Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9]COC)[CH:6]=[CH:5][C:4]=1[C:13]1[C:22]([CH2:23][N:24]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[O:48][CH3:49])[C:25]([O:27][CH2:28][CH:29]2[C:41]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[C:35]3[C:30]2=[CH:31][CH:32]=[CH:33][CH:34]=3)=[O:26])=[C:21]2[C:16]([NH:17][C:18]([CH3:53])([CH3:52])[C:19](=[O:51])[N:20]2[CH3:50])=[CH:15][CH:14]=1.Cl.O1CCOCC1>O1CCOCC1.C(OCC)(=O)C>[OH:9][C:7]1[CH:6]=[CH:5][C:4]([C:13]2[C:22]([CH2:23][N:24]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[O:48][CH3:49])[C:25]([O:27][CH2:28][CH:29]3[C:41]4[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=4[C:35]4[C:30]3=[CH:31][CH:32]=[CH:33][CH:34]=4)=[O:26])=[C:21]3[C:16]([NH:17][C:18]([CH3:52])([CH3:53])[C:19](=[O:51])[N:20]3[CH3:50])=[CH:15][CH:14]=2)=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COCOc1ccc(-c2ccc3c(c2CN(C(=O)OCC2c4ccccc4-c4ccccc42)c2ccccc2OC)N(C)C(=O)C(C)(C)N3)c(OC)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1cc(O)ccc1-c1ccc2c(c1CN(C(=O)OCC1c3ccccc3-c3ccccc31)c1ccccc1OC)N(C)C(=O)C(C)(C)N2
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
7-(2-Methoxy-4-methoxymethoxyphenyl)-8-[N-(2-methoxyphenyl)-N-(9-fluorenylmethoxycarbonyl)aminomethyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Compound No. 12-1, 137 mg, 0.192 mmol) was dissolved in 1,4-dioxane (1 mL) and 4N hydrochloride/1,4-dioxane solution (144 μL, 0.576 mmol) was added thereto. After the reaction mixture was stirred at room temperature for 2 hours, the mixture was diluted with ethyl acetate (100 mL). The mixture was washed with water (100 mL) and saturated brine (50 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (71.6 mg) as a colorless solid. (Yield 56%)
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][SH:10](=S)=S)=[CH:5][CH:4]=1.[CH:13]1([Mg]Br)[CH2:15][CH2:14]1>C1COCC1.[Cl-].[NH4+].C(OCC)(=O)C>[CH:13]1([S:10][CH2:9][C:6]2[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=2)[CH2:15][CH2:14]1
Reactant: Br[Mg]C1CC1
Reactant: CSc1ccc(C[SH](=S)=S)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CSc1ccc(CSC2CC2)cc1
Temperature: 21 °C
Reaction time: 18 h

