Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:13]=[CH:12][C:11]([C:14](=[N:16][O:17][CH2:18][CH2:19][OH:20])[CH3:15])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[C:22]1[CH:54]=[CH:53][C:25]([CH2:26][CH:27]2[S:31][C:30](=[O:32])[N:29]([C:33]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28]2=[O:52])=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[C:1]1([S:7][C:8]2[CH:13]=[CH:12][C:11]([C:14](=[N:16][O:17][CH2:18][CH2:19][O:20][C:22]3[CH:54]=[CH:53][C:25]([CH2:26][CH:27]4[S:31][C:30](=[O:32])[N:29]([C:33]([C:46]5[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=5)([C:40]5[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=5)[C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[C:28]4=[O:52])=[CH:24][CH:23]=3)[CH3:15])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=NOCCO)c1ccc(Sc2ccccc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(=NOCCOc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1)c1ccc(Sc2ccccc2)cc1
Yield: 88.5 %

Procedure:
Following a procedure similar to that described in Example 1(a), but using 862 mg of 2-[1-(4-phenylthiophenyl)ethylideneaminooxy]ethanol (prepared as described in Preparation 36), 1.40 g of 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione, 866 mg of triphenylphosphine and 549 mg of diethyl azodicarboxylate, 1.95 g of the title compound were obtained as a foam-like solid.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.C(N(C(C)C)CC)(C)C.[Cl:24][C:25]1[CH:33]=[C:32]([C:34]#[N:35])[CH:31]=[CH:30][C:26]=1[C:27](Cl)=[O:28]>ClCCl>[Cl:24][C:25]1[CH:33]=[C:32]([CH:31]=[CH:30][C:26]=1[C:27]([N:7]1[C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[CH2:10][N:4]2[CH:3]=[CH:2][CH:1]=[C:5]2[CH2:6]1)=[O:28])[C:34]#[N:35]
Reactant: N#Cc1ccc(C(=O)Cl)c(Cl)c1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: N#Cc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)c(Cl)c1
Reaction time: 1 h

Procedure:
To a stirred suspension of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (7.32 g) and diisopropylethylamine (13.6 ml) in dichloromethane (35 ml) was added under nitrogen the cloudy solution of 2-chloro-4-cyanobenzoyl chloride. After one hour at room temperature, the mixture was diluted with dichloromethane and washed sequentially with water, 5% sodium bicarbonate, and 50% saturated brine, After drying over anhydrous sodium sulfate, the solvent was removed in vacuo to afford a crude product (18.0 g). Purification by column chromatography on silica gel (250 g), eluting with 20% ethyl acetate/hexane, followed by 25% ethyl acetate/hexane, yielded the title compound (13.56 g) as a straw yellow foam, MS (EI), m/z: 347 (M)+.
Reaction SMILES: [C:1]([NH:9][CH2:10][C:11]1([C:17]([O:19]CC)=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].O>C(O)C>[C:1]([NH:9][CH2:10][C:11]1([C:17]([OH:19])=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1(CNC(=O)c2ccccc2)CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(NCC1(C(=O)O)CCCCC1)c1ccccc1
Yield: 74.5 %

Procedure:
To a solution of ethyl 1-[(benzoylamino)methyl]cyclohexanecarboxylate (10.2 g, 35.1 mmol) in ethanol (50 ml) was added 50% aqueous potassium hydroxide solution (4 ml), and the mixture was heated under reflux for 6 hrs. Water (400 ml) was added and the reaction mixture was washed with diethyl ether. The aqueous layer was acidified (pH 2) with 5N hydrochloric acid, the precipitate was collected by filtration, washed with water and dried at 50° C. under reduced pressure. Recrystallization from ethanol-toluene gave the title compound (6.83 g, 74%) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:11][CH3:12])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.[H-].[Na+].[CH3:15]I>CN(C)C=O.O.C(OCC)(=O)C>[Br:1][C:2]1[C:3]([O:11][CH3:12])=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:15])[N:6]=[CH:5]2
Reactant: CI
Reactant: COc1c(Br)ccc2[nH]ncc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1c(Br)ccc2c1cnn2C
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 65.6 %

