+:20]([O-:6])=[CH:19][C:18]=2[N:17]=[C:16]1[NH:28][C:29](=[O:32])[O:30][CH3:31]
Reactant: COC(=O)Nc1nc2cnc3ccccc3c2n1CC(C)(C)O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COC(=O)Nc1nc2c[n+]([O-])c3ccccc3c2n1CC(C)(C)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 76.2 %

Procedure:
3-Chloroperoxybenzoic acid (1.83 g of approximately 75% pure material) was added to a stirred solution of methyl [1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-2-yl]carbamate (1.0 g, 3.18 mmol) in dichloromethane (25 mL), and the reaction was stirred for 24 hours at room temperature. A precipitate formed and was collected by filtration, washed with a minimal amount of dichloromethane, and dried to provide 0.8 g of methyl [1-(2-hydroxy-2-methylpropyl)-5-oxido-1H-imidazo[4,5-c]quinolin-2-yl]carbamate as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:5]([C:6]([OH:8])=[O:7])[C:4]=1[CH:12]=O.[S:14]1[CH2:20][C:18](=[O:19])[NH:17][C:15]1=[S:16].C(O)(=O)C.C([O-])(=O)C.[Na+]>O>[C:6]([C:5]1[CH:9]=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[C:4]=1[CH:12]=[C:20]1[S:14][C:15](=[S:16])[NH:17][C:18]1=[O:19])([OH:8])=[O:7]
Reactant: O=C1CSC(=S)N1
Reactant: COc1cccc(C(=O)O)c1C=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1cccc(C(=O)O)c1C=C1SC(=S)NC1=O

Procedure:
To a stirred hot solution of 0.45 g. (2.50 mM) of 3-methoxyphthalaldehydic acid and 0.34 g. (2.50 mM) rhodanine in 3 ml. of acetic acid is added 0.68 g. (8.2 mM) of anhydrous sodium acetate. The resulting solution is refluxed 1.5 hours, cooled, and poured into 40 ml. of water to give a yellow gum which slowly solidifies to a yellow solid. The solid is collected, washed with water, and air-dried to give 5-(2-carboxy-6-methoxybenzylidene)rhodanine.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7](=O)[CH2:8][Br:9].[C:11]([NH:14][C:15]([NH2:17])=[S:16])(=[NH:13])[NH2:12]>CC(C)=O>[BrH:9].[NH:14]([C:15]1[S:16][CH:8]=[C:7]([C:6]2[NH:5][CH:4]=[N:3][C:2]=2[CH3:1])[N:17]=1)[C:11]([NH2:13])=[NH:12]
Reactant: Cc1nc[nH]c1C(=O)CBr
Reactant: N=C(N)NC(N)=S
Solvent: CC(C)=O
Product: Br
Product: Cc1nc[nH]c1-c1csc(NC(=N)N)n1
Temperature: 25 °C

Procedure:
A mixture of 1.65 g (8.13 mmol) of 1-(4-methyl-5-imidazolyl)-2-bromoethanone in 165 ml of acetone was heated until homogeneous. 0.96 g (8.13 mmol) of amidinothiourea was added and the mixture was heated at reflux for 1 hour. The mixture was allowed to cool to room temperature and the resulting precipitate was collected by filtration. This solid amounted to 0.98 g (40%) of 2-guanidino-4-(4-methyl-5-imidazolyl)thiazole hydrobromide, mp 245° (dc); nmr D6DMSO) (δ): 8.52 (s, 1H); 7.67 (b, 4H); 7.20 (s, 1H); 2.49 (s, 3H). Anal Calcd. for C8H10N6S.HBr: C, 31.69, H, 3.66; N, 27.72; Found: C, 31.80; H, 3.90; N, 26.90.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][OH:8].O1COCO[CH2:10]1>[Cl-].[In+3].[Cl-].[Cl-].C(#N)CCC>[S:1]1[C:2]2[CH2:6][CH2:7][O:8][CH2:10][C:3]=2[CH:4]=[CH:5]1
Reactant: C1OCOCO1
Reactant: OCCc1cccs1
Agent: [Cl-]
Agent: [In+3]
Solvent: CCCC#N
Product: c1cc2c(s1)CCOC2
Temperature: 25 °C
Yield: 121.2 %

