Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClCC([NH:5][C:6]([CH3:17])([CH3:16])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([F:15])[CH:9]=1)=O.NC(N)=S>C(O)(=O)C.C(O)C>[F:15][C:10]1[CH:9]=[C:8]([CH2:7][C:6]([NH2:5])([CH3:16])[CH3:17])[CH:13]=[CH:12][C:11]=1[CH3:14]
Reactant: Cc1ccc(CC(C)(C)NC(=O)CCl)cc1F
Agent: NC(N)=S
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1ccc(CC(C)(C)N)cc1F
Temperature: 100 °C
Reaction time: 8 h
Yield: 62.6 %

Procedure:
2-Chloro-N-[1-(3-fluoro-4-methylphenyl)-2-methylpropan-2-yl]acetamide (131.6 g) obtained in Step 6 was dissolved in acetic acid (200 ml) and ethanol (1 L), and thiourea (46.6 g) was added. The mixture was stirred overnight at 100° C. The reaction mixture was cooled to room temperature, and the precipitated crystals were filtered. The filtrate was concentrated under reduced pressure, and 4N-sodium hydroxide solution (300 ml) was added to the obtained residue. The mixture was extracted 3 times with toluene. The organic layer was washed with brine, and concentrated under reduced pressure. The obtained residue was dissolved in diethyl ether (1 L) and 4N-hydrochloric acid/ethyl acetate solution (255 ml) was added dropwise under ice-cooling. The mixture was stirred for 1 hr and the precipitated crystals were collected by filtration. The obtained crystals were added to a mixture of toluene and 4N-aqueous sodium hydroxide solution. The toluene layer was separated, washed twice with water, and concentrated under reduced pressure to give the title compound (57.9 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][CH2:17][S:16](=[O:21])(=[O:20])[CH2:15]1.[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1B(O)O.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[O:20]=[S:16]1(=[O:21])[CH2:17][CH2:18][CH2:19][CH:14]([C:5]2[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=[C:2]([C:23]4[S:22][CH:26]=[CH:25][CH:24]=4)[CH:3]=3)[NH:7][CH:6]=2)[CH2:15]1
Reactant: OB(O)c1cccs1
Reactant: NC(=O)c1cc(Br)cc2c(C3CCCS(=O)(=O)C3)c[nH]c12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: NC(=O)c1cc(-c2cccs2)cc2c(C3CCCS(=O)(=O)C3)c[nH]c12
Temperature: 100 °C
Yield: 27.9 %

Procedure:
5-Bromo-3-(1,1-dioxidotetrahydro-2H-thiopyran-3-yl)-1H-indole-7-carboxamide (0.050 g, 0.134 mmol) and 2-thienylboronic acid (0.022 g, 0.174 mmol) was dissolved in a 6:1 solution of 1,4 dioxane (3 mL)/water (0.5 mL) in a 20 mL microwave reaction vessel. Potassium carbonate (0.093 g, 0.670 mmol) was added and the solution was degassed with Nitrogen. PdCl2(dppf)2 (0.017 g, 0.023 mmol) was added and the reaction was heated in a microwave at 100° C. for 20 min. The solution was passed through a StratoSphere SPE PL-Thiol MP SPE column to remove palladium and purified on Gilson preparative HPLC using Acetonitrile/Water. The desired fractions were concentrated, giving 0.014 g (28%) of the title compound.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:24](=[O:36])[NH:25][C:26]1[CH:27]=[N:28][C:29]2[C:34]([CH:35]=1)=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:10][CH:11]1[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]1)=O)(C)(C)C.Cl.CCOC(C)=O>>[NH2:8][C@@H:9]([CH2:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[C:24]([NH:25][C:26]1[CH:27]=[N:28][C:29]2[C:34]([CH:35]=1)=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:36]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCN(C(=O)OC(C)(C)C)CC1)C(=O)Nc1cnc2ccccc2c1
Agent: Cl
Solvent: CCOC(C)=O
Product: N[C@@H](CC1CCNCC1)C(=O)Nc1cnc2ccccc2c1

