Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.[O:7]1[CH2:12][CH2:11][C:10]2([C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH2:13]2)[CH2:9][CH2:8]1.Cl.CN(C)CCCN=C=NCC.[CH3:33][N:34]1[C:39](=[O:40])[CH:38]=[C:37]([N:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)[N:36]=[C:35]1[CH2:47][C:48]([O-])=[O:49].[Na+]>CN(C)C=O>[CH3:33][N:34]1[C:39](=[O:40])[CH:38]=[C:37]([N:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)[N:36]=[C:35]1[CH2:47][C:48](=[O:49])[N:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:10]2([CH2:11][CH2:12][O:7][CH2:8][CH2:9]2)[CH2:13]1
Reactant: c1ccc2c(c1)NCC21CCOCC1
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cn1c(CC(=O)N2CC3(CCOCC3)c3ccccc32)nc(N2CCOCC2)cc1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 5.3 %

Procedure:
3.8 ml of pyridine, 378 mg of 1,2,2′,3′,5′,6′-hexahydrospiro[3H-indole-3,4′-[4H]pyran] and 575 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride are successively added to a solution of 770 mg of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate (example 4d, step 2d) in 11.3 ml of N,N-dimethylformamide. The reaction mixture is stirred at ambient temperature for 16 hours, and then concentrated under reduced pressure. The residue is taken up in 15 ml of water and 20 ml of ethyl acetate, and then left to stir at ambient temperature for 1 hour. The precipitate formed is filtered off, and then rinsed successively with water and diethyl ether. 45 mg of 3-methyl-6-(morpholin-4-yl)-2-[2-oxo-2-(2′,3′,5′,6′-tetrahydrospiro[indole-3,4′-pyran]-1(2H)-yl)ethyl]pyrimidin-4(3H)-one are thus obtained in the form of an off-white powder, the characteristics of which are the following:
Reaction SMILES: [Na].[CH2:2]([N:9]1[C:17]2[C:16](=[O:18])[N:15]([CH2:19][CH2:20][CH2:21][OH:22])[C:14](=[O:23])[N:13]([CH2:24][CH3:25])[C:12]=2[N:11]=[C:10]1Cl)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:27]([OH:29])[CH3:28]>>[CH2:2]([N:9]1[C:17]2[C:16](=[O:18])[N:15]([CH2:19][CH2:20][CH2:21][OH:22])[C:14](=[O:23])[N:13]([CH2:24][CH3:25])[C:12]=2[N:11]=[C:10]1[O:29][CH2:27][CH3:28])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCO
Reactant: CCn1c(=O)n(CCCO)c(=O)c2c1nc(Cl)n2Cc1ccccc1
Agent: [Na]
Product: CCOc1nc2c(c(=O)n(CCCO)c(=O)n2CC)n1Cc1ccccc1
Temperature: 40 °C
Reaction time: 4 h
Yield: 77.9 %

Procedure:
A solution of sodium (50 mg, 2.17 mmol) in ethyl alcohol (10 mL) was stirred at 40° C. under nitrogen until the sodium was consumed. Then 7-benzyl-8-chloro-3-ethyl-1-(3-hydroxypropyl)-1H-purine-2,6(3H,7H)-dione (150 mg, 0.414 mmol) was added at 0° C. and the mixture was stirred at 40° C. for 4 h. The mixture was quenched with ice-water (15 mL) and concentrated. The aqueous residue was extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated to give 7-benzyl-8-ethoxy-3-ethyl-1-(3-hydroxypropyl)-1H-purine-2,6(3H,7H)-dione (120 mg, 77.9% yield) as yellow solid. LCMS retention time 1.488 min; LCMS MH+ 373.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:12]1[C:16]2[CH:17]=[CH:18][C:19]([CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([NH:28][C:29]4[C:38]5[C:33](=[CH:34][CH:35]=[C:36]([O:39][CH3:40])[CH:37]=5)[O:32][C:31](=[O:41])[CH:30]=4)[CH2:24][CH2:23]3)=[CH:20][C:15]=2[O:14][CH2:13]1.[Cl:42]N1C(=O)CCC1=O.C(O)(=O)C>C(#N)C>[O:12]1[C:16]2[CH:17]=[CH:18][C:19]([CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([NH:28][C:29]4[C:38]5[C:33](=[CH:34][CH:35]=[C:36]([O:39][CH3:40])[CH:37]=5)[O:32][C:31](=[O:41])[C:30]=4[Cl:42])[CH2:24][CH2:23]3)=[CH:20][C:15]=2[O:14][CH2:13]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc2oc(=O)cc(NC3CCN(Cc4ccc5c(c4)OCO5)CC3)c2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: CC(=O)O
Product: COc1ccc2oc(=O)c(Cl)c(NC3CCN(Cc4ccc5c(c4)OCO5)CC3)c2c1

