Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[CH:9][C:10]2[CH2:11][C@H:12]3[N:24]([CH2:25][CH:26]4[CH2:28][CH2:27]4)[CH2:23][CH2:22][C@:18]45[C:19]=2[C:20]=1[O:21][C@H:17]4[C:16](=[O:29])[CH2:15][CH2:14][C@@:13]35[OH:30])(=O)=O.[CH3:33][N:34](C=O)C>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.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:26]1([CH2:25][N:24]2[CH2:23][CH2:22][C@:18]34[C:19]5[C:20]6[O:21][C@H:17]3[C:16](=[O:29])[CH2:15][CH2:14][C@@:13]4([OH:30])[C@H:12]2[CH2:11][C:10]=5[CH:9]=[CH:8][C:7]=6[C:33]#[N:34])[CH2:27][CH2:28]1
Reactant: CN(C)C=O
Reactant: O=C1CC[C@@]2(O)[C@H]3Cc4ccc(OS(=O)(=O)C(F)(F)F)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: N#Cc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(O)[C@@H](C2)N(CC2CC2)CC[C@]314
Temperature: 120 °C
Yield: 61 %

Procedure:
A mixture of (5a)-17-(cyclopropylmethyl)-14-hydroxy-6-oxo-4,5-epoxymorphinan-3-yl trifluoromethanesulfonate [P1](38.0 g, 80.3 mmol), zinc cyanide (18.85 g, 160.5 mmol), and tetrakis(triphenylphosphine)palladium(0) (8.5 g, 7.36 mmol) in DMF (500 mL—degassed with argon for 3 hours) was heated at 120° C. under argon for 3 hours. The reaction mixture was allowed to return to room temperature then diluted with ethyl acetate (1 L) and passed through a pad of celite. The solution was washed with water (3×1 L) and the organic phase dried (MgSO4). Filtration and removal of the solvent under reduced pressure gave crude product that was triturated with methanol to give (5a)-17-(cyclopropylmethyl)-14-hydroxy-6-oxo-4,5-epoxymorphinan-3-carbonitrile [P2] (17.12 g, 61% yield); LC/MS (r.t. 12.7 minutes [5 to 95% B]), 351 (M+H)+.
Reaction SMILES: [NH2:1]/[C:2](/[CH3:8])=[CH:3]\[C:4]([O:6][CH3:7])=[O:5].N1C=CC=CC=1.[Br:15][CH2:16][C:17](Br)=[O:18]>C(Cl)Cl>[Br:15][CH2:16][C:17]([NH:1]/[C:2](/[CH3:8])=[CH:3]\[C:4]([O:6][CH3:7])=[O:5])=[O:18]
Reactant: O=C(Br)CBr
Reactant: COC(=O)/C=C(/C)N
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)/C=C(/C)NC(=O)CBr
Temperature: -20 °C
Reaction time: 0.33 h
Yield: 15.1 %

Procedure:
A mixture of methyl 3-aminocrotonate (3.20 g, 27.79 mmol) and pyridine (2.64 g, 33.33 mmol) in CH2Cl2 (60 mL) was stirred at −20° C. for 20 min. To the mixture was added a solution of bromoacetyl bromide (5.61 g, 27.79 mmol) in CH2Cl2 (20 mL) dropwise. The mixture was stirred at rt for 2 h. The organic phase was washed with brine (100 mL×3), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=5:1) to give the title compound as a reddish solid (0.99 g, 15%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[C:9]([Cl:10])=[C:8](Cl)[CH:7]=[CH:6][N:5]=1.[F:12][CH:13]([F:25])[O:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([NH2:24])[CH2:22][CH3:23])=[CH:17][CH:16]=1>>[Cl:10][C:9]1[C:4]([CH2:3][O:2][CH3:1])=[N:5][CH:6]=[CH:7][C:8]=1[NH:24][CH:21]([C:18]1[CH:19]=[CH:20][C:15]([O:14][CH:13]([F:12])[F:25])=[CH:16][CH:17]=1)[CH2:22][CH3:23]
Reactant: CCC(N)c1ccc(OC(F)F)cc1
Reactant: COCc1nccc(Cl)c1Cl
Product: CCC(Nc1ccnc(COC)c1Cl)c1ccc(OC(F)F)cc1