Procedure:
To a solution of (4-methylsulfanyl-phenyl)-methanethiol disulfide from Step 1 in THF (50 mL) at 21° C. was added cyclopropylmagnesium bromide (excess) dropwise. The reaction mixture was stirred 18 h at 21° C., then diluted with a saturated ammonium chloride solution and ethyl acetate. The organic extracts were washed (H2O), (brine), dried (MgSO4), filtered and concentrated. Purification by flash chromatography (eluting with hexane/ethyl acetate, 98:2) provided the 1-cyclopropylsulfanylmethyl-4-methylsulfanyl-benzene compound as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].Cl.[NH2:14][OH:15].C([O-])(=O)C.[Na+]>O1CCCC1.O>[CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:14][OH:15])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: NO
Reactant: Cc1ccc(C=O)cc1[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C=NO)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
A solution of 4-methyl-3-nitrobenzaldehyde (3.5 g) in tetrahydrofuran (50 mL) was added dropwise to a solution of hydroxylamine hydrochloride (3.0 g) and sodium acetate (4.0 g) in tetrahydrofuran (50 mL) and water (50 mL) under ice cooling, and, on completion of the dropwise addition, the mixture was stirred for one hour at room temperature. The reaction solution was diluted with water and then extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a crude product of 4-methyl-3-nitrobenzaldehyde oxime (3.5 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([N:12]1[N:16]=[C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]2=[N:13]1)[CH2:9][C:10]#[CH:11]>>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:11]#[C:10][CH2:9][CH2:8][N:12]1[N:13]=[C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]2=[N:16]1
Reactant: C#CCCn1nc2ccccc2n1
Reactant: Brc1ccccn1
Product: C(#Cc1ccccn1)CCn1nc2ccccc2n1
Yield: 62.5 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (92 mg, 0.58 mmol) and 2-(but-3-ynyl)-2H-benzo[d][1,2,3]triazole (100 mg, 0.58 mmol). Reaction time: 3 hours. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 90 mg of 2-(4-(pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)=[O:10])=[CH:4][CH:3]=1.CCN(CC)CC.[Br:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36](Cl)=[O:37]>C(Cl)Cl>[C:19]([C:16]1[CH:15]=[CH:14][C:13]([C:12]([NH:11][C:9](=[O:10])[NH:8][C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:36](=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32][Br:31])=[CH:7][CH:6]=2)=[O:23])=[CH:18][CH:17]=1)([CH3:20])([CH3:22])[CH3:21]
Reactant: O=C(Cl)CCCCBr
Reactant: CC(C)(C)c1ccc(C(=O)NC(=O)Nc2ccc(N)cc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(C(=O)NC(=O)Nc2ccc(NC(=O)CCCCBr)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.1 %

Procedure:
The deprotected amine (368 mg, 0.70 mmol) was stirred in dry CH2Cl2 (10 mL) under N2 atmosphere and NEt3 (98 μL, 0.70 mmol) was added to give a clear brown solution. 5-Bromovaleryl chloride (140 μL, 1.05 mmol, 1.5. equiv.) was added followed by triethylamine (98 μL, 0.70 mmol). The reaction mixture was stirred at rt for 16 h then diluted with CH2Cl2 (1×20 mL) and washed with 1 M aqueous hydrochloric acid (1×20 mL), 1 M aqueous sodium hydroxide (1×20 mL) and saturated brine (1×20 mL). The organic phase was dried over MgSO4 and concentrated in vacuo to give a crude yellow chalky solid which was purified by column chromatography on silica (50% ethyl acetate/petroleum ether) to give 29 (153 mg, 48%) as a yellow solid.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[H-].[Na+].[SH:14][CH2:15][C:16]([O:18][CH3:19])=[O:17]>>[CH3:19][O:18][C:16]([C:15]1[S:14][C:2]2[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=2[CH:4]=1)=[O:17]
Reactant: COC(=O)CS
Reactant: COc1ccc(C=O)c(F)c1
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1cc2ccc(OC)cc2s1

Procedure:
Using 2.5 g (16.2 mmol) of 2-fluoro-4-methoxybenzaldehyde, 0.97 g (24.3 mmol) of sodium hydride (60% pure) and 1.89 g (17.8 mmol) of methyl mercaptoacetate, 3.05 g (84.7% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][CH:2]1[N:6]=[C:5]2[CH:7]=[CH:8][N:9]=[C:4]2[S:3]1.[CH2:10]1[CH2:16][S:13](=[O:15])(=[O:14])[O:12][CH2:11]1>>[CH3:1][CH:2]1[N+:6]([CH2:11][CH2:10][CH2:16][S:13]([O-:15])(=[O:14])=[O:12])=[C:5]2[CH:7]=[CH:8][N:9]=[C:4]2[S:3]1
Reactant: O=S1(=O)CCCO1
Reactant: CC1N=C2C=CN=C2S1
Product: CC1SC2=NC=CC2=[N+]1CCCS(=O)(=O)[O-]
Temperature: 130 °C
Yield: 92.2 %

