Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:3]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=2)=[N:4][NH:5][CH:6]=1.C(N(CC)CC)C.[CH3:23][Si:24]([C:27]#[CH:28])([CH3:26])[CH3:25]>O1CCCC1.[Pd+2].[Cl-].[Cl-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[N+:13]([C:9]1[CH:8]=[C:7]([C:3]2[C:2]([C:28]#[C:27][Si:24]([CH3:26])([CH3:25])[CH3:23])=[CH:6][NH:5][N:4]=2)[CH:12]=[CH:11][CH:10]=1)([O-:15])=[O:14]
Reactant: C#C[Si](C)(C)C
Reactant: O=[N+]([O-])c1cccc(-c2n[nH]cc2I)c1
Agent: [Pd+2]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1c[nH]nc1-c1cccc([N+](=O)[O-])c1
Reaction time: 4 h

Procedure:
415 mg (1.32 mmol) of 4-iodo-3-(3-nitrophenyl)-1H-pyrazole (prepared as described in Example 27) were dissolved in 15 ml of dry tetrahydrofuran and 494 μL (3.42 mmol) of triethylamine, 80 mg (0.106 mmol) of palladium(II)-bis(triphenylphosphine) dichloride, 26 mg (0.166 mmol) of cuprous iodide and 406 μL (2.9 mmol) of trimethylsilylacetylene were added consecutively in a nitrogen atmosphere. The reaction was refluxed under stirring for 4 hours. The solvent was then removed in vacuo and the residue re-dissolved with dichloromethane and washed with water. The organic phase was dried over sodium sulphate and evaporated, affording, after trituration with diisopropylether, 300 mg (80%) of the title compound, that was employed for the next step without any further purification.
Reaction SMILES: C(O)(=O)C.C([O:7][C:8](=[O:39])[CH:9]([NH:29][C:30]1[CH:35]=[CH:34][C:33]([C:36](=[NH:38])[NH2:37])=[CH:32][CH:31]=1)[C:10]1[CH:15]=[C:14]([O:16][CH2:17][CH3:18])[CH:13]=[C:12]([O:19][CH2:20][CH:21]2[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]2)[C:11]=1[F:28])C.[Li+].[OH-].C(O)(=O)C>C1COCC1>[C:36]([C:33]1[CH:34]=[CH:35][C:30]([NH:29][CH:9]([C:10]2[CH:15]=[C:14]([O:16][CH2:17][CH3:18])[CH:13]=[C:12]([O:19][CH2:20][CH:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[C:11]=2[F:28])[C:8]([OH:39])=[O:7])=[CH:31][CH:32]=1)(=[NH:37])[NH2:38]
Reactant: CCOC(=O)C(Nc1ccc(C(=N)N)cc1)c1cc(OCC)cc(OCC2CCN(C)CC2)c1F
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOc1cc(OCC2CCN(C)CC2)c(F)c(C(Nc2ccc(C(=N)N)cc2)C(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.7 %

Procedure:
A solution of 340 mg (RS)-(4-carbamimidoyl-phenylamino)-[5-ethoxy-2-fluoro-3-(1-methyl-piperidin-4-ylmethoxy)-phenyl]-acetic acid ethyl ester acetate in 5 ml THF was treated with 2.8 ml 1N LiOH and stirred at room temperature for 2 hours. The reaction mixture was neutralized with acetic acid and evaporated in vacuo. The residue was stirred in 1.5 ml of water. Suction filtration and drying gave 173 mg (RS)-(4-carbamimidoyl-phenylamino)-[5-ethoxy-2-fluoro-3-(1-methyl-piperidin-4-ylmethoxy)-phenyl]-acetic acid. Mp.: 232° C. Light brown solid. MS: 459 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[NH2:32][C:33]1[N:37]=[CH:36][NH:35][N:34]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:32][C:33]3[N:37]=[CH:36][NH:35][N:34]=3)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: Nc1nc[nH]n1
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Product: Cc1cc(F)ccc1-c1nc(Nc2nc[nH]n2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Yield: 18.9 %