Procedure:
was prepared analogously to Example 84 using 2-methoxymethyl-3,4-dichloropyridine and 1-(4-difluoromethoxyphenyl)-propylamine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([N+:14]([O-])=O)[C:12]=1[CH3:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6]>C(O)C.[Pd]>[NH2:14][C:11]1[CH:10]=[C:4]([CH:3]=[C:2]([F:1])[C:12]=1[CH3:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)c1cc(F)c(C)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1cc(N)c(C)c(F)c1
Yield: 96.7 %

Procedure:
3-Fluoro-4-methyl-5-nitro-benzoic acid, ethyl ester (Example 169a, 1.43 g) in ethanol (30 mL) was pumped continuously through a Pd/C cartridge for 4 h under an atmosphere of hydrogen. The solvents were removed to give the subtitle product (1.20 g) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21]#[C:22][CH2:23][OH:24])[CH:17]=3)[N:12]([CH3:25])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[H][H]>[Pt].C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][CH2:22][CH2:23][OH:24])[CH:17]=3)[N:12]([CH3:25])[CH:11]=2)=[O:9])=[CH:26][CH:27]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCO)ccc21
Reactant: [H][H]
Agent: [Pt]
Solvent: CO
Solvent: C1CCOC1
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCCO)ccc21
Yield: 89.1 %

Procedure:
A mixture of 0.50 g of N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide from Example No. 31 and 50 mg of 5% platinum on carbon catalyst in 20 mL of 1:1 THF-methanol is stirred under 1 atm hydrogen for 3 h, then filtered through diatomaceous earth. The filtrate is concentrated under reduced pressure and the residual solid flash chromatographed on silica gel using 4-5% methanol in dichloromethane to afford 0.45 g of the title compound as a yellow solid. Further purification is achieved by recrystallization of the solid from 15 mL of acetonitrile.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8](Cl)[C:7]([Cl:11])=[C:6]([CH3:12])[C:3]=1[C:4]#[N:5].[CH3:13][O-:14].[Na+].O>CO>[Cl:1][C:2]1[N:9]=[C:8]([O:14][CH3:13])[C:7]([Cl:11])=[C:6]([CH3:12])[C:3]=1[C:4]#[N:5]
Reactant: C[O-]
Reactant: Cc1c(Cl)c(Cl)nc(Cl)c1C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1nc(Cl)c(C#N)c(C)c1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
To a slurry of 2,5,6-trichloro-4-methyl-nicotinonitrile (11.0 g, 49.67 mmol, Tetrahedron, 1977, 33, 113-117) in MeOH (125 ml) is added sodium methoxide solution (25% wt. in MeOH)(11.92 ml, 52.15 mmol). The reaction mixture is stirred at 0° C. for 30 minutes, then room temperature for 1 hour. The reaction is quenched by the addition of water (300 ml) and a thick, white precipitate is formed. An additional 200 ml of water is added and the mixture is stirred at 0° C. for 10 minutes. The precipitate is collected by filtration and dried (vacuum oven for 16 hours at 60° C.) to give the title compound as an off-white solid (10.05 g, 93%). Mass (m/z): 217.0 (M++1).
Reaction SMILES: C(OC(=O)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])[N:8]=[C:7]1[C@@H:19]([NH:24][C:25]([O:27]CC1C=CC=CC=1)=O)[CH2:20][CH2:21][CH2:22][CH3:23])C>CC(O)=O.[Pd]>[CH2:20]([C:19]1[C:7]2[N:6]([CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH3:18])[N:8]=2)[CH2:5][C:25](=[O:27])[N:24]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCC[C@H](NC(=O)OCc1ccccc1)c1nc(-c2ccccc2OC)cn1CC(=O)OCC
Agent: [Pd]
Solvent: CC(=O)O
Product: CCCCC1=NC(=O)Cn2cc(-c3ccccc3OC)nc21
Temperature: 70 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
The product from Step 1.d. (compound v where R3 is n-butyl, R4 is 2-methoxyphenyl, and R5 and R6 are H) (11.5 g, 23.9 mmol) was dissolved in HOAc (100 ml) containing 10% Pd on carbon catalyst (500 mg) and hydrogenated under 50 psi of H2 for about 3 hours at room temperature. The catalyst was removed by filtration through a 3 cm pad of diatomaceous earth and the filtrate was warmed at about 70° C. for about 2 hours. The mixture was concentrated to a solid under reduced pressure, dissolved in CH2Cl2 (100 ml) and washed with saturated NaHCO3 solution (125 ml). The CH2Cl2 layer was dried over Na2SO4, filtered and 275 ml hexanes was added. Product was filtered off and dried to constant weight to yield 6.21 g (87%) of product, m.r.=200-202° C., NMR (300 MHz, DMSO-d6, 30° C.) 8.5-8.6 (1H, s), 8.0-8.1 (1H, d), 7.4-7.6 (1H, s), 7.1-7.3 (1H, t), 7.0-7.1 (1H, d), 6.9-7.1 (1H, t), 4.55-4.8 (2H, q), 4.55-4.7 (1H, t), 3.8-4.0 (3H, s), 1.75-1.95 (2H, m), 1.1-1.5 (4H, m), 0.8-0.9 (3H, t).
Reaction SMILES: Br.[CH3:2][C:3]1[C:8]2[N:9]=[C:10]([N:12](C)C)[S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.O.[NH2:16]N>C(O)CO>[CH3:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][NH2:16])[S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: Cc1cccc2sc(N(C)C)nc12
Reactant: NN
Agent: Br
Solvent: OCCO
Solvent: O
Product: Cc1cccc2sc(NN)nc12
Temperature: 140 °C
Yield: 79 %