Procedure:
To a solution of tert-butyl 4-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-2-[(quinolin-3-yl)carbamoyl]ethyl]piperidine-1-carboxylate (425 mg, 0.85 mmol) was added HCl/EtOAc (5 M solution, 6 mL) at r.t. overnight. The precipitate was filtered, washed with ethyl acetate, diethyl ether and dried to give crude (2S)-2-amino-3-(piperidin-4-yl)-N-(quinolin-3-yl)propanamide LXXVI as the hydrochloride salt (351 mg). ESIMS found for C17H22N4O m/z 299 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.C(=O)([O-])[O-].[K+].[K+].[CH2:21]([O:23][C:24](=[O:28])[CH:25](Br)[CH3:26])[CH3:22].C1(C)C=CC=CC=1>CN(C)C=O.O>[CH2:21]([O:23][C:24](=[O:28])[CH:25]([N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1)[CH3:26])[CH3:22]
Reactant: CCOC(=O)C(C)Br
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 80 °C
Reaction time: 14 h

Procedure:
To a suspension of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (21.3 g) and potassium carbonate (20.7 g) in dimethylformamide (100 ml) was added 2-bromo-propionic acid ethyl ester (13 ml) and the mixture was stirred at 80° C. for 14 hr. The reaction mixture was cooled to 0° C., and toluene (100 ml) and water (150 ml) were successively added dropwise. The mixture was partitioned, and the aqueous layer was extracted with toluene (50 ml). The combined organic layer was successively washed once with 10% aqueous potassium carbonate (50 ml), twice with water (50 ml) and once with saturated brine (50 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (21.6 g).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[C:8]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=3)[N:7]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[C:6]=2[C:5](=[O:30])[NH:4][C:3]1=[O:31].CC1C=CC(S(O[CH2:43][CH2:44][CH:45]([OH:47])[CH3:46])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCCC[N+](CCCC)(CCCC)CCCC.[I-]>[OH:47][CH:45]([CH3:46])[CH2:44][CH2:43][N:4]1[C:5](=[O:30])[C:6]2[N:7]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[C:8]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=3)=[N:9][C:10]=2[N:2]([CH3:1])[C:3]1=[O:31]
Reactant: Cn1c(=O)[nH]c(=O)c2c1nc(Cc1cccc(OC(F)(F)F)c1)n2Cc1ccccn1
Reactant: Cc1ccc(S(=O)(=O)OCCC(C)O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CC(O)CCn1c(=O)c2c(nc(Cc3cccc(OC(F)(F)F)c3)n2Cc2ccccn2)n(C)c1=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 31.8 %

Procedure:
To a solution of 3-methyl-7-(pyridin-2-ylmethyl)-8-(3-(trifluoromethoxy)benzyl)-1H-purine-2,6(3H,7H)-dione (30 mg, 0.07 mmol) in DMF (1 mL) was added 3-hydroxybutyl 4-methylbenzenesulfonate (25.6 mg, 0.105 mmol, intermediate 33) followed by potassium carbonate (14.5 mg, 0.105 mmol) and a catalytic amount of TBAI. The reaction was stirred at 60° C. for 2 h. The reaction was partitioned between ethyl acetate and brine. The organic phase was dried and concentrated to give crude product, which was purified by preparative HPLC to give 1-(3-hydroxybutyl)-3-methyl-7-(pyridin-2-ylmethyl)-8-(3-(trifluoromethoxy)benzyl)-1H-purine-2,6(3H,7H)-dione (11.2 mg, 32% yield) as white solid. 1H-NMR (CD3OD) δ 8.38-8.39 (d, 1H), 7.65-7.69 (t, 1H), 7.23-7.31 (m, 2H), 7.07-7.17 (m, 2H), 5.72 (s, 2H), 4.32 (s, 2H), 4.01-4.11 (m, 2H), 3.75-3.77 (m, 1H), 3.58 (s, 3H), 1.71-1.75 (m, 2H), 1.17-1.19 (d, 3H). LCMS retention time 2.480 min; LCMS MH+ 504.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[NH:13][C:12](=[O:15])[CH:11]=[CH:10]2)(=[O:3])[CH3:2]>O1CCOCC1.[C].[Pd]>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[NH:13][C:12](=[O:15])[CH2:11][CH2:10]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc2ccc(=O)[nH]c12
Agent: [Pd]
Solvent: C1COCCO1
Product: CC(=O)Nc1cccc2c1NC(=O)CC2
Yield: 0.1 %