Procedure:
The 4-(1-Benzo[1,3]dioxol-5-ylmethyl-piperidin-4-ylamino)-6-methoxy-chromen-2-one para-toluene sulfonic acid salt (0.025 g, 0.043 mmol), N-chlorosuccinimide (0.0061 g, 0.046 mmol), and 0.2 mL Acetic Acid were shaken at room temperature overnight. Solution was diluted with Acetonitrile and purified on a C-18 RP HPLC. Product fractions were combined, treated with K2CO3, extracted with CH2Cl2, dried over sodium sulfate and concentrated to dryness to give the title compound as an off white solid. MS ESI(+)Q1MS m/z 451 (M−H)+; 1H NMR (300 MHz, CDCl3) δ ppm partially buried 1.47-1.78 (m, 2H), 2.03-2.21 (m, 4H), 2.8-2.91 (br d, 2H), 3.39-3.46 (s, 2H), 3.8-3.87 (s, 3H), 4.01-4.13 (m, 1H), 4.83-4.91 (br s, 1H), 5.93-5.97 (s, 2H), 6.71-6.78 (m, 2H), 6.83-6.86 (s, 1H), 7.05-7.16 (m, 2H), 7.27-7.36 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Br:11])[N:3]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13].S(=O)(=O)(O)O.O>C(O)(=O)C.CCOCC>[C:12]([NH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Br:11])[N:3]=1)(=[O:14])[CH3:13]
Reactant: Nc1nc(Br)ccc1[N+](=O)[O-]
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1nc(Br)ccc1[N+](=O)[O-]
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 2-amino-6-bromo-3-nitropyridine (23.9 g) in acetic acid (48 ml) were added acetic anhydride (48 ml) and sulfuric acid (2.9 ml), and the mixture was heated at 65° C. for 40 min. The mixture was uniform so that it quickly became a suspension containing a precipitate. After cooling, the reaction mixture was poured into cold water (480 ml) and the mixture was stirred for 30 min. The precipitate was collected by filtration and washed with water to give a crude product. The crude product was suspended in ether (60 ml) and collected by filtration to give the objective compound (27.2 g) as a pale-yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.[CH2:11]([Mg]Br)[CH2:12][CH:13]=[CH2:14]>C1COCC1>[CH2:14]([C:6]1[CH:7]=[C:2]([Cl:1])[N:3]=[C:4]([S:9][CH3:10])[N:5]=1)[CH2:13][CH:12]=[CH2:11]
Reactant: C=CCC[Mg]Br
Reactant: CSc1nc(Cl)cc(Cl)n1
Solvent: C1CCOC1
Product: C=CCCc1cc(Cl)nc(SC)n1
Reaction time: 8 h