Procedure:
10.0 g of 2-thiopheneethanol, 3.5 g of 1,3,5-trioxane, and 862 mg of indium(III) chloride were added to 1,500 mL of butyronitrile, and the resulting mixture was refluxed for 6 hours. The reaction product solution was cooled to room temperature and concentrated by evaporation under reduced pressure. The residue was distilled under reduced pressure to obtain 6.6 g (yield of 60%) of the title compound, of which analysis data were the same as obtained in Example 14.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:44])[N:20]([CH2:39][C:40]([CH3:43])([CH3:42])[CH3:41])[C:21](=[O:38])[C:22]=1[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)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:44])[N:20]([CH2:39][C:40]([CH3:43])([CH3:42])[CH3:41])[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCc1nc(C)n(CC(C)(C)C)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(CC(C)(C)C)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 31.7 %

Procedure:
A mixture of hydroxylammonium chloride (0.7 g), sodium hydrogen carbonate (1.06 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-{[4-butyl-1-(2,2-dimethylpropyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.36 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.16 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.14 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate 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 (0.13 g, 31%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:11]=1)[C:7](OC)=[O:8].[Cl:13][C:14]1[CH:15]=[C:16]([OH:21])[CH:17]=[C:18]([F:20])[CH:19]=1.Cl.[NH2:23][C@H:24]([C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=1)[CH3:25]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][C:16]2[CH:17]=[C:18]([F:20])[CH:19]=[C:14]([Cl:13])[CH:15]=2)=[C:6]([CH:11]=1)[C:7]([NH:23][C@H:24]([C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=1)[CH3:25])=[O:8]
Reactant: Oc1cc(F)cc(Cl)c1
Reactant: COC(=O)c1cc(Cl)ccc1F
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)ccc2Oc2cc(F)cc(Cl)c2)cc1

Procedure:
The title compound was prepared according to the three steps procedure described in step 1 of Example 67, step 2 of Example 43, and step 3 of Example 1. Firstly, methyl 5-chloro-2-fluorobenzoate was reacted with 3-chloro-5-fluorophenol. Next, the crude product was hydrolyzed to the corresponding carboxylic acid. Finally, the carboxylic acid was condensed with methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 3 of Example 5): 1H-NMR (CDCl3) δ 8.12 (1H, d, J=2.8 Hz), 7.94 (2H, d, J=8.3 Hz), 7.43 (1H, dd, J=8.8, 2.8 Hz), 7.38 (1H, d, J=7.3 Hz), 7.28 (2H, d, J=8.4 Hz), 6.92 (1H, d, J=8.8 Hz), 6.93–6.86 (1H, m), 6.69 (1H, br.s), 6.53 (1H, td, J=9.4, 2.2 Hz), 5.36–5.19 (1H, m), 3.90 (3H, s), 1.49 (3H, d, J=7.0 Hz).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:9]2)=[CH:4][CH:3]=1.[CH3:16][Si:17]([C:20]#[CH:21])([CH3:19])[CH3:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:16][Si:17]([CH3:19])([CH3:18])[C:20]#[C:21][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:9]2)=[CH:4][CH:3]=1
Reactant: Brc1ccc2c(c1)CC1(CC2)OCCO1
Reactant: C#C[Si](C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc2c(c1)CC1(CC2)OCCO1
Yield: 40.2 %