Procedure:
8-Acetylaminocarbostyril (15.0 g, 74.2 mols) was suspended in 300 ml of dioxane. After adding 2.0 g of 10% palladium-carbon, the suspension was subjected to catalytic reduction at 70° to 80° C. under atmospheric pressure. After completion of reaction, the catalyst was removed by filtration and the solvent was distilled off under reduced pressure to give 14.3 g of 8-acetylamino-3,4-dihydrocarbostyril.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[CH2:10]([O:12][C:13](=[O:23])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]=O)[CH:16]=1)[CH3:11].[BH4-].[Na+].C([O-])(O)=O.[Na+]>CO.O>[CH2:10]([O:12][C:13](=[O:23])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([CH3:1])=[CH:3][CH:4]=2)[CH:16]=1)[CH3:11]
Reactant: CCOC(=O)Cc1cccc(C=O)c1
Reactant: Cc1ccc(CN)cc1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCOC(=O)Cc1cccc(CNCc2ccc(C)cc2)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 107.9 %

Procedure:
A solution of 4-methylbenzylamine (0.097 mL, 0.76 mmol) and (3-formyl-phenyl)-acetic acid ethyl ester (138 mg, 0.72 mmol) in MeOH (2 mL) was stirred for 3 h at room temperature. The reaction was cooled to 0° C. and NaBH4 (43 mg, 1.15 mmol) was added. After stirring at room temperature for 10 minutes, a 1:1 mixture of saturated aqueous NaHCO3:H2O was added. The product was extracted into CH2Cl2 (3×) and the organic solution was dried over MgSO4, filtered, and concentrated to yield the title compound (231 mg). 1H NMR (400 MHz, CDCl3) δ 7.13-7.30 (m, 8H), 4.14 (q, 2H), 3.83 (d, 4H), 3.78 (s, 2H), 2.34 (s, 3H), 1.25 (t, 3H); MS 298 (M+1).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[O:15][N:14]=[C:13]([NH2:16])[N:12]=3)[CH:9]=2)[NH:4][CH:3]=1.[CH:17]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Sn](CCCC)(CCCC)CCCC)[N:22]=1)([CH3:19])[CH3:18].N#N>CN(C=O)C.[Cu]I.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>[CH:17]([O:20][C:21]1[N:22]=[C:23]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]4[O:15][N:14]=[C:13]([NH2:16])[N:12]=4)[CH:9]=3)[NH:4][CH:3]=2)[CH:24]=[CH:25][CH:26]=1)([CH3:19])[CH3:18]
Reactant: Nc1noc(-c2ccc3[nH]cc(I)c3c2)n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(OC(C)C)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: CN(C)C=O
Product: CC(C)Oc1cccc(-c2c[nH]c3ccc(-c4nc(N)no4)cc23)n1
Temperature: 90 °C
Yield: 3.2 %