Procedure:
2-Methylpyrrolo[3,2-d]thiazole (0.70 g) (5mmol) and 0.67 g of 1,3-propanesultone (5.5 mmol) were stirred with heating at 130° C. for 6 hours. After cooling, the crystals precipitated were filtered out and washed with acetone, thereby 1.2 g of 3-[2-methyl-1-pyrrolo[3,2-d]thiazolio]propanesulfonate was obtained (yield: 92%). 3-[5- Chloro-2-(3-sulfopropyl)thio-1-benzothiazolio]propanesulfonate (0.45 g) (1 mmol), 2 ml of dimethyl sulfoxide and 2 ml of acetonitrile were added to 0.26 g of the quaternary salt of 3-[2-methyl-1-pyrrolo[3,2-d]thiazolio]propanesulfonate (1 rmmol) and the mixture was stirred at 50° C. with adding 0.56 ml of triethylamine (4 mmol), followed by further stirring for 1 hour. The solution was concentrated, and then refined with column chromatography, thereby 0.10 g of the objective Methine Dye S-125 was obtained. Yield: 15%, ?max (MeOH)=447.5 nm.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:19]2[C:14](=[N:15][CH:16]=[N:17][C:18]=2[NH2:20])[NH:13][N:12]=1.C([O-])([O-])=O.[K+].[K+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O>CN(C=O)C>[CH2:27]([N:13]1[C:14]2=[N:15][CH:16]=[N:17][C:18]([NH2:20])=[C:19]2[C:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[N:12]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Nc1ncnc2[nH]nc(-c3ccc4ccccc4c3)c12
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(-c1ccc3ccccc3c1)nn2Cc1ccccc1
Temperature: 60 °C

Procedure:
3-(naphthalen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (110 mg, 0.42 mmol) was dissolved in DMF (2 mL) and K2CO3 (220 mg, 1.6 mmol) and benzyl bromide (71.8 mg, 0.42 mmol) were added. The reaction was heated to 60° C. overnight, then cooled to RT and poured into water (30 mL). The precipitate was collected by filtration and then purified further by silica gel chromatography (5% MeOH/CH2Cl2) to yield a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6]([CH3:8])=[O:7])[CH3:2].N1C[CH2:13][CH2:12][CH2:11]1.O>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6](=[O:7])[CH2:8][CH:12]([CH3:13])[CH3:11])[CH3:2]
Reactant: CCOC(=O)CC(C)=O
Reactant: C1CCNC1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(=O)CC(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 81.7 %

Procedure:
26 g of acetoacetic acid ethyl ester and 15 g of pyrrolidine were boiled in 70 ml of toluene on a water separator until the theoretical quantity of water was separated. The solution was added drop by drop at -40° C. to a suspension of 8.6 g of sodium amide in 300 ml of liquid ammonia. By heating to room temperature, the ammonia was removed. After the reaction solution had been cooled again to 0° C., isopropyl iodide dissolved in 100 ml of toluene was added at the same temperature. The solution was allowed to react for 3 hours at 0° C. The reaction solution was poured into 200 ml of water. The phases were separated and the toluene of the organic phase was removed using a rotary evaporator. Of the residue, 1.2 g of the first runnings was then distilled off at 1.5 torr (2×102Pa) and up to a still temperature of 60° C., which contained above all 2 -isopropyl acetoacetic acid ethyl ester. The brownish oil remaining behind was dissolved in 70 ml of methylene chloride, and 21 g of concentrated hydrochloric acid was added. The material was hydrolyzed for 1.5 hours at ambient temperature. The two phases were separated. The organic phase was dried, the solvent was removed and the residue was distilled. 28.1 g of 5-methyl-3-oxohexanoic acid ethyl ester (82 percent) was obtained.
Reaction SMILES: [N:1]1([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.CN(C)CCN(C)C.C([Li])(CC)C.Cl[C:31]([O:33][CH3:34])=[O:32]>C(OCC)C.O>[N:1]1([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:31]([O:33][CH3:34])=[O:32])[CH2:3][CH2:2]1
Reactant: COC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCc2ccccc21
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: CCOCC
Solvent: O
Product: COC(=O)c1cccc2c1N(C(=O)OC(C)(C)C)CC2
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 77.7 %