Procedure:
A solution of 5-bromo-4-methoxy-1H-indazole (0.125 g, 0.550 mmol) in N,N-dimethylformamide (2.20 mL) was treated with sodium hydride (0.0166 g, 0.659 mmol) at 20° C. and then stirred at 20° C. for 30 min. The resultant reaction mixture was treated with methyl iodide (0.0410 mL, 0.658 mmol) and stirred at 20° C. for 1 h. The reaction mixture was diluted with water and ethyl acetate. Layers were separated and the organic layer was washed with brine, dried with sodium sulfate, filtered, and concentrated in vacuo to give the crude product. Purification by flash column chromatography (100% hexanes to 100% EtOAc) gave the desired product (87 mg, 66%) as a white solid. LCMS calculated for C9H10BrN2O (M+H)+: m/z=241.0, 243.0. found: 240.9, 242.9.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:11][CH:12]=1.C(O[B:26]1[O:30][C:29]([CH3:32])([CH3:31])[C:28]([CH3:34])([CH3:33])[O:27]1)(C)C>C1COCC1>[N:17]1([CH2:16][CH2:15][CH2:14][O:13][C:10]2[CH:9]=[CH:8][C:7]([B:26]3[O:30][C:29]([CH3:32])([CH3:31])[C:28]([CH3:34])([CH3:33])[O:27]3)=[CH:12][N:11]=2)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: Brc1ccc(OCCCN2CCCC2)nc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccc(OCCCN3CCCC3)nc2)OC1(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.5 %

Procedure:
n-Butyllithium (5.68 mL, 14.20 mmol) was added dropwise to a mixture of 5-bromo-2-(3-pyrrolidin-1-ylpropoxy)pyridine (2.7 g, 9.47 mmol) and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.64 g, 14.20 mmol) in THF (20 mL) at −78° C. over a period of 10 minutes under an inert atmosphere. The resulting mixture was allowed to warm to ambient temperature and stirred for 12 h. The reaction mixture was quenched by the addition of a sat. aqueous solution of ammonium chloride, extracted with EtOAc (2×50 mL) and the organic layer dried over Na2SO4, filtered and evaporated to afford the desired material (3.10 g, 99%) as a yellow oil. The product was used in the next step directly without further purification, NMR Spectrum: 1H NMR (400 MHz, CDCl3) δ 1.26-1.41 (12H, m), 1.77-1.80 (4H, m), 1.95-2.04 (2H, m), 2.50-2.58 (4H, m), 2.62 (2H, t), 4.37 (2H, t), 6.69 (1H, d), 7.91 (1H, d), 8.52 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=251.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[CH:13][N:14]=[CH:15]2)=[CH:10][CH:9]=1.Br[CH:19]([CH2:25][CH2:26][CH3:27])[C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(#N)C>[CH:15]1[C:16]2[C:11](=[CH:10][CH:9]=[C:8]([O:7][CH:19]([CH2:25][CH2:26][CH3:27])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:17]=2)[CH:12]=[CH:13][N:14]=1
Reactant: CCCC(Br)C(=O)OCC
Reactant: Oc1ccc2ccncc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCCC(Oc1ccc2ccncc2c1)C(=O)OCC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
6.70 g (20.6 mmol) of caesium carbonate are added to a solution of 3.00 g (20.7 mmol) of 7-hydroxyisoquinoline and 4.33 g (20.7 mmol) of ethyl 2-bromopentanoate in 30 ml of acetonitrile, and the mixture is stirred at room temperature for 18 hours. The reaction mixture is filtered, and the filtrate is evaporated, giving ethyl 2-(isoquinolin-7-yloxy)-pentanoate as a colourless solid; ESI 274.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[N:10]=[C:4]2[N:3]=1.[NH:15]1[C:23]2[C:18](=[CH:19][C:20](B(O)O)=[CH:21][CH:22]=2)[CH:17]=[CH:16]1.C(O)(C(F)(F)F)=O>O.CC#N>[NH:15]1[C:23]2[C:18](=[CH:19][C:20]([C:2]3[CH:7]=[CH:6][N:5]4[C:8]5[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=5[N:10]=[C:4]4[N:3]=3)=[CH:21][CH:22]=2)[CH:17]=[CH:16]1
Reactant: Brc1ccn2c(n1)nc1ccccc12
Reactant: OB(O)c1ccc2[nH]ccc2c1
Solvent: O
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: c1ccc2c(c1)nc1nc(-c3ccc4[nH]ccc4c3)ccn12
Yield: 50 %