Procedure:
To a solution of 5-(3-iodo-1H-indol-5-yl)-1,2,4-oxadiazol-3-amine (0.3 g, 0.92 mmol) and 2-isopropoxy-6-(tributylstannyl)pyridine (0.471 g, 1.1 mmol) in DMF (10 mL) was bubbled with N2 gas for 15 min. To the mixture was added CuI (0.140 g, 0.73 mmol) and Pd(PPh3)4 (0.100 g, 0.092 mmol) and N2 gas was bubbled for another 15 min. The reaction was heated at 90° C. for 1 h. The reaction mixture was cooled to RT, and quenched with water (100 mL) and extracted in EtOAc (2×100 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified with preparative HPLC (eluent: 30-70% MeCN in water with 0.01% TFA) to afford 5-(3-(6-isopropoxypyridin-2-yl)-1H-indol-5-yl)-1,2,4-oxadiazol-3-amine (0.01 g, 7%) as a white solid. MS (ESI, pos. ion) m/z: 336.2 (M+1); 1H-NMR (400 MHz, CD3OD): δ 9.36 (s, 1H), 7.99 (s, 1H), 7.89 (d, J=8.4 Hz, 1H), 7.64 (m, 2H), 7.37 (d, J=7.6 Hz, 1H), 6.52 (d, J=8.4 Hz, 1H), 5.65 (m, 1H), 1.51 (d, J=6.0 Hz, 6H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:2]=1.[ClH:37].C(O)C.C(=O)([O-])[O-].[NH4+:45].[NH4+]>ClCCl.C(O)C>[ClH:37].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([C:25](=[NH:45])[NH2:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:2]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C#N)cc1)n2C)c1cccnc1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C(=N)N)cc1)n2C)c1cccnc1
Yield: 91 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[2-(4-cyanophenyl)ethyl]benzimidazol-5-yl-carboxylic acid-N-(3-pyridyl)-N-(2-ethoxycarbonylethyl)amide and ethanolic hydrochloric acid, ethanol, and ammonium carbonate. Yield: 91% of theory, C28H30N6O3 (498.6); Rf value: 0.19 (silica gel; dichloromethane/ethanol=4:1); EKA mass spectrum: (M+H)+=499.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[C:6]([CH3:11])[CH:5]=1.[S-:14][C:15]#[N:16].[K+].BrBr>C(O)(=O)C.C1CCCCC1>[CH3:11][C:6]1[C:7]2[N:8]=[C:15]([NH2:16])[S:14][C:9]=2[CH:10]=[C:4]([O:3][C:2]([F:12])([F:13])[F:1])[CH:5]=1
Reactant: Cc1cc(OC(F)(F)F)ccc1N
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: C1CCCCC1
Solvent: CC(=O)O
Product: Cc1cc(OC(F)(F)F)cc2sc(N)nc12
Yield: 71.1 %

Procedure:
The procedure is as in Example 1, starting with 4-trifluoromethoxy-2-methylaniline (0.65 g), potassium thiocyanate (1.3 g) and bromine (0.35 cc) in acetic acid (12 cc). After purification on a column of silica (200 g; particle size: 0.063-0.200 mm), eluting with a cyclohexane/ethyl acetate mixture (50:50 by volume), the white solid obtained (0.65 g) is ground in cyclohexane (20 cc), drained and dried at 60° C. under reduced pressure (1 mm Hg; 0.13 kPa), to give 4-methyl-6-trifluoromethoxy-2-benzothiazolamine (0.6 g), m.p. 162° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([OH:7])[CH2:6][CH2:5][CH2:4]1.C(N(CC)CC)C.Cl[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=[CH:18][C:17]=1[N+:26]([O-:28])=[O:27]>ClCCl>[N+:26]([C:17]1[CH:18]=[N:19][C:20]2[C:25]([C:16]=1[NH:1][CH2:2][C:3]1([OH:7])[CH2:6][CH2:5][CH2:4]1)=[CH:24][CH:23]=[CH:22][CH:21]=2)([O-:28])=[O:27]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: NCC1(O)CCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cnc2ccccc2c1NCC1(O)CCC1
Temperature: 25 °C
Reaction time: 240 h
Yield: 75.1 %