Procedure:
To a mixture of 4,6-dichloro-2-(methylthio)pyrimidine (5.20 g, 26.66 mmol) and tris(acetylacetonate)iron (III) (0.47 g, 1.33 mmol) in THF (130 mL) and DMP (13 mL) at 0° C. was added slowly 3-butenylmagnesium bromide (0.5M in THF, 56 mL, 28.0 mmol). The reaction mixture was stirred overnight. After the reaction was completed, THF was removed by evaporation in vacuo. The residue was dissolved in dichloromethane (100 mL), and washed with water (50 mL×2), dried over MgSO4, filtered and evaporated in vacuo to provide the title compound. MH+215.
Reaction SMILES: NC1C=CNN=1.O/[CH:8]=[C:9]1\[C:10](=[O:18])[NH:11][C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[CH3:19][C:20]1[CH:21]=[C:22]([C:27]2[CH:28]=[C:29]([NH2:32])[NH:30][N:31]=2)[CH:23]=[C:24]([CH3:26])[CH:25]=1>O1CCCC1>[CH3:26][C:24]1[CH:23]=[C:22]([C:27]2[CH:28]=[C:29]([NH:32][CH:8]=[C:9]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:11][C:10]3=[O:18])[NH:30][N:31]=2)[CH:21]=[C:20]([CH3:19])[CH:25]=1
Reactant: O=C1Nc2ccccc2/C1=C/O
Reactant: Cc1cc(C)cc(-c2cc(N)[nH]n2)c1
Agent: Nc1cc[nH]n1
Solvent: C1CCOC1
Product: Cc1cc(C)cc(-c2cc(NC=C3C(=O)Nc4ccccc43)[nH]n2)c1

Procedure:
The named compound is prepared by substituting 5-(3,5-dimethyl-phenyl)-2H-pyrazol-3-ylamine for 3-aminopyrazole in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one (0.100 gms.) is reacted with 0.2381 gms. 5-(3,5-dimethyl-phenyl)-2H-pyrazol-3-ylamine by refluxing in tetrahydrofuran (2.0 mL) over the weekend.
Reaction SMILES: [N+:1]([O-])([O-])=O.[NH4+].[CH3:6][CH:7]([N:9]1[S:19](=[O:21])(=[O:20])[N-:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:10]1=[O:11])[CH3:8].[Na+]>O>[CH3:8][CH:7]([N:9]1[S:19](=[O:21])(=[O:20])[NH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:10]1=[O:11])[CH3:6].[NH4+:1]
Reactant: O=[N+]([O-])[O-]
Reactant: CC(C)N1C(=O)c2ccccc2[N-]S1(=O)=O
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Product: CC(C)N1C(=O)c2ccccc2NS1(=O)=O
Temperature: 20 °C
Yield: 73.2 %

Procedure:
8 g of ammonium nitrate were introduced at 50° C. with stirring into a solution of 26.3 g of bentazone-sodium in 21.7 g of water, and the reaction mixture was subsequently stirred for a further hour. After cooling to 20° C., the precipitate was filtered off, washed twice with 5 ml of ice water in each case and dried under reduced pressure and at 50° C. 18.9 g of bentazone-ammonium of 99% purity were obtained.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)[C:8](=[O:19])[N:7]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=1)[C:6]2=[O:31].[O-:32][C:33]#[N:34].[K+]>C(O)(=O)C>[CH3:30][O:29][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][C:24]=1[O:27][CH3:28])[CH2:20][N:7]1[C:6](=[O:31])[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([CH2:2][NH:1][C:33]([NH2:34])=[O:32])[CH:4]=2)[N:9]([CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:8]1=[O:19]
Reactant: N#C[O-]
Reactant: COc1ccc(Cn2c(=O)c3cc(CN)ccc3n(C3CCOCC3)c2=O)cc1OC
Agent: [K+]
Solvent: CC(=O)O
Product: COc1ccc(Cn2c(=O)c3cc(CNC(N)=O)ccc3n(C3CCOCC3)c2=O)cc1OC
Yield: 54.5 %

Procedure:
A mixture of 0.1 g of 6-(aminomethyl)-3-(3,4-dimethoxybenzyl)-1-(tetrahydro-2H-pyran-4-yl)quinazoline-2,4(1H,3H)-dione and 0.025 g of potassium cyanate in 2 ml of acetic acid is irradiated in a microwave field for 4 minutes at 120° C. The resulting mixture is evaporated under reduced pressure. The residue is chromatographed on silica gel, eluting with a DCM/MeOH mixture from (100/0, v/v) to (93/7, v/v) to give 0.06 g of the expected product.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[CH2:7]([O:9][C:10]([C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=[C:14]([C:22]2[O:23]C=CC=2)[CH:13]=1)=[O:11])[CH3:8]>ClC(Cl)(Cl)Cl.C(#N)C.O.[Ru](Cl)(Cl)Cl>[CH2:7]([O:9][C:10]([C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=[C:14]([C:22]([OH:23])=[O:2])[CH:13]=1)=[O:11])[CH3:8]
Reactant: CCOC(=O)c1cc(-c2ccco2)nc2ccccc12
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CCOC(=O)c1cc(C(=O)O)nc2ccccc12