Procedure:
1,1-dimethylethyl 2,3-dihydro-1H-indole-1-carboxylate (5 g, 22.8 mmol) and N,N,N′,N′-tetramethyl-1,2-ethanediamine (4.6 mL, 30.5 mmol) was dissolved in dry diethyl ether (300 mL) and cooled to −78° C. in an acetone/dry ice bath. Sec-butyl lithium (1.4 M solution in cyclohexanes, 17.6 mL, 24.6 mmol) was added dropwise over 10 minutes and the reaction left stirring for 90 minutes at this temperature. Methyl chloroformate (8.8 mL, 10.8 g, 0.1 mol) was added to the mixture and the reaction was allowed to warm up to room temperature over 1 hour. Water was added carefully to the mixture and the organic layer separated and washed 3 times with more water. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound (4.91 g) as a gummy yellow solid.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[CH:5][C:6]([N:17]2[CH:21]=[CH:20][N:19]=[C:18]2[CH2:22]O)=[C:7]([CH:16]=1)[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9].[C:26]1(=[O:36])[NH:30][C:29](=[O:31])[C:28]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:27]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[F:25][C:2]([F:1])([F:24])[C:3]1[CH:4]=[CH:5][C:6]([N:17]2[CH:21]=[CH:20][N:19]=[C:18]2[CH2:22][N:30]2[C:26](=[O:36])[C:27]3=[CH:35][CH:34]=[CH:33][CH:32]=[C:28]3[C:29]2=[O:31])=[C:7]([CH:16]=1)[C:8]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:9]
Reactant: O=C(c1ccccc1)c1cc(C(F)(F)F)ccc1-n1ccnc1CO
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C(c1ccccc1)c1cc(C(F)(F)F)ccc1-n1ccnc1CN1C(=O)c2ccccc2C1=O

Procedure:
In the manner given in Example 17, 5-(trifluoromethyl)-2-[2-(hydroxymethyl)imidazol-1-yl]benzophenone is treated with phthalimide and triphenylphosphine and finally with diethyl azocarboxylate to give 5-(trifluoromethyl)-2-[2-(phthalimidomethyl)imidazol-1-yl]benzophenone.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[N:7]([CH:9]([C:11](=[O:38])[NH:12][CH:13]([C:18]([N:20]1[CH2:24][CH2:23][CH:22]2[NH:25][CH2:26][CH:27]([CH2:28][O:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[C:32]([F:37])[CH:31]=3)[CH:21]12)=[O:19])[C:14]([CH3:17])([CH3:16])[CH3:15])[CH3:10])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[C:40](OC(=O)C)(=[O:42])[CH3:41]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6](=[O:39])[N:7]([CH:9]([C:11](=[O:38])[NH:12][CH:13]([C:18]([N:20]1[CH2:24][CH2:23][CH:22]2[N:25]([C:40](=[O:42])[CH3:41])[CH2:26][CH:27]([CH2:28][O:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[C:32]([F:37])[CH:31]=3)[CH:21]12)=[O:19])[C:14]([CH3:16])([CH3:17])[CH3:15])[CH3:10])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C(=O)NC(C(=O)N1CCC2NCC(COc3ccc(F)c(F)c3)C21)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)N1CC(COc2ccc(F)c(F)c2)C2C1CCN2C(=O)C(NC(=O)C(C)N(C)C(=O)OC(C)(C)C)C(C)(C)C
Reaction time: 18 h
Yield: 103.8 %