Procedure:
To a solution of 1-(aminomethyl)cyclobutanol (62.5 mmol) in dichloromethane (312 mL) was added triethylamine (8.71 mL, 62.5 mmol) and 4-chloro-3-nitroquinoline (13.04 g, 62.5 mmol). More triethylamine (3 mL) was added almost immediately. The reaction was stirred under N2 for 10 days at room temperature, then was diluted with dichloromethane and washed with 1 M aqueous NaOH. A solid formed and was isolated by filtration. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to yield a solid that was crystallized from 2-propanol. The resulting crystals were combined with the solid that was isolated from the extraction and the mixture was triturated with hot 2-propanol. The solid was isolated by filtration, washed with diethyl ether, and air dried to yield 12.83 g of 1-{[(3-nitroquinolin-4-yl)amino]methyl}cyclobutanol as yellow crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([C:16]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)=O)=[N:6][N:7]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[N:8]=1)[CH3:2].II.[PH2](O)=O.[OH-].[Na+].C(=O)(O)[O-].[Na+]>C(O)(=O)C>[CH2:1]([O:3][C:4]1[C:5]([CH2:16][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]([F:25])([F:26])[F:27])[CH:19]=2)=[N:6][N:7]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[N:8]=1)[CH3:2]
Reactant: CCOc1nn(-c2ccc(F)cc2)nc1C(=O)c1ccnc(C(F)(F)F)c1
Agent: II
Agent: O=C([O-])O
Agent: O=[PH2]O
Solvent: CC(=O)O
Product: CCOc1nn(-c2ccc(F)cc2)nc1Cc1ccnc(C(F)(F)F)c1
Temperature: 110 °C

Procedure:
To a solution of [5-ethoxy-2-(4-fluorophenyl)-2H-1,2,3-triazol-4-yl][2-(trifluoromethyl)-4-pyridinyl]methanone (i.e. the product of Step C, 2.7 g, 7.1 mmol) in acetic acid (15 mL) was added iodine (1.8 g, 7.1 mmol) and hypophosphorous acid (50% in water, 3.1 mL, 28.4 mmol). The mixture was heated to 110° C. under a nitrogen atmosphere for 6 h. The reaction mixture was cooled to 23° C. and neutralized to ˜pH 7 with 1 M NaOH and a saturated aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate (2×15 mL), dried (MgSO4) and concentrated under reduced pressure. The crude residue was purified by chromatography on silica gel eluting with 0 to 20% ethyl acetate in hexanes to afford the title compound (2.1 g) as an off-white solid.
Reaction SMILES: C([Si](C)(C)[N:6]1[C:10]2=[N:11][CH:12]=[C:13]([S:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:14]=[C:9]2[CH:8]=[CH:7]1)(C)(C)C.Cl.C([O-])(O)=O.[Na+]>CO>[CH2:16]([S:15][C:13]1[CH:14]=[C:9]2[CH:8]=[CH:7][NH:6][C:10]2=[N:11][CH:12]=1)[CH2:17][CH2:18][CH3:19]
Reactant: CCCCSc1cnc2c(ccn2[Si](C)(C)C(C)(C)C)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCCCSc1cnc2[nH]ccc2c1
Yield: 35.5 %