Procedure:
Following the general procedure outlined in Example 217, the product of Example 48 (150 mg, 0.33 mmol) and 3-amino-1,2,4-triazole (141 mg, 1.68 mmol) were reacted to give the crude material. Preparative hplc afforded the title compound 28 mg (15%). LC-MS: 450.2 (MH+, m/z), 1.79 (Rt, min).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH3:14])[CH:7]=[C:6]2[C:15]1[N:27](S(C2C=CC(C)=CC=2)(=O)=O)[C:18]2=[N:19][CH:20]=[CH:21][C:22]([CH:23]([OH:26])[CH2:24][CH3:25])=[C:17]2[CH:16]=1.[OH-].[K+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH3:14])[CH:7]=[C:6]2[C:15]1[NH:27][C:18]2=[N:19][CH:20]=[CH:21][C:22]([CH:23]([OH:26])[CH2:24][CH3:25])=[C:17]2[CH:16]=1
Reactant: CCC(O)c1ccnc2c1cc(-c1cn(C)c3cc(OC)c(OC)cc13)n2S(=O)(=O)c1ccc(C)cc1
Agent: [K+]
Agent: [OH-]
Product: CCC(O)c1ccnc2[nH]c(-c3cn(C)c4cc(OC)c(OC)cc34)cc12
Yield: 94.8 %

Procedure:
[2-(5,6-Dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyrid-4-yl]propan-1-ol is prepared as described in Example 179a starting with 0.090 g of [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-yl]propan-1-ol instead of the [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl](4-trifluoromethylsulfanylbenzyl)amine used in Example 179a and 0.80 cm3 of 5N potassium hydroxide. 0.060 g of [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]-pyrid-4-yl]propan-1-ol is obtained, the characteristics of which are as follows:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=O)[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:30]4[N:31]=[C:32]([C:34](=[O:37])[NH:35][OH:36])[N:33]=[C:29]4[N:28]=[C:27]([CH3:38])[CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1.Cl.[NH2:41][O:42][C:43]([CH3:59])([CH3:58])[C:44]([NH:46][NH:47][C:48](=[O:57])[C:49]1[CH:54]=[CH:53][C:52]([OH:55])=[C:51]([OH:56])[CH:50]=1)=[O:45]>CC(N(C)C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:41]/[O:42][C:43]([C:44](=[O:45])[NH:46][NH:47][C:48](=[O:57])[C:49]2[CH:54]=[CH:53][C:52]([OH:55])=[C:51]([OH:56])[CH:50]=2)([CH3:58])[CH3:59])/[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:30]4[N:31]=[C:32]([C:34](=[O:37])[NH:35][OH:36])[N:33]=[C:29]4[N:28]=[C:27]([CH3:38])[CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1
Reactant: CC(C)(ON)C(=O)NNC(=O)c1ccc(O)c(O)c1
Reactant: Cc1cc(SCC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)C(=O)c4csc(N)n4)[C@H]3SC2)n2nc(C(=O)NO)nc2n1
Agent: Cl
Solvent: CC(=O)N(C)C
Product: Cc1cc(SCC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)/C(=N\OC(C)(C)C(=O)NNC(=O)c4ccc(O)c(O)c4)c4csc(N)n4)[C@H]3SC2)n2nc(C(=O)NO)nc2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 72.8 %

Procedure:
(6R,7R)-7-(2-Amino-4-thiazoleglyoxylamido)-3-[[[2-(hydroxycarbamoyl)-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (60 mg) (0.101 mmol) and 40 mg (0.1318 mmol) of 1-[2-(aminooxy)-2-methylpropionyl]-2-(3,4-dihydroxybenzoyl)hydrazine hydrochloride are dissolved in 3 ml of absolute dimethylacetamide. After stirring at room temperature for 24 hours the solvent is removed at room temperature in a high vacuum. The residual oil is treated with water and the precipitated product is filtered off. The whole is washed in succession with water, ethanol and diethyl ether and dried at room temperature in a high vacuum. There are obtained 62 mg of (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[1-[3-(3,4-dihydroxybenzoyl)carbazoyl]-1-methylethoxy]imino]acetamido]-3-[[[2-(hydroxycarbamoyl)-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl]thio]methyl]- 8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid as a beige powder.
Reaction SMILES: [C:1]([O:4][C@H:5]([CH3:25])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:18](=[O:19])[C:17]2[N:16]3[CH2:20][CH2:21][NH:22][C:15]3=[N:14][C:13]=2[N:12]([CH3:23])[C:11]1=[O:24])(=[O:3])[CH3:2].C(N(C(C)C)CC)(C)C.[CH2:35]([O:37][CH2:38]Cl)[CH3:36]>C(Cl)(Cl)Cl>[C:1]([O:4][C@H:5]([CH3:25])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:18](=[O:19])[C:17]2[N:16]3[CH2:20][CH2:21][N:22]([CH2:38][O:37][CH2:35][CH3:36])[C:15]3=[N:14][C:13]=2[N:12]([CH3:23])[C:11]1=[O:24])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(nc3n2CCN3)n(C)c1=O
Reactant: CCOCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCOCN1CCn2c1nc1c2c(=O)n(CCCC[C@@H](C)OC(C)=O)c(=O)n1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.1 %