Procedure:
A solution of amine 84 (480 mg, 0.87 mmol) in DCM (8 mL) was treated with acetic anhydride (0.12 mL, 1.3 mmol) followed by DMAP (11 mg, 0.087 mmol). After 18 h, the solution was diluted with DCM, washed successively with 1M HCl, and brine, dried over anhydrous Na2SO4, filtered and concentrated to afford 86 (537 mg, 100%) as a white foam that was used without further purification. 1H NMR (CDCl3, 300 MHz): δ7.11-6.99 (m, 1H), 6.89 (br s, 1H), 6.74-6.67 (m, 1H), 6.61-6.56 (m, 1H), 4.77-4.69 (m, 1H), 4.63-4.57 (m, 2H), 4.39 (d, J=6.3 Hz, 1H), 4.10-3.95 (m, 2H), 3.82-3.67 (m, 2H), 3.54-3.48 (m, 1H), 3.45-3.36 (m, 1H), 2.87-2.79 (m, 4H), 2.44-2.38 (m, 1H), 2.23-2.08 (m, 6H), 1.65 (s, 1H), 1.49 (s, 9H), 1.32 (d, J=6.9 Hz, 3H), 0.99 (s, 9H) ppm.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[N:17][C:18]([Cl:22])=[C:19](Br)[CH:20]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([Sn](CCCC)(CCCC)[C:28]1[N:33]=[CH:32][CH:31]=[CH:30][N:29]=1)CCC>C1(C)C=CC=CC=1>[C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[N:17][C:18]([Cl:22])=[C:19]([C:31]2[CH:30]=[N:29][CH:28]=[N:33][CH:32]=2)[CH:20]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cnc(Cl)c(Br)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cnc(Cl)c(-c2cncnc2)c1
Yield: 77.9 %

Procedure:
To the solution of 3-(1-BOC-2-(R)-pyrrolidinylmethoxy)-5-bromo-6-chloropyridine (400 mg, 1.1 mmol) in toluene (10 mL) was added tetrekis(triphenylphosphine)palladium (40 mg, 1%) and tributyl(pyrimidinyl)tin (0.51 g, 1.38 mmol). The mixture was stirred and heated under reflux for 16 h. Solvent was evaporated and the residue was chromatographed (silica gel; hexane/EtOAc, 10:1 to 2:1) to afford an oil (335 mg, 80%): 1H NMR (CDCl3, 300 MHz) δ 1.40 (s, 9H), 1.85-2.00 (m, 2H), 2.00-2.10 (m, 2H), 3.38 (m, 1H), 4.00 (m 1H), 4.14 (m, 1H), 4.24 (m, 1H), 7.40 (s, 1H), 8.20 (d, 1H, J=3.0 Hz), 8.88 (s, 2H), 9.28 (s, 1H); MS (CI/NH3) m/z 277 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][C:21]=1Cl)[C:7]([C:9]1[CH:14]=[CH:13][C:12](Cl)=[C:11]([N+:16]([O-])=O)[CH:10]=1)=[O:8])([O-])=O.[O-2].[Ca+2].[H][H]>[Pd].ClCCCl>[NH2:1][C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH2:16])[CH:10]=1)=[O:8]
Reactant: [H][H]
Reactant: O=C(c1ccc(Cl)c([N+](=O)[O-])c1)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Pd]
Agent: [Ca+2]
Agent: [O-2]
Solvent: ClCCCl
Product: Nc1cccc(C(=O)c2cccc(N)c2)c1
Temperature: 70 °C

Procedure:
To an autoclave there are added 50 g (0.15 moles) of 3,3'-dinitro-4,4'-dichloro benzophenone, 21 g (0.38 moles) of calcium oxide, 1 g of 5% palladium/alumina catalyst (available from Nihon-Engelhardt Co., Ltd.) and 350 ml of 1,2-dichloro ethane. The reaction is carried out for ten hours by introducing hydrogen into the autoclave, with the mixture being stirred at 30°-35° C., to keep the pressure at 10 Kg/cm2.G. After the completion of the reaction, the reaction mixture is heated up to 70° C. and subjected to a hot filtering so as to remove the catalyst and the inorganic salt. On cooling the mixture there are obtained yellow needle-like crystals of 3,3'-diamino benzophenone. The crystals are filtered, washed with 10 ml of 1,2-dichloro ethane and dried. Yield 21.2 g (67%). M.P. 149°-150.5° C. Recrystallization from ethanol gives pure crystals. M.P. 150°-151° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.CCN=C=NCCCN(C)C.C(N(CC)CC)C.[NH2:29][CH:30]([CH2:32][OH:33])[CH3:31]>ClCCl>[OH:33][CH2:32][CH:30]([NH:29][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=1)[CH3:31]
Reactant: O=C(O)c1cccc(I)c1
Reactant: CC(N)CO
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(CO)NC(=O)c1cccc(I)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 33.7 %