Procedure:
4-Methyl-2-dimethylaminobenzothiazole hydrobromide (10.95 g.; 0.04 mole), 85% hydrazine hydrate representing 8.01 g., 0.12 mole, and 33 ml. of ethylene glycol were mixed at room temperature and the mixture heated to 140°C. under nitrogen atmosphere. The reaction mixture was maintained at this temperature overnight. After 39 hours of reaction time, the reaction was cooled, diluted with 33 ml. of water, and filtered to separate the desired 4-methyl-2-hydrazinobenzothiazole compound. It was washed with water and dried 2 hours at 65°C. in vacuo, 5.43 g., 79% yield. The product was subjected to nmr, which showed about 5-10% of starting material. The melting point was 161°-166°C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:12]\[C:13]1[NH:17][C:16]([CH3:18])=[C:15]([C:19](ON2C3=NC=CC=C3N=N2)=[O:20])[C:14]=1[CH3:31].[CH2:32]([N:34]([CH2:38][CH3:39])[CH2:35][CH2:36][NH2:37])[CH3:33]>CN(C=O)C>[CH3:33][CH2:32][N:34]([CH2:35][CH2:36][NH:37][C:19]([C:15]1[C:14]([CH3:31])=[C:13](/[CH:12]=[C:5]2/[C:4]3[CH:3]=[C:2]([F:1])[CH:10]=[CH:9][C:8]=3[NH:7][C:6]/2=[O:11])[NH:17][C:16]=1[CH3:18])=[O:20])[CH2:38][CH3:39]
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)On1nnc2cccnc21
Reactant: CCN(CC)CCN
Solvent: CN(C)C=O
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c1C
Temperature: 25 °C
Yield: 88 %