Procedure:
To a vigorously stirred of 8 g of sodium periodate and 20 mg of ruthenium trichloride in 37 ml of tetrachloro-methane, 37 ml of acteonitrile and 54 ml of water 2.5 g of 2-Furan-2-yl-quinoline-4-carboxylic acid ethyl ester was added at RT. Then, after 4 h additional 8 g of sodium periodate and 10 mg of ruthenium trichloride was added and the reaction mixture was stirred for an additional hour. Then, the reaction mixture was diluted with water and extracted with DCM (3×150 ml). The combined organic phases were dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was used in the next reaction step without further purification. Yield: 2.0 g.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH:12](O)([CH3:14])[CH3:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH:12]([CH3:14])[CH3:13])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Oc1ccc2nc(Cl)sc2c1
Reactant: CC(C)O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)Oc1ccc2nc(Cl)sc2c1
Reaction time: 1 h
Yield: 91.1 %

Procedure:
2-Chlorobenzo[d]thiazol-6-ol (0.800 g, 4.31 mmol), isopropanol (0.36 mL, 4.74 mmol) and triphenylphosphine (1.24 g, 4.74 mmol) were mixed in THF (1.4 mL) and sonicated. DIAD (0.933 mL, 4.74 mmol) was added dropwise over ˜2 min. After 1 h, the reaction mixture was concentrated under reduced pressure. The material was purified by column chromatography (0 to 10% EtOAc in Hexanes gradient), yielding 0.894 g (91%) of the title compound as a light brown oil. LC-MS: RT=10.21 min., [M+H]+=228.0. Rf=0.50 in 10% EtOAc/Hexanes.
Reaction SMILES: [C:1]1([C:7]2[C:12]3[S:13][CH:14]=[CH:15][C:11]=3[CH:10]=[C:9]([C:16]([OH:18])=O)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:26][CH:27]([NH2:30])[CH2:28][CH3:29].C1CCCCC1.C(OCC)(=O)C>C1(C)C=CC=CC=1.S(Cl)(Cl)=O>[CH3:26][CH:27]([NH:30][C:16]([C:9]1[CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:12]2[S:13][CH:14]=[CH:15][C:11]=2[CH:10]=1)=[O:18])[CH2:28][CH3:29]
Reactant: O=C(O)c1cc(-c2ccccc2)c2sccc2c1
Reactant: CCC(C)N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCC(C)NC(=O)c1cc(-c2ccccc2)c2sccc2c1

Procedure:
the reaction is carried out as in Example 1, starting with 7-phenylbenzo[b]thiophene-5-carboxylic acid (3 g) in toluene (30 cc) and thionyl chloride (2.6 cc) and then adding triethylamine (9.94 cc) and 2-butanamine (1.2 cc) in toluene (30 cc). After chromatography of the residue on silica gel using a cyclohexane:ethyl acetate (50:50 by volume) mixture as the eluent, N-(1-methylpropyl)-7-phenylbenzo[b]thiophene-5-carboxamide (2.35 g), m.p. 195° C., is obtained.
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH:14]=2)=[CH:9][CH:8]=1)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH:14]=2)=[CH:11][CH:12]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C2=CCC(=O)CC2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C1CC=C(c2ccc(O)cc2)CC1
Reaction time: 0.17 h