Procedure:
The title compound was prepared using General Experimental Procedure A (Suzuki coupling reaction) from 2-bromobenzo[4,5]imidazo[1,2-a]pyrimidine and (1H-indol-5-yl)boronic acid on a 0.12 mmol scale. The crude product was subjected to reversed phase HPLC (TFA buffered water/MeCN) to afford 2-(1H-indol-5-yl)benzo[4,5]imidazo[1,2-a]pyrimidine (T759) as a orange solid (20 mg, 50%). 1H NMR (400 MHz, DMSO-d6): 9.85 (d, J=7.2 Hz, 1H), 8.80 (s, 1H), 8.52 (d, J=8.0 Hz, 1H), 8.46 (d, J=7.2 Hz, 1H), 8.26 (dd, J=8.8, 1.2 Hz, 1H), 7.87 (d, J=7.6 Hz, 1H), 7.77 (t, J=7.2 Hz, 1H), 7.68-7.64 (m, 2H), 7.55 (t, J=2.4 Hz, 1H), 6.70 (m, 1H); MS (ESI) m/z [M+H]+285.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]([CH2:12][C:13]([OH:15])=O)=[CH:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH2:16]([NH-:19])[CH2:17][CH3:18]>>[CH2:16]([NH:19][C:13](=[O:15])[CH2:12][C:10]1[O:9][C:8]2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=2[CH:11]=1)[CH2:17][CH3:18]
Reactant: COc1cccc2cc(CC(=O)O)oc12
Reactant: CCC[NH-]
Product: CCCNC(=O)Cc1cc2cccc(OC)c2o1
Yield: 75 %