Procedure:
To a stirring solution of (R)-3-(5-acetoxyhexyl)-7,8-dihydro-1-methyl-1H-imidazo[2,1-f]-purine-2,4(3H,6H)-dione (3.5 g, 10.0 mmol) and diisopropylethylamine (10.32 g, 80 mmol) in chloroform (100 ml) was added chloromethyl ethyl ether (3.78 g, 40 mmol). After stirring at room temperature for 16 hours, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with ethyl acetate to provide (R)-3-(5-acetoxyhexyl)-7,8-dihydro-8-ethoxymethyl-1-methyl-1H-imidazo[2,1-f]-purine-2,4(3H,6H)-dione (2.0 g, 49% yield).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([NH:10][C:11]1[C:15]([C:16]([O:18]C)=O)=[CH:14][S:13][CH:12]=1)=[O:9].Cl.[F:21][C:22]([F:36])([F:35])[C:23]1[CH:24]=[C:25]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:26]=[CH:27][CH:28]=1>>[F:36][C:22]([F:21])([F:35])[C:23]1[CH:24]=[C:25]([N:29]2[CH2:34][CH2:33][N:32]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]3[C:16](=[O:18])[C:15]4=[CH:14][S:13][CH:12]=[C:11]4[NH:10][C:8]3=[O:9])[CH2:31][CH2:30]2)[CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)c1cscc1NC(=O)NCCCCCBr
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Agent: Cl
Product: O=c1[nH]c2cscc2c(=O)n1CCCCCN1CCN(c2cccc(C(F)(F)F)c2)CC1
Yield: 96.7 %

Procedure:
The title compound was prepared by the procedure in Example 18 starting with 10.13 g (29 mmol) of the N-(5-bromopentyl)-N'-(4-carbomethoxythien-3-yl]urea of Example 12 and 15.47 g (58 mmol) of 1-(3-trifluoromethylphenyl)piperazine hydrochloride. There was obtained 13.08 g (96%) of the known 3-[5-[4-(3-trifluoromethylphenyl)piperazin-1-yl]pentyl]thieno[3,4-d]pyrimidine-2,4-dione (J. Press and R. Russell, U.S. Pat. No. 4,670,560) which was crystallized from CH2Cl2 /hexane to afford a white solid, mp 118°-123° C.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([NH:9][C:10]([NH:12][C:13]2[N:14]=[C:15]3[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]3=[N:17][CH:18]=2)=[O:11])[CH2:4]1.[CH2:30]([S:32](Cl)(=[O:34])=[O:33])[CH3:31]>>[CH2:30]([S:32]([N:3]1[CH2:8][CH2:7][CH2:6][CH:5]([NH:9][C:10]([NH:12][C:13]2[N:14]=[C:15]3[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]3=[N:17][CH:18]=2)=[O:11])[CH2:4]1)(=[O:34])=[O:33])[CH3:31]
Reactant: CCS(=O)(=O)Cl
Reactant: C[Si](C)(C)CCOCn1ccc2nc(NC(=O)NC3CCCNC3)cnc21
Agent: Cl
Product: CCS(=O)(=O)N1CCCC(NC(=O)Nc2cnc3c(ccn3COCC[Si](C)(C)C)n2)C1

Procedure:
1-[(1-Ethane sulfonyl)-piperidin-3-yl]-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea was prepared in the same manner from 1-piperidin-3-yl-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea dihydrochloride and ethanesulfonyl chloride.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([NH2:11])=[N:8][C:7]=1[CH3:12])=[O:5])[CH3:2].[CH3:13][S:14](Cl)(=[O:16])=[O:15]>ClCCl.N1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([NH:11][S:14]([CH3:13])(=[O:16])=[O:15])=[N:8][C:7]=1[CH3:12])=[O:5])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1sc(N)nc1C
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1sc(NS(C)(=O)=O)nc1C
Yield: 86.6 %