Procedure:
4-[4-(tert-Butyl-dimethyl-silanyloxy)-phenyl]-cyclohex-3-enone (2.0 g, 6.62 mmol) in THF was treated with TBAF (1N in THF, 10 mL, 9.93 mmol) at room temperature. After 10 min., the solvent was removed and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and the filtrate concentrated in vacuo to give colorless oil, which was purified on a silica gel column by a CombiFlash® system using hexanes and ethyl acetate as eluent (from pure hexanes to pure ethyl acetate) to afford the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]5[O:34][CH:33]=[N:32][CH:31]=5)[CH:25]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C1COCC1.C1C=CC2N(O)N=NC=2C=1.[S:50]1[CH:54]=[CH:53][C:52]([CH2:55][C:56](O)=[O:57])=[CH:51]1>CC(N(C)C)=O>[O:34]1[C:30]([C:26]2[CH:25]=[C:24]([NH:23][C:19]3[N:18]=[C:17]([C:16]4[C:8]([C:4]5[CH:3]=[C:2]([NH:1][C:56](=[O:57])[CH2:55][C:52]6[CH:53]=[CH:54][S:50][CH:51]=6)[CH:7]=[CH:6][CH:5]=5)=[N:9][N:10]5[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=45)[CH:22]=[CH:21][N:20]=3)[CH:29]=[CH:28][CH:27]=2)=[CH:31][N:32]=[CH:33]1
Reactant: O=C(O)Cc1ccsc1
Reactant: Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(-c4cnco4)c3)n2)c1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: O=C(Cc1ccsc1)Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(-c4cnco4)c3)n2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 47 %

Procedure:
To a solution of 4-[2-(3-aminophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-[3-(1,3-oxazol-5-yl)phenyl]-2-pyrimidinamine (50 mg, 0.112 mmol) in 5:1 THF:DMA (2 mL) was added HOBT (46 mg, 0.34 mmol), 0.28 g polystyrene-bound carbodiimide resin (280 mg, 0.34 mmol), and 3-thienylacetic acid (48 mg, 0.34 mmol). After stirring at rt for 48 h, excess Dowex 550A OH anion-exchange resin was added and the resulting mixture was allowed to stir overnight. The solids were then removed by vacuum filtration and rinsed with THF (25 mL) and MeOH (25 mL). The filtrate was concentrated under reduced pressure and purified by mass-guided prep LC (C18, 15% H20 (with 0.1% formic acid)/CH3OH to 100% CH3OH gradient) to afford the title compound (30 mg, 47%). 1H NMR (400 MHz, DMSO-d6) δ 3.65 (s, 2H), 6.51 (d, 1H, J=5.37 Hz), 7.07-7.12 (m, 2H), 7.23-7.48 (m, 7H), 7.55 (s, 1H), 7.68-7.76 (m, 2H), 7.89 (s, 1H), 8.20 (s, 1H), 8.27 (d, 1H, J=5.37 Hz), 8.38 (s, 1H), 8.50-8.51 (m, 1H), 8.81 (d, 1H, J=6.84 Hz), 9.73 (s, 1H), 10.28 (s, 1H). ES-LC/MS m/z=570 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][C:13]2[C:21]3[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=3)[NH:15][C:14]=2[CH3:23])[CH:7]=1)[CH3:2].Br[C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1>>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][C:13]2[C:21]3[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=3)[N:15]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[C:14]=2[CH3:23])[CH:7]=1)[CH3:2]
Reactant: Brc1cccnc1
Reactant: CCOC(=O)Cc1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Product: CCOC(=O)Cc1cccc(Sc2c(C)n(-c3cccnc3)c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 27, Step 1, using the following starting materials: [3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-phenyl]-acetic acid ethyl ester and 3-bromopyridine.
Reaction SMILES: CS([O:5][C:6]1[N:11]=[C:10]2[N:12]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[C:13]([Cl:15])=[N:14][C:9]2=[CH:8][CH:7]=1)(=O)=O>[Li+].[OH-].C1COCC1.CO>[Cl:15][C:13]1[N:12]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:10]2=[N:11][C:6]([OH:5])=[CH:7][CH:8]=[C:9]2[N:14]=1
Reactant: CS(=O)(=O)Oc1ccc2nc(Cl)n(C3CCCCC3)c2n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Oc1ccc2nc(Cl)n(C3CCCCC3)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 5.2 %