Procedure:
15 (10 g, 33.3 mmol) was suspended in DMF (50 ml, 5 P.) and stirred for 5 minutes. DIPEA (9.0 mL, 54.5 mmol) was then added and the mixture was stirred for 10 minutes. HATU (13.95 g, 36.7 mmol) was added and the reaction mixture was stirred at 25° C. for completion. HPLC was applied to detect the completion of the reaction. Most of the DMF was removed by rotary evaporating and the residue was suspended in MeCN (100 mL, 10 P.) and stirred for another 1 hour. The solid was collected by filtration, washed with MeCN, and dried under vacuum at 40° C. overnight. The intermediate (Z)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl 5-((5-fluoro-2-oxoindolin-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxylate (15b) (12 g, 86.5 percent yield) with 86.8% HPLC purity as a yellow powder was got. 1H NMR (300 MHz, DMSO-d6): δ 2.61 (s, 3H, H-31), 2.68 (s, 3H, H-16), 6.87 (m, 1H, H-2), 7.01 (m, 1H, H-6), 7.64 (m, 1H, H-10), 7.85 (m, 1H, H-3), 8.73 (dd, J=1.5, 1.2 Hz, 1H, H-28), 8.83 (dd, J=1.2, 1.5 Hz, 1H, H-27), 13.11 (s, 1H, NH). To a 15b (10.0 g, 23.9 mmol) DMF solution was added N,N-diethylethane-1,2-diamine (7; 3.33 g, 28.7 mmol), the reaction mixture was stirred at 25° C. for completion. HPLC was applied to detect the completion of the reaction. Most of the DMF was removed by rotary evaporating and the residue was suspended in MeCN (100 mL, 10 P.) and stirred for another 1 hour. The solid was collected by filtration, washed with MeCN, and dried under vacuum at 40° C. overnight to give Sunitinib (8.38 g, 88% yield) with 77.6% HPLC purity.
Reaction SMILES: F[C:2]1[C:3]([CH3:23])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH:18]([CH3:21])[CH2:17][NH:16][C:15](=[O:22])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[CH3:24][NH:25][CH3:26]>CS(C)=O.O>[CH3:24][N:25]([CH3:26])[C:2]1[C:3]([CH3:23])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH:18]([CH3:21])[CH2:17][NH:16][C:15](=[O:22])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)C(C)CNC4=O)c2nc1F
Reactant: CNC
Solvent: O
Solvent: CS(C)=O
Product: Cc1nc2cccc(-c3cc4c([nH]3)C(C)CNC4=O)c2nc1N(C)C
Temperature: 60 °C
Reaction time: 18 h
Yield: 66 %

Procedure:
A solution of rac-2-(3-fluoro-2-methylquinoxalin-5-yl)-7-methyl-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 156; 32.0 mg, 0.103 mmol) and dimethylamine (2.0M in THF; 0.155 mL, 0.309 mmol) in DMSO (0.8 mL) was stirred under argon in a sealed microwave flask at 25° C. for 10 min, then at 60° C. for 18 h. Additional dimethylamine (2.0M in THF; 0.155 mL, 0.309 mmol) was added, and the resulting mixture was stirred under argon in a sealed microwave flask at 60° C. for 4.5 h. The reaction was cooled to 25° C. and diluted with water (10 mL). The precipitated solid was collected by vacuum filtration, washed with water (2×5 mL), and dried in vacuo to provide rac-2-(3-(dimethylamino)-2-methylquinoxalin-5-yl)-7-methyl-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (22.7 mg, 0.068 mmol, 66% yield) as a yellow-orange solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 11.81 (1H, br. s.), 7.96 (1H, dd, J=7.5, 1.1 Hz), 7.66 (1H, dd, J=8.1, 0.9 Hz), 7.47 (1H, t, J=7.8 Hz), 7.08 (1H, d, J=2.2 Hz), 6.99 (1H, br. s.), 3.40-3.49 (1H, m), 3.13-3.15 (6H, m), 3.06-3.18 (2H, m), 2.71 (3H, s), 1.30 (3H, d, J=6.5 Hz). m/z (ESI, +ve) 336.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[NH:22]1[CH2:27][CH2:26][CH:25]([C:28]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:29]=2[CH2:30][C:31](=[O:37])[NH:32]3)[CH2:24][CH2:23]1>>[CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=[C:30]1[C:29]2[C:33](=[CH:34][CH:35]=[CH:36][C:28]=2[CH:25]2[CH2:24][CH2:23][NH:22][CH2:27][CH2:26]2)[NH:32][C:31]1=[O:37]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Reactant: O=C1Cc2c(cccc2C2CCNCC2)N1
Product: Cc1c(C=C2C(=O)Nc3cccc(C4CCNCC4)c32)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Yield: 27.9 %