Procedure:
Following the procedure of Example 1 Part B, but using 1.19 g of 7-methoxy-3-benzofuranacetic acid and 0.53 g of n-propylamide in place of cyclopropylmethylamine, and heating to 48° for 19 hours, there was obtained 1.07 g (96%) of N-(n-propyl)-7-methoxy-3-benzofuranacetamide as a solid. NMR spectrum (200 mHz in CDCl3): δ0.8 (t, J=7 Hz, 3H), 1.4 (m, 2H), 3.15 (q, J=6 Hz, 2H), 3.63 (s, 2H), 4.0 (s, 3H), 5.5-5.7 (broad s, 1H), 6.85 (d/d, J=7.0/0.5 Hz, 1H) 7.1-7.3 (m, 2H) and 7.61 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9](Cl)(=[O:12])[CH:10]=[CH2:11].C(N(CC)CC)C>O1CCCC1>[C:9]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=1)(=[O:12])[CH:10]=[CH2:11]
Reactant: Nc1ccc(F)cc1
Reactant: C=CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CC(=O)Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
4-Fluoroaniline (7 ml) and acryloyl chloride (7.2 ml) were dissolved in tetrahydrofuran (100 ml), then triethylamine (15 ml) was added thereto, and the mixture was stirred overnight at room temperature. The organic layer was partitioned by adding aqueous saturated sodium bicarbonate and ethyl acetate, and the organic layer was washed with water and dried over sodium sulfate anhydrous, and after the drying agent was filtered off, the filtrate was evaporated, whereby the title compound (12.2g, 100%) was obtained as pale yellow solid.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.[CH2:24]([O:31][NH:32][C:33]([C@H:35]1[CH2:40][N:39]([S:41]([N:44]([CH3:46])[CH3:45])(=[O:43])=[O:42])[CH2:38][CH2:37][N:36]1[S:47]([N:50]1[CH2:55][CH2:54][CH:53]([C:56]2[C:64]3[C:59](=[CH:60][CH:61]=[C:62]([C:65]#[N:66])[CH:63]=3)[N:58](S(CC[Si](C)(C)C)(=O)=O)[CH:57]=2)[CH2:52][CH2:51]1)(=[O:49])=[O:48])=[O:34])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>Cl>[CH2:24]([O:31][NH:32][C:33]([C@H:35]1[CH2:40][N:39]([S:41]([N:44]([CH3:46])[CH3:45])(=[O:43])=[O:42])[CH2:38][CH2:37][N:36]1[S:47]([N:50]1[CH2:51][CH2:52][CH:53]([C:56]2[C:64]3[C:59](=[CH:60][CH:61]=[C:62]([C:65]#[N:66])[CH:63]=3)[NH:58][CH:57]=2)[CH2:54][CH2:55]1)(=[O:49])=[O:48])=[O:34])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CN(C)S(=O)(=O)N1CCN(S(=O)(=O)N2CCC(c3cn(S(=O)(=O)CC[Si](C)(C)C)c4ccc(C#N)cc34)CC2)[C@@H](C(=O)NOCc2ccccc2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)N1CCN(S(=O)(=O)N2CCC(c3c[nH]c4ccc(C#N)cc34)CC2)[C@@H](C(=O)NOCc2ccccc2)C1
Yield: 99 %

Procedure:
A solution of tetrabutylammonium fluoride in tetrahydrofuran (1.54 ml, 1.54 mmol) was added to a solution of N-benzyloxy-1-{4-[5-cyano-1-(2-trimethylsilylethanesulfonyl)-indole-3-yl]piperidine-1-sulfonyl}4-(N,N-dimethylaminosulfonyl)piperazine-2-(R)-carboxamide (0.49 g, 0.62 mmol) and the reaction was placed in a 55° C. oil bath for 30 min. The reaction was diluted with 1 M HCl and concentrated in vacuo. The residue was extracted with ethyl acetate and the organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo to give N-benzyloxy-1-[4-(5-cyanoindol-3-yl)piperidine-1-sulfonyl]-4-(N,N-dimethylamino-sulfonyl)piperazine-2-(R)-carboxamide (99%) as a tan solid. This material was converted to N-hydroxy-1-[4-(5-cyanoindol-3-yl)piperidine-1-sulfonyl]4-(N,N-dimethylamino-sulfonyl)piperazine-2-(R)-carboxamide by following Example 16, Step 5.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16](O)=[O:17])=[N:4][NH:3]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl.[F:47][C:48]([F:59])([F:58])[C:49]1[N:53]2[CH2:54][CH2:55][NH:56][CH2:57][C:52]2=[N:51][N:50]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O.O>[F:59][C:48]([F:58])([F:47])[C:49]1[N:53]2[CH2:54][CH2:55][N:56]([C:16]([C:15]3[CH:14]=[C:13]([CH2:12][C:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C:2](=[O:1])[NH:3][N:4]=4)[CH:21]=[CH:20][CH:19]=3)=[O:17])[CH2:57][C:52]2=[N:51][N:50]=1
Reactant: FC(F)(F)c1nnc2n1CCNC2
Reactant: O=C(O)c1cccc(Cc2n[nH]c(=O)c3ccccc23)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1cccc(Cc2n[nH]c(=O)c3ccccc23)c1)N1CCn2c(nnc2C(F)(F)F)C1
Reaction time: 12 h
Yield: 20.6 %