Procedure:
A stirred solution of ethyl-2-amino-4-methyl-thiazole-5-carboxylate (558 mg, 3 mmol) in dichloromethane (15 mL) and pyridine (5 mL) was treated with methanesulfonyl chloride (687 mg, 6 mmol) at rt overnight. The solution was diluted with dichloromethane (50 mL) and washed with 2N aq. HCl solution (15 mL, 3×), dried (MgSO4), filtered and concentrated. The crude residue was diluted with ether (25 mL) and the solid was filtered, washed with 1:1 ether:hexane mixture (10 mL, 3×), and dried in vacuo to obtain the title compound (687 mg, 87%) as an off-white solid.
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CN(C)C=O.Cl[C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[CH:18][N:17]=1>O>[N+:22]([C:21]1[C:16]([O:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[N:17][CH:18]=[CH:19][CH:20]=1)([O-:24])=[O:23]
Reactant: Oc1ccccc1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccnc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 12.2 %

Procedure:
3.6 g (150 mmol) of sodium hydride were added, a little at a time, to a mixture of 12 g (128 mmol) of phenol and 100 ml of dimethylformamide. After the evolution of gas had ceased, the resulting mixture was treated with 18 g (114 mmol) of 2-chloro-3-nitropyridine. After the reaction mixture had been stirred at room temperature (approximately 25° C.) for 3 hours, it was treated with water. Following extraction with tert-butyl methyl ether, washing and drying the organic phase and removal of the solvent under reduced pressure, the product crystallized out. It was purified further by stirring with tert-butyl methyl ether/n-pentane. This gave 6.6 g (27%) of the title compound. A further 3.0 g (12%) of the title compound were obtained from the mother liquor.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:10]([NH:12][C@H:13]2[CH2:21][CH2:20][CH2:19][C@H:18]([O:22][CH2:23][CH2:24][CH3:25])[C@@H:17]([CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[C@H:16]([CH3:31])[O:15][C:14]2=[O:32])=[O:11])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:33](Cl)(=[O:35])[CH3:34]>C(Cl)Cl>[C:33]([O:1][C:2]1[C:3]([C:10](=[O:11])[NH:12][C@H:13]2[CH2:21][CH2:20][CH2:19][C@H:18]([O:22][CH2:23][CH2:24][CH3:25])[C@@H:17]([CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[C@H:16]([CH3:31])[O:15][C:14]2=[O:32])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH3:9])(=[O:35])[CH3:34]
Reactant: CC(=O)Cl
Reactant: CCCO[C@H]1CCC[C@H](NC(=O)c2nccc(OC)c2O)C(=O)O[C@@H](C)[C@@H]1CCC(C)C
Solvent: ClCCl
Product: CCCO[C@H]1CCC[C@H](NC(=O)c2nccc(OC)c2OC(C)=O)C(=O)O[C@@H](C)[C@@H]1CCC(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.4 %

Procedure:
To a solution of 3-hydroxy-N-((3S,7S,8S,9S)-8-isopentyl-9-methyl-2-oxo-7-propoxyoxonan-3-yl)-4-methoxypicolinamide (75 mg, 0.166 mmol) were added TEA (34.8 μL, 0.250 mmol) and acetyl chloride (17.8 μL, 0.250 mmol) in DCM (0.832 mL). The reaction was stirred at room temperature for 4 h and then treated with Celite® (3 scoopula tip-fulls). The solvent was removed under reduced pressure and the resulting adsorbed material was directly loaded onto a column and purified using flash column chromatography (24 g SiO2, 0→100% EtOAc/hexanes) to afford the title compound (74 mg, 0.150 mmol, 90%) as a white powder (hygroscopic): IR (thin film): 3383, 2953, 2871, 1772, 1737, 1678, 1506, 1197, 1173 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.53 (d, J=8.2 Hz, 1H), 8.33 (d, J=5.4 Hz, 1H), 7.00 (d, J=5.4 Hz, 1H), 4.74 (dq, J=9.9, 6.3 Hz, 1H), 4.65-4.53 (m, 1H), 3.90 (s, 3H), 3.52 (app dt, J=8.9, 6.4 Hz, 1H), 3.31-3.22 (m, 1H), 3.15 (app dt, J=8.9, 6.6 Hz, 1H), 2.43-2.30 (m, 4H), 2.22-2.07 (m, 1H), 1.96-1.84 (m, 1H), 1.83-1.69 (m, 1H), 1.68-0.98 (m, 12H), 0.96-0.84 (m, 10H); HRMS-ESI m/z [M+H]+ calcd for: C26H41N2O7, 493.2908; found 493.2936.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([CH3:14])[CH:6]=1)(=O)[CH3:2].O[CH2:16]C(CO)O.OS(O)(=O)=O>>[CH3:14][C:7]1[CH:6]=[C:5]2[C:10]([CH:16]=[CH:2][CH:1]=[N:4]2)=[CH:9][C:8]=1[N+:11]([O-:13])=[O:12]
Reactant: OCC(O)CO
Reactant: CC(=O)Nc1ccc([N+](=O)[O-])c(C)c1
Agent: O=S(=O)(O)O
Product: Cc1cc2ncccc2cc1[N+](=O)[O-]
Yield: 34.4 %