Procedure:
The title compound was prepared under the same conditions as described in Example 25 with 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 4-piperidin-4-yl-1,3-dihydro-indol-2-one as starting materials to give 3-methyl-2-(2-oxo-4-piperidin-4-yl-1,2-dihydro-indol-3-ylidenemethyl)-5-(2-piperidin-1-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (18 mg, 27.9%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([OH:23])=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].[Cl:24][C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][C:34]=1[O:35][CH2:36][C@@H:37]([NH:39][CH3:40])[CH3:38])[C:28]([O:30][CH3:31])=[O:29].C1C=CC2N(O)N=NC=2C=1>CN(C1C=CN=CC=1)C.CN(C=O)C.CCOC(C)=O>[Cl:24][C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][C:34]=1[O:35][CH2:36][C@@H:37]([N:39]([CH3:40])[C:21](=[O:23])[CH2:20][C:5]1[CH:6]=[CH:7][C:8]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])=[O:11])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:38])[C:28]([O:30][CH3:31])=[O:29]
Reactant: CN[C@@H](C)COc1ccc(C(=O)OC)cc1Cl
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OC[C@H](C)N(C)C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.2 %

Procedure:
A mixture of 3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetic acid (261 mg, 0.83 mmol), methyl (S)-3-chloro-4-(2-methylamino-1-propoxy)benzoate (214 mg, 0.83 mmol), EDC(hydrochloride) (239 mg, 1.25 mmol), HOBt (168 mg, 1.24 mmol), and DMAP (20 mg, 0.16 mmol) in DMF (8 mL) was stirred at room temp for 2 hr. The mixture was diluted with EtOAc, washed with 0.5 N HCl, brine, dried over Na2SO4 and evaporated. The residue was purified by column chromatography on silica-gel with CHCl3-MeOH (50:1, v/v) as eluent to give 470 mg (100%) methyl (S)-3-chloro-4-[2-[N-methyl-N-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetyl]amino]-1propoxy]benzoate as a pale yellow amorphous solid.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[OH-].[Na+].[F:12][C:13]([F:23])([F:22])[C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17]Br>CN(C=O)C.O>[F:12][C:13]([F:22])([F:23])[C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: c1ccc2[nH]nnc2c1
Reactant: FC(F)(F)c1cccc(CBr)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1cccc(Cn2nnc3ccccc32)c1
Reaction time: 0.42 h

Procedure:
To a solution of benzotriazole (3 g) in DMF (38 mL) at r.t. was added a solution of 10N NaOH (2.75 mL). After stirring for 25 min., 3-trifluoromethylbenzyl bromide (4.39 mL) was added. The mixture was further stirred for 30 min., diluted with H2O, and extracted with EtOAc. The EtOAc extract was washed brine (2×), water, brine, dried (MgSO4) and concentrated. The residue was stirred in diethyl ether/hexane to afford 3.96 g of the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:8]=[C:9]([NH:15][C:16](=[O:28])[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([C:26]#[N:27])([CH3:25])[CH3:24])[CH:18]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])=[CH:4][CH:3]=1.[S-:31][C:32]#[N:33].[K+].BrBr>>[NH2:33][C:32]1[S:31][C:3]2[CH:4]=[C:5]([O:6][C:7]3[CH:8]=[C:9]([NH:15][C:16](=[O:28])[C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([C:26]#[N:27])([CH3:25])[CH3:24])[CH:18]=4)[CH:10]=[CH:11][C:12]=3[O:13][CH3:14])[CH:29]=[CH:30][C:2]=2[N:1]=1
Reactant: COc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc(N)cc1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Product: COc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(N)sc2c1
Yield: 79.6 %