Procedure:
3-[(4-Oxo-3H-phthalazin-1-yl)methyl]benzoic acid 15a (300 mg, 1.07 mmol, prepared according to a known method disclosed by “patent application WO2004080976”) was dissolved in 10 mL of N,N-dimethylformamide, followed by addition of O-(1-benzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (730 mg, 1.93 mmol), 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride 1b (269 mg, 1.40 mmol) and N,N-diisopropylethylamine (0.9 mL, 5.30 mmol). After stirring for 12 hours, the reaction mixture was added with 15 mL of H2O, extracted with ethyl acetate (20 mL×3). The organic phase was combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain 4-[[3-[3-(trifluoromethyl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazine-7-carbonyl]phenyl]methyl]-2H-phthalazin-1-one 15 (100 mg, yield 20.6%) as a white solid.
Reaction SMILES: [OH:1][NH:2][CH2:3][CH2:4][CH2:5][P:6](=[O:9])([OH:8])[OH:7].C[Si](C([Si](C)(C)C)C(N)=O)(C)C.ClCCl.[CH3:25][N:26]=[C:27]=[S:28]>O>[OH:1][N:2]([CH2:3][CH2:4][CH2:5][P:6](=[O:8])([OH:7])[OH:9])[C:27](=[S:28])[NH:26][CH3:25]
Reactant: O=P(O)(O)CCCNO
Reactant: CN=C=S
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Solvent: ClCCl
Solvent: O
Product: CNC(=S)N(O)CCCP(=O)(O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 13.3 %

Procedure:
A mixture of 3-(N-hydroxyamino)propylphosphonic acid (1.64 g), bis(trimethylsilyl)acetamide (10 g) and dichloromethane (30 ml) was stirred at ambient temperature for 3 hours and cooled to 0°-5° C. To the mixture was added methylisothiocyanate (800 mg) under ice-cooling. The reaction mixture was stirred at the same temperature for an hour and concentrated under reduced pressure to give a residue. To this residue was added water (50 ml) and stirred at ambient temperature for 30 minutes. After the remaining dichloromethane was removed by evaporation under reduced pressure, an additional 50 ml of water was added. The aqueous solution was subjected to a column chromatography using activated charcoal. The column was washed with water (650 ml) and then the object compound was eluted with 70% aqueous acetone. The eluate was concentrated under reduced pressure to give crystals, which were separated by filtration, washed with ethanol and dried to give crystalline 3-[N-hydroxy-N-{(N-methyl)thiocarbamoyl}amino]propylphosphonic acid (320 mg). Further, the ethanol washing was concentrated under reduced pressure to give a residue which was pulverized to give the same object compound (450 mg). Mp 190°-194° C. (dec.).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[O:9])[S:8][C:4]=2[CH:3]=1.Cl[CH2:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:18][CH2:17]1)=[O:15]>C(OCC)C>[F:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][CH:19]2[CH2:20][CH2:21][N:16]([C:14](=[O:15])[CH2:13][NH:1][C:2]3[CH:11]=[CH:10][C:5]4[NH:6][C:7](=[O:9])[S:8][C:4]=4[CH:3]=3)[CH2:17][CH2:18]2)=[CH:24][CH:25]=1
Reactant: Nc1ccc2[nH]c(=O)sc2c1
Reactant: O=C(CCl)N1CCC(Cc2ccc(F)cc2)CC1
Solvent: CCOCC
Product: O=C(CNc1ccc2[nH]c(=O)sc2c1)N1CCC(Cc2ccc(F)cc2)CC1

Procedure:
The title compound is prepared from 6-amino-3H-benzothiazol-2-one and 2-chloro-1-[4-(4-fluoro-benzyl)-piperidin-1-yl]-ethanone (Example 197a) according to the method described in Example 206. Melting Point: 149-155° C. (diethylether)
Reaction SMILES: [CH3:1][C:2]1[C:3]([OH:16])=[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[OH:15])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH:26](Cl)[C:27]([OH:29])=[O:28]>CC(O)C>[CH3:1][C:2]1[C:3]2[O:16][CH:26]([C:27]([OH:29])=[O:28])[O:15][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[CH2:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(Cc2ccccc2O)c1O
Reactant: O=C(O)C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)O
Product: Cc1cccc2c1OC(C(=O)O)Oc1ccccc1C2
Reaction time: 30 h