Procedure:
4-Acetamido-2-methylnitrobenzene (4.5 g; 23.2 mmol) glycerol (9 g; 100 mmol), H2SO4 conc (6.75 g) and As2O5.5H2O (3.6 g; 46.4 mmol) were heated at 130° C. for 20 h. The reaction mixture was poured on water, adjusted to pH 7-8 by adding NH3conc. and extracted with EtOAc three times. The combined organic phases were dried over Na2SO4, evaporated and purified via chromatography (SiO2; TBME/hexanes 70/30) to yield the title compound (1.5 g; 34%). The isomeric 5-methyl-6-nitroquinoline was eluted from the column after the title compound (850 mg; 19%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30](O)=[O:31])[C:25]=1[CH3:33])(=[O:12])=[O:11].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH:56]1[CH2:60][CH2:59][CH2:58][C@H:57]1[CH2:61][OH:62]>CN(C=O)C>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([N:56]2[CH2:60][CH2:59][CH2:58][C@@H:57]2[CH2:61][OH:62])=[O:31])[C:25]=1[CH3:33])(=[O:12])=[O:11]
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)O
Reactant: OC[C@@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)N1CCC[C@@H]1CO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (100 mg, 0.2 mmol) in DMF (5 mL) was added HOBt (32 mg, 1.2 eq.), EDAC.HCl (46 mg, 1.2 eq.) and TEA (50 mg, 2.5 eq.). After stirring at rt for 30 mins, to the mixture was added (S)-(+)-2-pyrrolidine methanol (2 eq.). After stirring at rt for overnight, the reaction was concentrated and the residue was purified on a silica gel column to give 52 mg of the titled compound.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][NH:9][C:10]2=[O:13])=[CH:5][CH:4]=1.Br[C:17]1[CH:18]=[N:19][CH:20]=[C:21]([F:23])[CH:22]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[F:23][C:21]1[CH:22]=[C:17]([N:9]2[CH2:8][CH2:7][C:6]3[C:11](=[CH:12][C:3]([C:2]([F:1])([F:14])[F:15])=[CH:4][CH:5]=3)[C:10]2=[O:13])[CH:18]=[N:19][CH:20]=1
Reactant: Fc1cncc(Br)c1
Reactant: O=C1NCCc2ccc(C(F)(F)F)cc21
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=C1c2cc(C(F)(F)F)ccc2CCN1c1cncc(F)c1
Yield: 26.9 %

Procedure:
Using analogous reaction conditions as described in Example 1, 7-trifluoromethyl-3,4-dihydro-2H-isoquinolin-1-one (I-16c: 90 mg, 0.419 mmol) was reacted with 3-bromo-5-fluoro-pyridine (73.67 mg, 0.419 mmol), 1,4-dioxane (10 mL), copper iodide (7.98 mg, 0.0419 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (17.85 mg, 0.126 mmol) and potassium phosphate (222 mg, 1.048 mmol) to afford the crude product. Purification by column chromatography on silica gel (0.5% methanol in DCM) afforded 35 mg of the product (27.19% yield).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@H:10]1[C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[C:42]([CH2:47][C:48]2[S:49][C:50](Br)=[CH:51][CH:52]=2)[CH:41]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:54]([C:56]1[CH:57]=[C:58](B(O)O)[CH:59]=[CH:60][CH:61]=1)#[N:55].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@H:10]1[C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[C:42]([CH2:47][C:48]2[S:49][C:50]([C:60]3[CH:59]=[CH:58][CH:57]=[C:56]([C:54]#[N:55])[CH:61]=3)=[CH:51][CH:52]=2)[CH:41]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc(Br)s1
Reactant: N#Cc1cccc(B(O)O)c1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: N#Cc1cccc(-c2ccc(Cc3cc([C@@H]4O[C@H](COCc5ccccc5)[C@@H](OCc5ccccc5)[C@H](OCc5ccccc5)[C@H]4OCc4ccccc4)ccc3Cl)s2)c1