Procedure:
A solution of 7′-bromo-3′,4′-dihydrospiro[1,3-dioxolane-2,2′(1H)-naphthalene] (3.40 g, 12.6 mmol), trimethylsilylacetylene (7.0 ml, 50 mmol) (Aldrich), triphenylphosphine (0.66 g, 2.50 mmol), and palladium acetate (0.28 g, 1.25 mmol) in triethylamine (18 ml) was stirred at 70° C. for 18 hours and then concentrated in vacuo. The residue was absorbed onto silica gel from a diethyl ether solution and partially purified by elution through silica gel (15 g) with diethyl ether:hexane (1:9). Further purification by chromatography on silica gel eluting with ethyl acetate:hexane (1:19) gave 3′,4′-dihydro-7′[2-(trimethylsilyl)-ethynyl]spiro[1,3-dioxolane-2,2′(1′H)-naphthalene] (1.45 g). 1H NMR (CDCl3 200 MHz) δ: 0.23 (s, 9H, SiMe3), 1.93 (t, J=7 Hz, 2CH2), 2.95 (t, J=7 Hz, 2H, CH2), 4.02 (s, 4H, OCH2CH2O), 7.03 (d, J=8 Hz, 1H, Ar), 7.17 (s, 1H, Ar), 7.21 (d, J=8 Hz, 1H, Ar).
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[C:8](=[O:9])[O:7][CH2:6][C:5]=12.CN(C)C(=O)C.[Cl:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][C:23]=1[F:24])[NH2:20]>CCO>[Cl:16][C:17]1[CH:18]=[C:19]([NH:20][C:8]([C:4]2[C:5]([CH2:6][OH:7])=[N:1][O:2][N:3]=2)=[O:9])[CH:21]=[CH:22][C:23]=1[F:24]
Reactant: O=C1OCc2nonc21
Reactant: Nc1ccc(F)c(Cl)c1
Solvent: CC(=O)N(C)C
Solvent: CCO
Product: O=C(Nc1ccc(F)c(Cl)c1)c1nonc1CO
Temperature: 80 °C
Yield: 74.1 %

Procedure:
4H,6H-Furo[3,4-c][1,2,5]oxadiazol-4-one (2.00 g, 0.0159 mol) was dissolved in EtOH (80 mL) and N,N-dimethylacetamide (10 mL) and then 3-chloro-4-fluoroaniline (2.5 g, 0.017 mol) was added as a solid. The reaction was heated at 80° C. overnight. The crude reaction mixture was concentrated in vacuo. The oil was extracted twice with EtOAc and washed with water. The organic was dried over Na2SO4 and concentrated. The crude residue was purified by flash column chromatography eluting with EtOAc:Hexane (1:1) to yield the desired product (3.2 g, 74%). 1H NMR (400 MHz, DMSO-d6) δ: 11.30 (s, 1H), 8.30 (dd, J=7.0, 2.7 Hz, 1H), 7.69 (ddd, J=9.1, 4.4, 2.6 Hz, 1H) 7.45 (dd, J=9.1, 9.1 Hz, 1H), 4.86 (d=5.8 Hz, 2H), 5.78 (t, 5.8 Hz, 1H); MF═C10H7ClFN3O3; LCMS calculated for C10H8ClFN3O3(M+H)+: m/z=272.024.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:17][S:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]#[C:28][CH3:29])=[CH:21][CH:20]=2)([C:14](O)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:30][N:31]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.NO>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:17][S:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]#[C:28][CH3:29])=[CH:21][CH:20]=2)([C:14]([NH:31][OH:30])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC#CCOc1ccc(SCC2(C(=O)O)CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NO
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC#CCOc1ccc(SCC2(C(=O)NO)CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.2 %