Procedure:
(3-Methyl-2-hydroxyphenyl)(2-hydroxyphenyl)-methane (3.4 g, 16 mmol), potassium carbonate (8.84 g, 64 mmol), potassium iodide (0.53 g, 3.2 mmol), dichloroacetic acid (2.06 g, 16 mmol), and 65 ml of 2-propanol were heated at reflux with stirring under nitrogen for 30 hours. Another 2.05 g (16 mmol) of dichloroacetic acid was added and heating at reflux continued for 60 hours. The 2-propanol was then removed by evaporation under reduced pressure and the residue was diluted with distilled water and acidified with 2N hydrochloric acid. This mixture was extracted with ether and the ether extract was dried over magnesium sulfate and evaporated under reduced pressure to obtain 1.8 g (42 percent of theory) of the title compound as a solid residue. A purified sample melting at 171° C. was obtained by recrystallization from a mixture of methylcyclohexane and acetone. The proton nmr spectrum was consistent with the assigned structure.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([CH:7]1[CH2:12][CH2:11][CH2:10][NH2+:9][CH2:8]1)=[O:6])[CH3:3].Br[CH2:14][CH2:15][Cl:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:16][CH2:15][CH2:14][N:9]1[CH2:10][CH2:11][CH2:12][CH:7]([C:5]([O:4][CH2:2][CH3:3])=[O:6])[CH2:8]1
Reactant: ClCCBr
Reactant: CCOC(=O)C1CCC[NH2+]C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1CCCN(CCCl)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 3-(ethoxycarbonyl)piperidinium hydrochloride (10 g, 65 mmol) in acetone was treated with 1-bromo-2-chloroethane (14.7 g, 0.1 mol) and anhydrous potassium carbonate (13.8 g, 0.1 mol) and the mixture stirred at room temperature for 24 h, the mixture was concentrated and the reside was treated with water and extracted with ether. The extracts were combined and concentrated and the crude was purified by chromatography (silica gel, ethyl acetate:petroleum ether 1:5) to give ethyl 1-(2-chloroethyl)piperidine-3-carboxylate. (3.73 g, Y: 26%). 1HNMR (400 MHz, CDCl3); δ: 1.25 (t, J=7 Hz, 3H), 1.40-3.10 (m, 11H), 3.58 (t, J=7 Hz, 2H), 4.15 (q, 2H). LC-MS (ESI) (m/z): 220 (M+1)+.
Reaction SMILES: [C:1]1([C:7]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:8]2[CH:12]=[N:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]3[CH:19]=[C:20]([CH2:24][NH2:25])[CH:21]=[CH:22][CH:23]=3)=[N:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:38]=[C:39]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[N:42]=[C:41]([C:49](OCC)=[O:50])[NH:40]1.C(N(CC)C(C)C)(C)C>CCO>[O:38]=[C:39]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[N:42]=[C:41]([C:49]([NH:25][CH2:24][C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([O:17][CH2:16][CH2:15][CH2:14][O:13][C:10]3[N:11]=[CH:12][N:8]([C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[N:9]=3)[CH:19]=2)=[O:50])[NH:40]1
Reactant: NCc1cccc(OCCCOc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Reactant: CCOC(=O)c1nc2ccccc2c(=O)[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: O=C(NCc1cccc(OCCCOc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1)c1nc2ccccc2c(=O)[nH]1
Temperature: 25 °C
Yield: 78 %