Procedure:
To a solution of 3-iodobenzoic acid (10.02 g, 40.30 mmol), in dry dichloromethane, at room temperature (180 mL) under a nitrogen atmosphere, EDCI (7.72 g, 40.30 mmol) was added followed by triethylamine (8.0 mL, 60.45 mmol) and the mixture was stirred at room temperature for further 5 minutes. DL Alaninol (3.02 g, 40.3 mmol) was then added and the mixture stirred at room temperature for 16 hrs. The reaction mixture was washed with a mixture of saturated brine and saturated sodium bicarbonate (1:1; 2×150 mL) followed by saturated brine solution (100 mL). The organics were separated and dried over magnesium sulfate and the solvent evaporated under vacuum. The residue was purified by flash column chromatography on silica gel (DCM:MeOH, 1% to 8% methanol gradient) to afford compound 1 (4.14 g, 13.6 mmol, 34% yield) as an off white solid.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([OH:15])[C@H:13]2[CH2:16][O:17][C@H:11]([O:12]2)[C@@H:10]1[O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].[CH2:27](Br)[CH2:28][CH3:29]>CS(C)=O>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:27][CH2:28][CH3:29])[C@H:13]2[CH2:16][O:17][C@H:11]([O:12]2)[C@@H:10]1[O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O[C@@H]1[C@@H](OCc2ccccc2)[C@@H](OC2CCCCO2)[C@@H]2OC[C@H]1O2
Reactant: CCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCCO[C@@H]1[C@@H](OCc2ccccc2)[C@@H](OC2CCCCO2)[C@@H]2OC[C@H]1O2
Temperature: 50 °C

Procedure:
A solution of 10 g of 1,6-anhydro-3-O-benzyl-2-O-tetrahydropyranyl-β-D-gulopyranose in 20 ml of absolute dimethylsulphoxide is treated with 3 g of potassium hydroxide powder, while stirring and with the exclusion of moisture, in a nitrogen atmosphere, and the mixture is warmed to 50° C. A solution of 3 ml of propyl bromide in 10 ml of dimethylsulphoxide is added dropwise at this temperature in the course of 2 hours and the reaction mixture is stirred for a further 3 hours. A further 3 g of potassium hydroxide powder are added, a solution of 3 ml of propyl bromide in 10 ml of dimethylsulphoxide is added dropwise and the mixture is stirred for 2 hours. The reaction mixture is now cooled and poured into ice-water. The resulting mixture is extracted with ether and the ether phase is washed with water until neutral and dried over magnesium sulphate. After evaporating off the solvent, 1,6-anhydro-3-O-benzyl-4-O-propyl-2-O-tetrahydropyranyl-β-D-gulopyranose is obtained in the form of yellow oil with a Rf value of 0.42 on silica gel thin layer plates in the system methylene chloride/ethyl acetate, 85:15.
Reaction SMILES: Cl[C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[CH3:20][C:21]1[CH:34]=[CH:33][C:24]([C:25]([NH:27][N:28]2[NH:32][CH:31]=[CH:30][S:29]2)=[O:26])=[CH:23][C:22]=1B1OC(C)(C)C(C)(C)O1>>[CH3:17][O:16][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[CH2:9][NH:8][C:6](=[O:7])[C:5]1[CH:18]=[CH:19][C:2]([C:22]2[CH:23]=[C:24]([C:25](=[O:26])[NH:27][N:28]3[NH:32][CH:31]=[CH:30][S:29]3)[CH:33]=[CH:34][C:21]=2[CH3:20])=[N:3][CH:4]=1
Reactant: COc1cccc(CNC(=O)c2ccc(Cl)nc2)c1
Reactant: Cc1ccc(C(=O)NN2NC=CS2)cc1B1OC(C)(C)C(C)(C)O1
Product: COc1cccc(CNC(=O)c2ccc(-c3cc(C(=O)NN4NC=CS4)ccc3C)nc2)c1