Procedure:
The crude mixture containing 11 (5.38 g) was treated with MeOH (48 mL) and 10% aq. HCl (97 mL) for 0.5 h. The acid was neutralised by dropwise addition of sat. aqueous NaHCO3. The resulting solid was filtered off, washed with water (3×), dried in vacuum and extracted with CH2Cl2. The extracts were concentrated to afford a dark red oil, which was purified by SGC with CH2Cl2:MeOH as eluent (gradient elution up to 99:1, v/v) to give 12 as a brown oil (1.23 g, 37% over 2 steps); 1H NMR (400 MHz, CDCl3) δ 0.90 (t, J=7.3 Hz, 3H), 1.35-1.50 (m, 2H), 1.52-1.65 (m, 2H), 2.87 (t, J=7.4 Hz, 2H), 6.49 (dd, J=3.5, 1.8 Hz, 1H), 7.41 (dd, J=3.4, 2.3 Hz, 1H), 8.10 (d, J=2.0 Hz, 1H), 8.43 (d, J=2.0 Hz, 1H), 10.90-11.10 (bs, NH).
Reaction SMILES: [CH3:1][C:2]12[CH2:17][CH:5]([C:6]3([CH3:16])[C:10]1([CH3:11])[C:9]1[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=1[O:7]3)[CH2:4][CH2:3]2.[Br:18]N1C(=O)CCC1=O.C(Cl)(Cl)Cl>O1CCCC1.CN(C)C=O>[Br:18][C:13]1[CH:14]=[CH:15][C:8]2[O:7][C:6]3([CH3:16])[CH:5]4[CH2:17][C:2]([CH3:1])([C:10]3([CH3:11])[C:9]=2[CH:12]=1)[CH2:3][CH2:4]4
Reactant: O=C1CCC(=O)N1Br
Reactant: CC12CCC(C1)C1(C)Oc3ccccc3C21C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CC12CCC(C1)C1(C)Oc3ccc(Br)cc3C21C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
11.42 g (50 mmol) of (-)-1,2,3,4-tetrahydro1,4a,9b-trimethyl-1,4-methanodibenzofuran obtained in Example 1 were dissolved in 110 ml of tetrahydrofuran and were treated dropwise with a solution containing 8.9 g of N-bromosuccinimide (NBS) in 50 ml of dimethylformamide (DMF). The reaction medium was maintained under stirring at room temperature for 2 h, 30 min, then poured into ice-cold water and extracted with 500 ml of ethyl ether. After rinsing with water, drying over magnesium sulfate, filtration and evaporation, 13.8 g (90w) of the expected compound, melting at 119.8° C., were isolated after chromatography on silica in hexane; αD =+4.60 (c=1, chloroform).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:11]=[CH:10][CH:9]=[C:5]([C:6]([OH:8])=O)[C:4]=1[NH2:12].O=S(Cl)Cl.[Cl:19][C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH2:22].C(Cl)(Cl)Cl>C1C=CC=CC=1>[NH2:12][C:4]1[C:3]([C:2]([F:1])([F:14])[F:13])=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([NH:22][C:21]1[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=1[Cl:19])=[O:8]
Reactant: Nc1ccccc1Cl
Reactant: Nc1c(C(=O)O)cccc1C(F)(F)F
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccccc1
Product: Nc1c(C(=O)Nc2ccccc2Cl)cccc1C(F)(F)F
Yield: 77.6 %

Procedure:
Prepared according to Procedure A using 3-trifluoromethylanthranilic acid (2.0 g, 9.75 mmol) and SOCl2 (1.8 mL, 24.4 mmol) in benzene (50 mL), followed by 2-chloroaniline (2.1 mL, 19.5 mmol) and CHCl3 (50 mL). The product was purified by recrystallization from MeOH to provide 2.38 g yellow crystals (78%). 1H NMR (CDCl3) δ: 8.40 (dd, J=1.4, 8.3 Hz, 1H); 8.25 (br s, 1H); 7.71 (d, J=7.8 Hz, 1H); 7.60 (d, J=7.8 Hz, 1H); 7.43 (dd, J=1.4, 8.0 Hz, 1H); 7.34 (dt, J=1.3, 7.9 Hz, 1H); 7.11 (dt, J=1.5, 7.7 Hz, 1H); 6.77 (t, J=7.8 Hz, 1H); 6.24 (br s, 2H). MS (ES): m/z 315.0 (M+).
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10]>C(Cl)Cl>[C:1]([O:13][C:5]([CH3:6])=[CH2:4])(=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][C:2]([CH3:3])=[CH2:1])=[O:10]
Reactant: O=C(O)CCCCCCCC(=O)O
Solvent: ClCCl
Product: C=C(C)OC(=O)CCCCCCCC(=O)OC(=C)C

Procedure:
Azelaic acid (100 grams, 0.53 mole), methylene chloride (500 ml.) and mercuric acetate (18.2 grams, 0.057 mole) are treated with 1 ml. of boron trifluoride etherate, and propyne gas is bubbled through the mixture for 3 hours. Solid sodium bicarbonate (5 grams) is added, and the mixture is filtered free of solids and metallic mercury.
Reaction SMILES: [F:1][C:2](=[C:7]([F:9])[F:8])[CH2:3][C:4](Cl)=[O:5].O.[CH2:11]([NH2:15])[CH2:12][CH2:13][CH3:14]>ClCCl>[CH2:11]([NH:15][C:4](=[O:5])[CH2:3][C:2]([F:1])=[C:7]([F:9])[F:8])[CH2:12][CH2:13][CH3:14]
Reactant: CCCCN
Reactant: O=C(Cl)CC(F)=C(F)F
Solvent: O
Solvent: ClCCl
Product: CCCCNC(=O)CC(F)=C(F)F
Temperature: 0 °C
Yield: 92.6 %