Procedure:
A suspension of 1-{3-[(3-{[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]oxy}propyl)oxy]phenyl}methanamine obtained in Reference Example 85 (0.300 g, 0.611 mmol), ethyl 4-oxo-3,4-dihydro-2-quinazolinecarboxylate obtained according to the methods described in Journal of Organic Chemistry (1978), 43(23), 4485-7 and the like (0.133 g, 0.611 mmol) and N,N-diisopropylethylamine (0.213 mL, 1.22 mmol) in EtOH (4.5 mL) was stirred under microwave irradiation at 100° C. for 1.5 hr (Discover (trademark; CEM Corp), 50 W, run time: 5 min, hold time: 1.5 hr). After the reaction mixture was allowed to cool to room temperature, the precipitated solid was collected by filtration, and washed with EtOH to give the title compound as a white powder (0.315 g, 78%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=3)[CH:17]=2)[CH:12]=[C:11](Cl)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:28]1[CH:33]=[CH:32][CH:31]=[C:30](B(O)O)[CH:29]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=3)[CH:17]=2)[CH:12]=[C:11]([C:30]2[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cccc(-c2ccc3cc(Cl)nc(OCc4ccccc4)c3c2)c1
Reactant: OB(O)c1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cccc(-c2ccc3cc(-c4cccnc4)nc(OCc4ccccc4)c3c2)c1

Procedure:
To a mixture of 1-(benzyloxy)-3-chloro-7-(3-methoxyphenyl)isoquinoline (150 mg, 0.40 mmol, 1.0 eq), pyridin-3-ylboronic acid (74 mg, 0.60 mmol, 1.5 eq), K2CO3 (166 mg, 1.20 mmol, 3.0 eq) in dioxane (2 ml) and H2O (1 mL) was added Pd(PPh3)2Cl2 (14 mg, 0.02 mmol, 0.05 eq) under N2 atmosphere. The sealed tube was irradiated in the CEM microwave at 130° C. for 1 h. After the reaction was completed, the volatiles were removed in vacuo and the residue was purified with chromatography on silica gel (hexane/ethyl acetate 50:1) to give 200 mg of crude lxvii-a as a brown oil, which was used directly in the next step without purification, LCMS m/z=419.0 (M+1) (Method B) (retention time=2.25 min).
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH2:13])=[CH:6][C:7]2[O:11][CH2:10][O:9][C:8]=2[CH:12]=1)([O-])=[O:2].[N:14]#[C:15][NH2:16].[CH]Cl.[OH-].[Na+]>O>[N+:1]1([O-:2])[C:4]2[CH:12]=[C:8]3[O:9][CH2:10][O:11][C:7]3=[CH:6][C:5]=2[N:13]=[C:15]([NH2:16])[N:14]=1
Reactant: N#CN
Reactant: Nc1cc2c(cc1[N+](=O)[O-])OCO2
Agent: [CH]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1nc2cc3c(cc2[n+]([O-])n1)OCO3
Temperature: 50 °C
Reaction time: 3 h
Yield: 51.5 %

Procedure:
A mixture of nitroaniline 220 (5.55 g, 30.5 mmol) and cyanamide (5.37 g, 122 mmol) were melted together at 100° C., cooled to 50° C., cHCl (15 mL) added dropwise and the mixture heated at 100° C. for 4 h. The mixture was cooled to 50° C., 7.5 M NaOH solution added until the mixture was strongly basic and the mixture stirred at 100° C. for 3 h. The mixture was cooled, diluted with water (200 mL), filtered, washed with water (3×30 mL), washed with ether (3×5 mL) and dried to give 1-oxide 221 (3.24 g, 51%) as a yellow powder: mp (MeOH/DCM) 290-295° C.; 1H NMR [(CD3)2SO] δ 7.45 (s, 1H, H-9), 7.00 (br s, 2H, NH2), 6.94 (s, 1H, H-5), 6.23 (s, 2H, H-7); 13C NMR [(CD3)2SO] δ 160.0, 155.1, 149.0, 147.0, 125.3, 103.1, 101.3, 95.8. Anal. calcd for CBH6N4O3: C, 46.6; H, 2.9; N, 27.2. Found: C, 46.7; H, 2.9; N, 27.3%.