Procedure:
2-Chloro-3-cyclohexyl-3H-imidazo[4,5-b]pyridin-5-yl methanesulfonate (0.25 g, 0.758 mmol) was dissolved in 10 mL of a 1:4:1 of 1 M LiOH/THF/MeOH and stirred at room temperature for 1 h. The organic solvents were removed under reduced pressure and the remaining mixture was acidified with 1 M HCl to form a precipitate. The precipitate was collected, washed with water, and purified by HPLC to give the title compound (0.01 g). LCMS m/z=252.30 [M+H]+, 1H NMR (400 MHz, methanol-d4) δ ppm 1.39-1.43 (m, 1H), 1.45-1.54 (m, 2H), 1.8 (d, J=11.33 Hz, 1H), 1.88 (d, J=11.69 Hz, 2H), 1.98 (d, J=11.59 Hz, 2H), 2.59-2.69 (m, 2H), 4.52-4.59 (m, 1H), 6.64 (d, J=8.6 Hz, 1H), 7.79 (d, J=8.6 Hz, 1H).
Reaction SMILES: [P:1]([O-:10])([O:6][CH2:7][CH2:8][Cl:9])[O:2][CH2:3][CH2:4][Cl:5].C(Cl)(Cl)(Cl)[Cl:12]>C(N(CC)CC)C>[P:1]([Cl:12])(=[O:10])([O:6][CH2:7][CH2:8][Cl:9])[O:2][CH2:3][CH2:4][Cl:5]
Reactant: [O-]P(OCCCl)OCCCl
Reactant: ClC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: O=P(Cl)(OCCCl)OCCCl

Procedure:
A total of 1.1 moles of bis(2-chloroethyl) phosphite was reacted with 2.1 moles of carbon tetrachloride in the presence of 2 mls. of triethylamine. The bis(2-chloroethyl) phosphorochloridate thus formed was directly reacted with 0.5 mole of hydroquinone in the presence of 1.1 moles of pyridine. The reaction product was washed with aqueous sulfuric acid, water, and finally with aqueous ammonium hydroxide. After evaporating the carbon tetrachloride solvent and the chloroform which was formed, a 94% yield of product was obtained. This product had a refractive index (nD20) of 1.5093, and was identified by IR as tetrakis (2-chloroethyl) p-phenylene diphosphate. Upon analysis, the product was found to contain 28.05% chlorine and 12.55% phosphorus (compared to theoretical calculated percentages in
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:26]=[CH:25][C:6]2[N:7]3[C:11]([CH2:12][NH:13][CH2:14][C:5]=2[CH:4]=1)=[N:10][N:9]=[C:8]3[C@H:15]1[CH2:20][CH2:19][C@H:18]([O:21][CH:22]([CH3:24])[CH3:23])[CH2:17][CH2:16]1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>ClCCl>[Cl:2][C:3]1[CH:26]=[CH:25][C:6]2[N:7]3[C:11](=[N:10][N:9]=[C:8]3[C@H:15]3[CH2:16][CH2:17][C@H:18]([O:21][CH:22]([CH3:24])[CH3:23])[CH2:19][CH2:20]3)[CH2:12][N:13]([S:35]([CH3:34])(=[O:37])=[O:36])[CH2:14][C:5]=2[CH:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)O[C@H]1CC[C@H](c2nnc3n2-c2ccc(Cl)cc2CNC3)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)O[C@H]1CC[C@H](c2nnc3n2-c2ccc(Cl)cc2CN(S(C)(=O)=O)C3)CC1
Reaction time: 19 h

Procedure:
To a solution of trans-8-chloro-1-(4-isopropoxy-cyclohexyl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene hydrochloride (0.070 g, 0.18 mmol) and triethylamine (0.052 ml, 0.37 mmol) in dichloromethane (5 ml) was added methanesulfonyl chloride (0.015 ml, 0.19 mmol) at room temperature. After stirring for 19 h the reaction mixture was concentrated in vacuo. Flash-chromatography with n-heptane/2-propanol as eluent gave the title compound (0.004 g, 5%) as yellow solid. MS m/e: 439 (M+H+).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C@H:7]([NH2:11])[C:8]([NH2:10])=[O:9])=[CH:3][CH:2]=1>O>[CH:1]1[CH:2]=[CH:3][C:4]([CH:7]([NH2:11])[C:8]([NH2:10])=[O:9])=[CH:5][CH:6]=1
Reactant: NC(=O)[C@@H](N)c1ccccc1
Solvent: O
Product: NC(=O)C(N)c1ccccc1