Procedure:
2.5 g (0. 0158 mole) 3,4,4-trifluoro-3-butenoyl chloride is added to a mixture of water (15 mL), dichloromethane (15 mL) and n-butyl amine (2.34 g, 0.032 mole) with stirring at 0° C. After stirring for 30 min, the organic layer is successively washed with 2N HCl, water, 5% sodium bicarbonate and brine, and dried. Evaporation of the solvent gave 2.85 g of title compound as a white solid, a 92% yield. m.p. 34°-36° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:5][C:6](=[O:9])[C:7]=1[CH3:8])=[O:4].[K].Cl[CH2:12][CH2:13][CH2:14][Si:15]([O:20][CH3:21])([O:18][CH3:19])[O:16][CH3:17]>CN(C)C=O>[CH3:1][C:2]1[C:3]([N:5]([CH2:12][CH2:13][CH2:14][Si:15]([O:20][CH3:21])([O:18][CH3:19])[O:16][CH3:17])[C:6](=[O:9])[C:7]=1[CH3:8])=[O:4]
Reactant: CO[Si](CCCCl)(OC)OC
Reactant: CC1=C(C)C(=O)NC1=O
Agent: [K]
Solvent: CN(C)C=O
Product: CO[Si](CCCN1C(=O)C(C)=C(C)C1=O)(OC)OC
Temperature: 70 °C
Reaction time: 2 h
Yield: 55.7 %

Procedure:
A mixture of 16.3 g (0.1 mol) of potassium 2,3-dimethylmaleimide (prepared by reacting 2,3-dimethylmaleimide with potassium methylate in methanol) and 150 ml of dry N,N-dimethylformamide is heated to 70° C. At this temperature, 19.8 g (0.1 mol) of 3-chloropropyltrimethoxysilane are added dropwise. After the exothermic reaction has subsided, the reaction mixture is kept at 70° C. for a further 2 hours, and after cooling to room temperature (20°-25° C.) the salt which has precipitated is filtered off. The N,N-dimethylformamide is distilled off under a high vacuum, under 13.333 Pa. The residue is taken up in a little dry diethyl ether, filtered again and, after removing the solvent, fractionated under a high vacuum. 16 g (56% of theory) of 3-(2,3-dimethylmaleimido)-propyl-trimethoxysilane are obtained; boiling point 112° C. (0.133 Pa).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:4]=[C:5]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[S:6][CH:7]=1.ClC1C=C(C(OO)=[O:29])C=CC=1>ClCCl>[Cl:1][CH2:2][C:3]1[N:4]=[C:5]([CH:8]=[CH:9][C:10]2[CH:11]=[CH:12][C:13]([S:16]([C:17]([F:20])([F:19])[F:18])=[O:29])=[CH:14][CH:15]=2)[S:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: FC(F)(F)Sc1ccc(C=Cc2nc(CCl)cs2)cc1
Solvent: ClCCl
Product: O=S(c1ccc(C=Cc2nc(CCl)cs2)cc1)C(F)(F)F
Yield: 51.2 %

Procedure:
A solution of 0.50 g (1.5 mmol) 4-chloromethyl-2-[2-(4-trifluoromethylsulfanyl-phenyl)-vinyl]-thiazole in 20 ml dichloromethane was stirred with 0.31 g (1.8 mmol) 3-chloro-benzenecarboperoxoic acid at room temperature for 2 days. The solution was washed with diluted sodium hydroxide, dried, evaporated and purified on silica. Elution with ethyl acetate/heptane 1:6 yielded 270 mg (52%) 4-chloromethyl-2-[2-(4-trifluoromethanesulfinyl-phenyl)-vinyl]-thiazole as off-white solid, melting at 98-99° C.