Procedure:
Using N-[3-(4-aminophenoxy)-4-methoxyphenyl]-3-(1-cyano-1-methylethyl)benzamide (1.10 g, 2.74 mmol), potassium thiocyanate (0.97 g, 10.0 mmol) and bromine (0.60 g, 3.75 mmol), and in the same manner as in Example A18(iv), the title compound (1.00 g, 80%) was obtained as a yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[CH:9]=[N:8][C:7]([S:11][CH3:12])=[N:6]2.[I:13]N1C(=O)CCC1=O>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([I:13])[N:5]2[C:10]=1[CH:9]=[N:8][C:7]([S:11][CH3:12])=[N:6]2
Reactant: CSc1ncc2c(Cl)ccn2n1
Reactant: O=C1CCC(=O)N1I
Solvent: ClCCCl
Product: CSc1ncc2c(Cl)cc(I)n2n1
Temperature: 60 °C
Reaction time: 8 h
Yield: 55.7 %

Procedure:
5-Chloro-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (54 mg, 0.27 mmol) was dissolved in 1,2-Dichloroethane (2.0 mL and then N-Iodosuccinimide (75 mg, 0.33 mmol) was added in one portion and the reaction was stirred in a vial at 60° C. overnight. The heterogenous mixture was powdered onto silica gel (0.75 g) and purified on ISCO (12 g, 0-5% EtOAc:Hex) to afford 5-Chloro-7-iodo-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (49 mg; Yield=56%) as a yellow solid. m.p. 216-220° C.; LCMS (Bruker, Fragile): 4.0 min, m/z=326; 1H-NMR (CDCl3): 8.55 (s, 1H), 6.90 (s, 1H), 2.63 (s, 3H).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.[F:8][C:9]1[CH:10]=[C:11]([C:16]2[CH2:20][CH:19]([CH2:21][O:22][C:23]3[CH:27]=[CH:26][O:25][N:24]=3)[O:18][N:17]=2)[CH:12]=[CH:13][C:14]=1F>CN(C)C=O>[F:8][C:9]1[CH:10]=[C:11]([C:16]2[CH2:20][CH:19]([CH2:21][O:22][C:23]3[CH:27]=[CH:26][O:25][N:24]=3)[O:18][N:17]=2)[CH:12]=[CH:13][C:14]=1[N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: Fc1ccc(C2=NOC(COc3ccon3)C2)cc1F
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1cc(C2=NOC(COc3ccon3)C2)ccc1-n1ccnc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.5 %

Procedure:
A slurry of sodium hydride (60% in oil, 22 mg, 0.55 mM) in anhydrous N,N-dimethylformamide (0.5 ml) was stirred under an atmosphere of nitrogen and treated dropwise with a solution of imidazole (38 mg, 0.55 mM) in anhydrous N,N-dimethylformamide (0.5 ml) at 0°. The mixture was allowed to warm to ambient temperature over 20 minutes, then a solution of (5RS)-3-(3,4-difluorophenyl)-5-isoxazol-3-yloxymethyl-4,5-dihydroisoxazole (140 mg, 0.5 mM) in anhydrous N,N-dimethylformamide (1 ml) added, and the mixture stirred at 70° for 16 hours. After cooling, the mixture was partitioned between aqueous sodium bicarbonate solution (20 ml) and ethyl acetate (20 ml), and the organic extract washed with water (20 ml) and brine (20 ml). After drying (magnesium sulfate) and evaporation, the crude product was chromatographed on a 10 g silica Mega Bond Elut® column, eluting with a gradient from 0–2.5% methanol in dichloromethane. Relevant fractions were combined to give the desired product (68 mg). MS (ESP): 329 (MH+) for C16H13FN4O3
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>N1C=CC=CC=1>[C:17]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:6][CH:7]=1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1ccc(-c2nc3ccccc3s2)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1ccc(-c2nc3ccccc3s2)cc1)c1ccccc1
Yield: 82.2 %