Procedure:
N-(3-Methoxybenzyl)-6-[2-methyl-5-(thiadiazol-2-ylcarbamoyl)-phenyl]-nicotinamide was prepared from 6-chloro-N-(3-methoxybenzyl)nicotinamide (Intermediate 3) and 4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-N-(thiadiazol-2-yl)-benzamide (Intermediate 12) using General Method B. LCMS: retention time 3.02 min, MH− 460. NMR: δH [2H6]-DMSO 13.14, (1H, b), 9.32, (1H, t), 9.24, (1H, s), 9.18, (1H, d), 8.40, (1H, dd), 8.26, (1H, s), 8.10, (1H, d), 7.84, (1H, d), 7.55, (1H, d), 7.27, (1H, t), 6.94, (2H, m), 6.84, (1H, d), 4.53, (2H, d), 3.75, (3H, s), 2.46, (3H, s).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH:8]([F:10])[F:9])[C:5]([F:11])=[CH:4][N:3]=1.[Br:12][C:13]1[CH:14]=[C:15]([CH:17]=[C:18]([CH3:20])[CH:19]=1)[NH2:16]>O1CCOCC1>[Br:12][C:13]1[CH:14]=[C:15]([NH:16][C:2]2[N:7]=[C:6]([CH:8]([F:10])[F:9])[C:5]([F:11])=[CH:4][N:3]=2)[CH:17]=[C:18]([CH3:20])[CH:19]=1
Reactant: Fc1cnc(Cl)nc1C(F)F
Reactant: Cc1cc(N)cc(Br)c1
Solvent: C1COCCO1
Product: Cc1cc(Br)cc(Nc2ncc(F)c(C(F)F)n2)c1
Temperature: 105 °C
Reaction time: 72 h

Procedure:
2-Chloro-4-(difluoromethyl)-5-fluoropyrimidine (30 g, 162 mmol, 1.00 equiv) p-TsOH (37 g, 215 mmol, 1.33 equiv), 1,4-dioxane (600 mL), 3-bromo-5-methylaniline (46 g, 247 mmol, 1.53 equiv) were added into a 1000-mL pressure tank reactor purged and maintained with an inert atmosphere of nitrogen. The resulting solution was stirred for 72 h at 105° C. The reaction mixture was cooled to room temperature. The solid was filtered out and the filtrate was concentrated under reduced pressure. The residue was applied onto a silica gel and purified column chromatography on silica (1:20 ethyl acetate/petroleum ether) to afford N-(3-bromo-5-methylphenyl)-4-(difluoromethyl)-5-fluoropyrimidin-2-amine as a yellow solid. MS ESI calc'd. for C12H10BrF3N3 [M+H]+332/334. found 332/334. 1H NMR (400 MHz, CDCl3): δ 8.45 (1H, s), 7.73 (1H, s), 7.21 (1H, s), 7.18 (1H, s), 7.05 (1H, s), 6.63 (1H, t, J=53.37 Hz), 2.34 (3H, s).
Reaction SMILES: C(O[C:4](=[O:23])[CH:5]=[C:6]([C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[CH:18][N:19]2[CH3:22])=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.C(OC(=O)C=C(C1C=CC=C2C=1C(C#N)=[CH:39][NH:40]2)C1C=CC=CC=1)C>>[CH3:39][NH:40][C:4](=[O:23])[CH:5]=[C:6]([C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[CH:18][N:19]2[CH3:22])=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(=O)C=C(c1ccccc1)c1cccc2[nH]cc(C#N)c12
Reactant: CCOC(=O)C=C(c1ccccc1)c1ccc2ccn(C)c2c1
Product: CNC(=O)C=C(c1ccccc1)c1ccc2ccn(C)c2c1

Procedure:
N-Methyl-3-(1-methyl-1H-indol-6-yl)-3-phenyl-acrylamide CXLIV was prepared from 3-(1-methyl-1H-indol-6-yl)-3-phenyl-acrylic acid ethyl ester using the procedure described above for preparation of 3-(1H-Indol-7-yl)-N-methyl-3-phenyl-acrylamide XVIII (see Example 4).