Procedure:
To a solution of 0.204 g (0.49 mmol) of 4-(4-But-2-ynyloxy-phenylsulfanylmethyl)-piperidine-1,4-dicarboxylic acid mono-tert-butyl ester, 0.079 g (0.58 mmol) of 1-hydroxybenzotriazole in 2.5 mL of DMF was added 0.112 g (0.84 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and stirred at room temperature for 1 h. Then added 0.3 mL of 50% aqueous hydroxylamine and stirred for 18 h. The resulting mixture was diluted with EtOAc, washed with H2O, brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 1.5% MeOH/CH2Cl2 to provide 0.077 g (36%) of the desired product as a white solid. Electrospray Mass Spec: 435.2 (M+H)+
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC12CC3(C45CC6(C)CC(C)(CC(C(Cl)=O)(C6)C4)C5)CC(C)(CC([C:34](Cl)=[O:35])(C3)C1)C2.[C:37]1(C#CC2C=C(C(Cl)=O)C=C(C=2)C(Cl)=O)C=CC=CC=1.C(Cl)(=O)C1C=CC=CC=1>CN1CCCC1=O.O>[O:35]1[C:34]2[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=2[N:1]=[CH:37]1
Reactant: CC12CC3(C)CC(C(=O)Cl)(C1)CC(C14CC5(C)CC(C)(CC(C(=O)Cl)(C5)C1)C4)(C2)C3
Reactant: O=C(Cl)c1cc(C#Cc2ccccc2)cc(C(=O)Cl)c1
Reactant: c1ccncc1
Solvent: O=C(Cl)c1ccccc1
Solvent: O
Solvent: CN1CCCC1=O
Product: c1ccc2ocnc2c1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
In a 2 L four-neck flask provided with a thermometer, a Dimroth condenser and an agitator, 64.8 g of 4,6-di(3,5-dimethyl-1-adamantyl)-1,3-bis(4-amino-3-hydroxyphenoxy)benzene (0.10 mol) obtained in Synthesis example 2 was dissolved in 800 g of dried N-methyl-2-pyrrolidone under nitrogen flow followed by the addition of 17.4 g of pyridine (0.22 mol). The mixture was heated to 60° C. and 31.6 g of 5,5′,7,7′-tetramethyl-1,1′-biadamantane-3,3′-dicarboxylic acid chloride (0.070 mol) was gradually added and then agitated at 60° C. for three hours. 7.57 g of 5-phenylethynyl-isophthalic acid chloride (0.025 mol) was gradually added with the inner temperature of the flask kept at 5° C. or below in an ice bath. Then, 2.10 g of benzoic acid chloride (0.015 mol) was added with the inner temperature of the flask kept at 5° C. or below. A reaction solution was added to 4 L of distilled water in small droplets followed by collecting and drying precipitate, thus obtaining a benzoxazole resin precursor.
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:20])OCC(Cl)(Cl)Cl)=[CH:8][CH:7]=1)(=[O:4])[CH2:2][CH3:3].[C:21]1([C:27]2[N:31]=[C:30]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[S:29][N:28]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[C:21]1([C:27]2[N:31]=[C:30]([N:32]3[CH2:37][CH2:36][N:35]([C:13]([NH:12][C:9]4[CH:8]=[CH:7][C:6]([NH:5][C:1](=[O:4])[CH2:2][CH3:3])=[CH:11][CH:10]=4)=[O:20])[CH2:34][CH2:33]3)[S:29][N:28]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCC(=O)Nc1ccc(NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC(=O)Nc1ccc(NC(=O)N2CCN(c3nc(-c4ccccc4)ns3)CC2)cc1
Yield: 29.6 %

Procedure:
A solution of 2,2,2-trichloroethyl [4-(propionylamino)phenyl]carbamate (200 mg, 0.589 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (145 mg, 0.589 mmol), diisopropylethylamine (0.206 ml, 1.18 mmol) and dimethyl sulfoxide (4 ml) was stirred at 70° C. for 24 hours, the reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate to give 76.0 mg (29.6%) of the desired product as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1(O)[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:15])[CH:13]=2)[CH2:8][CH2:7]1)[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.O.[Cl-].[Cl-].[Ca+2]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:15])[CH:13]=2)[CH2:8][CH:7]=1)[CH3:2]
Reactant: CCOC(=O)CC1(O)CCc2ccc(F)cc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)CC1=CCc2ccc(F)cc21
Yield: 21.4 %

Procedure:
The crude (6-Fluoro-1-hydroxy-indan-1-yl)-acetic acid ethyl ester (Compound G in FIG. 7; 3.55 g), p-toluene sulfonic acid•H2O (PTSA; 5.67 g, 29.8 mmol), and CaCl2 (4.13 g, 37.2 mmol) in toluene (66 mL) were refluxed overnight. The solution was filtered and the solid residue washed with benzene. The combined organics were washed with water, NaHCO3, water, dried (MgSO4), filtered, and concentrated in vacuo. Purification using flash chromatography (13:1 hexane/EtOAc) afforded the title compound (Compound H in FIG. 7) as an orange solid (0.703 g). 1H NMR (CDCl3) δ 7.25 (m, 2H), 7.06 (m, 1H), 6.25 (d, J=2.3 Hz, 1H), 4.24 (q, J=7.0 Hz, 2H), 3.32 (s, 2H), 3.03 (s, 2H), 1.33 (t, J=7.1 Hz, 3H); ESI-CID 221 (M-H+).