Procedure:
In accordance with the process described in JP Patent Application Laying Open (Kokai) No. 62-55097, Enterobacter cloacae N-7901 (FERM BP-873) was cultured. This culture solution, 100 mL, was centrifuged, and the wet cells were then suspended in distilled water to prepare a 270 g cell suspension. D, L-phenylglycine amide, 30 g, was dissolved in this suspension, and the mixture was then allowed to react at 40° C. for 18 hours. After the reaction, cells were removed by centrifugation and 295 g of an aqueous solution containing 5.0% by mass each of L-phenylglycine and D-phenylglycine amide was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][S:8][C:9](=[NH:25])[C:10]([C:23]#[N:24])=[C:11]([SH:22])[NH:12][C:13]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:14])=[CH:5][CH:4]=1.N1C=CC=CC=1.II.Cl>C(OCC)(=O)C>[C:16]1([O:15][C:13](=[O:14])[NH:12][C:11]2[S:22][N:25]=[C:9]([S:8][CH2:7][C:6]3[CH:26]=[CH:27][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C:10]=2[C:23]#[N:24])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COc1ccc(CSC(=N)C(C#N)=C(S)NC(=O)Oc2ccccc2)cc1
Agent: Cl
Agent: II
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1ccc(CSc2nsc(NC(=O)Oc3ccccc3)c2C#N)cc1
Reaction time: 1 h
Yield: 62.9 %

Procedure:
To a mixture of 2-Cyano-3-mercapto-3-phenoxycarbonylamino-thioacrylimidic acid 4-methoxy-benzyl ester (11 g, 28 mmol) and ethyl acetate (250 mL) was added, at 0° C., pyridine (4.4 g, 55 mmol). A solution of iodine (7.0 g, 28 mmol) in 350 mL of ethyl acetate was added dropwise over 1 hour. The resulting suspension was stirred for 1 hour, treated with 200 mL of 1 M HCl and filtered, affording 7.0 g (64%) of [4-cyano-3-(4-methoxy-benzylsulfanyl)-isothiazol-5-yl]-carbamic acid phenyl ester as a colorless solid. The filtrate was extracted with 1 l of ethyl acetate, and the organic phase was washed with aqueous NaHCO3, dried over Na2SO4, filtered and concentrated, yielding an additional 2.8 g (26%) of [4-cyano-3-(4-methoxy-benzylsulfanyl)-isothiazol-5-yl]-carbamic acid phenyl ester. 1H NMR (400 MHz, CDCl3) δ 11.95 (s, 1H), 7.35 (t, 2H, J=8.4 Hz), 7.20 (m, 3H), 7.13 (d, 2H, J=8.0 Hz), 6.78 (t, 2H, J=8.6 Hz), 4.34 (s, 2H), 3.73 (s, 3H) ppm; MS (APCl, m/z): 398 [M+H]+.
Reaction SMILES: [C:1]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]([OH:19])=O)[CH:12]1[C:20]([OH:22])=[O:21])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]>C(OC(=O)C)(=O)C>[C:1]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]2[C:17]([O:22][C:20](=[O:21])[CH:12]12)=[O:19])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: O=C(O)C1CCCN(C(=O)OCc2ccccc2)C1C(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(=O)C2C1CCCN2C(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 59 %

Procedure:
Dissolve the 2:1 cis/trans mixture of N-carbobenzoxypiperidine-2,3-dicarboxylic acid diastereomers (20 g) in acetic anhydride (500 mL) and stir overnight under a dry nitrogen atmosphere. Vacuum distill off the acetic anhydride to leave the title compound as a red glass (11.1 g, 59%).