Procedure:
A mixture of 2-(4'-aminophenyl)benzothiazole (0.3 g, 1.32 mmol) and benzoyl chloride (0.3 ml) in pyridine (8 ml) was stirred at reflux for 2 hours, then cooled and poured into water (100 ml). The precipitate formed was filtered off, washed with water and dissolved in hot dichloromethane (12 ml). The resulting solution was cooled in an ice-bath and the solid was filtered off. The filtrate was evaporated and the residue was recrystallised from dichloromethane-methanol to give a white powder (0.36 g, 82.2%), m.p. 227.1-228.5° C.
Reaction SMILES: [CH2:1]([S:4][C:5]1[S:9][C:8]([SH:10])=[N:7][N:6]=1)[CH:2]=[CH2:3].[H-].[Na+].Cl[C:14]1[C:15]([C:20]#[N:21])=[N:16][CH:17]=[CH:18][N:19]=1>CN(C=O)C.C1C=CC=CC=1>[CH2:1]([S:4][C:5]1[S:9][C:8]([S:10][C:14]2[C:15]([C:20]#[N:21])=[N:16][CH:17]=[CH:18][N:19]=2)=[N:7][N:6]=1)[CH:2]=[CH2:3]
Reactant: N#Cc1nccnc1Cl
Reactant: C=CCSc1nnc(S)s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: C=CCSc1nnc(Sc2nccnc2C#N)s1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
The title compound was prepared according to the procedure described in Example 1 by using 5-(allylthio)-1,3,4-thiadiazole-2-thiol (460 mg, 2.42 mmol), NaH (60% dispersion in mineral oil, 107 mg, 2.66 mmol), and 3-chloropyrazine-2-carbonitrile (338 mg, 2.42 mmol) in DMF and benzene (8 ml, 1/1) by stirring at 85° C. under nitrogen atmosphere overnight.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[CH:6][C:7]=1[S:8][CH:9]1[CH2:11][CH2:10]1.S(=O)(=O)(O)O.[CH3:21]O>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([O:15][CH3:21])=[O:14])[CH:5]=[CH:6][C:7]=1[S:8][CH:9]1[CH2:11][CH2:10]1
Reactant: O=C(O)Cc1ccc(SC2CC2)c(Br)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(SC2CC2)c(Br)c1
Temperature: 25 °C

Procedure:
A mixture of [3-bromo-4-(cyclopropylsulfanyl)phenyl]acetic acid (13.5 g), concentrated sulfuric acid (0.135 mL), and methanol (40 mL) was stirred under heating and reflux for 4 hours. After leaving to be cooled at room temperature, the solvent was evaporated under reduced pressure, and then a 1 M aqueous sodium hydroxide solution (100 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (100 mL×3). The organic layer was washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate, and the solvent was then evaporated under reduced pressure to obtain methyl [3-bromo-4-(cyclopropylsulfanyl)phenyl]acetate (13.8 g) as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Cl:10])[CH2:5][C:6]([Cl:9])(O)[CH:7]=1.BrC1C=C[C:15]([OH:18])=[C:14](CC)C=1>>[CH2:15]([O:18][C:5]1[C:4]([Cl:10])=[CH:3][C:2]([Br:1])=[CH:7][C:6]=1[Cl:9])[CH3:14]
Reactant: CCc1cc(Br)ccc1O
Reactant: OC1(Cl)C=C(Br)C=C(Cl)C1
Product: CCOc1c(Cl)cc(Br)cc1Cl

Procedure:
The title compound was prepared analogously to step 2 in Example A(125), where 5-Bromo-1,3-dichloro-phenol was substituted in place of 4-bromo-2-ethyl-phenol in that example. 1H NMR (400 MHz, CDCl3): δ 1.46 (t, J=7.0 Hz, 3H), 4.10 (q, J=7 Hz, 2H), 7.09 (s, 2H).