Procedure:
A mixed solution of 1-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-chlorobenzene 53 (1.24 g) obtained in Example 119-(6), 3-cyanophenylboronic acid (270 ml), bis(triphenylphosphine)palladium (II) dichloride (54 mg) and 2M aqueous sodium carbonate solution (2.3 ml) in 1,2-dimethoxyethane (12 ml) was heated under reflux for 4 hours. The mixture was diluted with ethyl acetate and washed successively with a saturated aqueous sodium hydrogen carbonate solution and brine. The mixture was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:1-5:1) to give 1-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-4-chloro-3-(5-(3-cyanophenyl)-2-thienylmethyl)benzene (1.12 g) as colorless oil. APCI-Mass m/Z 849/851 (M+NH4). (2) The above 1-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-4-chloro-3-(5-(3-cyanophenyl)-2-thienylmethyl)benzene was used and treated in a manner similar to Example 3-(3) to give the target compound as colorless powder. APCI-Mass m/Z 489/491 (M+NH4).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[O:6][C:7]3[CH:18]=[CH:17][CH:16]=[CH:15][C:8]=3[CH2:9][N:10]([C:11]([NH:13][NH2:14])=[O:12])[C:4]=2[CH:3]=1.C(N(CC)CC)C.[C:28](Cl)(=[O:37])[CH:29]=[CH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1C=CC=CC=1>[C:28]([NH:14][NH:13][C:11]([N:10]1[CH2:9][C:8]2[CH:15]=[CH:16][CH:17]=[CH:18][C:7]=2[O:6][C:5]2[CH:19]=[CH:20][C:2]([Cl:1])=[CH:3][C:4]1=2)=[O:12])(=[O:37])[CH:29]=[CH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: O=C(C=Cc1ccccc1)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution containing 1.45 parts of 8-chloro-10,11-dihydrodibenz[b,f][1,4]oxazepine-10-carboxylic acid hydrazide dissolved in 50 parts by volume of benzene is added successively0.7 part by volume of triethylamine and 0.81 part of cinnamoyl chloride. The resulting reaction mixture is stirred at room temperature for about 48hours, then is washed successively with dilute hydrochloric acid, dilute aqueous sodium hydroxide, water and saturated aqueous sodium chloride. Drying over anhydrous sodium sulfate followed by removal of the solvent bydistillation under reduced pressure affords a residue, which is purified byadsorption on a silicic acid chromatographic column and elution with ethyl acetate-benzene mixtures. The 10% acetate in benzene eluate, upon removal of the solvents, affords 1-cinnamoyl-2-(8-chloro-10,11-dihydrodibenz[b,f][1,4]oxazepine-10-carbonyl)hydrazine.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:13])[CH3:12])=[C:7]([OH:14])[C:6]=1[CH2:15][CH2:16][CH3:17].[CH2:18]([O:20][C:21](=[O:29])[C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)[CH3:19].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C=O)C>[CH2:18]([O:20][C:21](=[O:29])[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:2][CH2:3][O:4][C:5]2[CH:10]=[CH:9][C:8]([C:11](=[O:13])[CH3:12])=[C:7]([OH:14])[C:6]=2[CH2:15][CH2:16][CH3:17])=[CH:24][CH:23]=1)[CH3:19]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: CCCc1c(OCCBr)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(OCCOc2ccc(C(=O)OCC)cc2)ccc(C(C)=O)c1O

Procedure:
A mixture of 1.5 g of 1-[4-(2-bromoethoxy)-2-hydroxy-3- propylphenyl]ethanone 0.83 g of 4-hydroxybenzoic acid ethyl ester and 0.95 g of anhydrous potassium carbonate in 30 ml of anhydrous acetone and 10 ml of anhydrous DMF was stirred at reflux for 20 hours. The mixture was filtered and solvent was removed in vacuo. The residue was dissolved in ethyl acetic and washed with water. The extract was dried over magnesium sulfate) and concentrated in vacuo to an oil which was purified by HPLC using 25% ethyl acetate-hexane to give 1.3 g, m.p. 99-100 (75%) of 4-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]-benzoic acid ethyl ester, the title compound. Analysis Calculated for C22H26O6 : C, 68.36; H, 6.78. Found: C, 68.39; H, 6.79.