Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](OS(C2C=CC=CC=2)(=O)=O)=[C:5]([O:19][CH3:20])[CH:4]=1)#[N:2].[CH2:21]([N:23]([CH2:27][CH3:28])[CH2:24][C:25]#[CH:26])[CH3:22]>CCCCCCC.CCOC(C)=O>[CH2:21]([N:23]([CH2:27][CH3:28])[CH2:24][C:25]#[C:26][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[O:19][CH3:20])[CH3:22]
Reactant: C#CCN(CC)CC
Reactant: COc1cc(C#N)ccc1OS(=O)(=O)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCN(CC)CC#Cc1ccc(C#N)cc1OC

Procedure:
This product was prepared from benzene-sulfonic acid 4-cyano-2-methoxy-phenyl ester and diethyl-prop-2-ynyl-amine following the general procedure for the Sonogashira cross-coupling process described above. Chromatography eluent: heptane/EtOAc 1:1; yield (90 mg, 74%); 1H NMR δ (CDCl3): 7.52 (d, J=8.35 Hz, 1H), 7.21 (d, J=8.21 Hz, 1H), 7.11 (s, 1H), 3.81 (s, 3H), 2.69 (t, J=7.22 Hz, 2H), 2.58 (t, J=7.21 Hz, 2H), 1.99 (p, J=7.11 Hz, 2H); LCMS m/z: 242.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]([O:23][CH3:24])=[O:22])=[CH:11][CH:10]=2)[C:6]([CH2:25][CH2:26][CH2:27][CH3:28])=[N:5][C:4]=1[Cl:29].[C:30]([O:34][C:35]([N:37]([CH2:41][CH:42]([OH:57])[CH2:43][O:44][C:45]1[CH:53]=[CH:52][CH:51]=[C:50]2[C:46]=1[CH:47]=[C:48]([C:54](O)=[O:55])[NH:49]2)[CH:38]([CH3:40])[CH3:39])=[O:36])([CH3:33])([CH3:32])[CH3:31].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C=O)C>[C:30]([O:34][C:35]([N:37]([CH2:41][CH:42]([OH:57])[CH2:43][O:44][C:45]1[CH:53]=[CH:52][CH:51]=[C:50]2[C:46]=1[CH:47]=[C:48]([C:54]([NH:1][CH2:2][C:3]1[N:7]([CH2:8][C:9]3[CH:10]=[CH:11][C:12]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[C:21]([O:23][CH3:24])=[O:22])=[CH:13][CH:14]=3)[C:6]([CH2:25][CH2:26][CH2:27][CH3:28])=[N:5][C:4]=1[Cl:29])=[O:55])[NH:49]2)[CH:38]([CH3:39])[CH3:40])=[O:36])([CH3:32])([CH3:33])[CH3:31]
Reactant: CC(C)N(CC(O)COc1cccc2[nH]c(C(=O)O)cc12)C(=O)OC(C)(C)C
Reactant: CCCCc1nc(Cl)c(CN)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCCCc1nc(Cl)c(CNC(=O)c2cc3c(OCC(O)CN(C(=O)OC(C)(C)C)C(C)C)cccc3[nH]2)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Reaction time: 96 h

Procedure:
5-Aminomethyl-2-n-butyl-1-[(2'-carbomethoxybiphenyl-4-yl)methyl]-4-chloroimidazole (prepared by the procedure of Example 148, Part C, in EP No. 0253310) (0.71 g, 1.7 mmol), 1 eq), 4-[3-(N-t-butoxycarbonyl-N-isopropylamino)-2-hydroxypropoxy]indole-2-carboxylic acid (prepared by the procedure of Example 1, Part g, in EPO No. 174162) (0.84 g, 1.7 mmol, 1 eq), 1-hydroxybenzotriazole (0.24 g, 1.8 mmol, 1.05 eq), dicyclohexylcarbodiimide (0.37 g, 1.8 mmol, 1.05 eg) and DMF (25 mL) were mixed at 0° C. and left in the refrigerator for 4 days at that temperature. The dicyclohexylurea was filtered off and the mixture concentrated and chromatographed in 1:1 hexane/ethyl acetate yielding 970 mg of a white solid; mp 157.5°-160° C.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:12]2([CH:17]=[CH:16][C:15](=[O:18])[CH:14]([OH:19])[CH:13]2[OH:20])[CH2:11][C:10]1=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[Si:27](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]>CN(C=O)C>[CH2:1]([O:8][N:9]1[C:12]2([CH:17]=[CH:16][C:15](=[O:18])[CH:14]([O:19][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[CH:13]2[OH:20])[CH2:11][C:10]1=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1C=CC2(CC(=O)N2OCc2ccccc2)C(O)C1O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC1C(=O)C=CC2(CC(=O)N2OCc2ccccc2)C1O
Reaction time: 12 h
Yield: 77.5 %

Procedure:
To a solution of rac-(4R,5S,6S)-1-benzyloxy-5,6-dihydroxy-1-azaspiro[3.5]nona-8-ene-2,7-dione (2) (123 mg, 0.425 mmol) and imidazole (35 mg, 0.510 mmol) in DMF (0.6 ml) was added at 0° C. a solution of tert-butyldimethylsilyl chloride (77 mg, 0.510 mmol) in DMF (1.2 ml). After 12 h at room temperature, the reaction was quenched with H2O (3 ml) and the mixture extracted with AcOEt (3×5 ml). The combined extracts were washed with saturated aqueous CuSO4 solution (2×10 ml) and brine (2×10 ml), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-AcOEt, 5:2) to give rac-(4R,5S,6S)-1-benzyloxy-6-tert-butyldimethylsilyloxy-5-hydroxy-1-azaspiro[3.5]nona-8-ene-2,7-dione (3) as a white solid (133 mg, 78%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[CH:14]=[C:13]([NH2:15])[NH:12][N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[N+:17]([CH:20]([CH:23]=O)[CH:21]=O)([O-:19])=[O:18].[Na].C(O)(=O)C>O>[CH2:1]([O:8][CH2:9][C:10]1[C:14]2[C:13](=[N:15][CH:21]=[C:20]([N+:17]([O-:19])=[O:18])[CH:23]=2)[NH:12][N:11]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cc(COCc2ccccc2)n[nH]1
Reactant: O=CC(C=O)[N+](=O)[O-]
Agent: [Na]
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1cnc2[nH]nc(COCc3ccccc3)c2c1
Temperature: 100 °C
Yield: 56 %

Procedure:
A round-bottom flask was charged with 3-(benzyloxymethyl)-1H-pyrazol-5-amine (1.74 g, 8.56 mmol, Honma, T. et al. “A Novel Approach for the Development of Selective Cdk4 Inhibitors: Library Design Based on Locations of Cdk4 Specific Amino Acid Residues.” J. Med. Chem. Vol. 44, No. 26 (2001): 4628-4640), sodium nitromalonaldehyde monohydrate (1.46 g, 9.42 mmol) and acetic acid (8.7 mL). The reaction mixture was heated at 100° C. for 24 hours. The reaction mixture was poured into water and then extracted with ethyl acetate (2×). The combined organic layers were dried with sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography to afford 3-(benzyloxymethyl)-5-nitro-1H-pyrazolo[3,4-b]pyridine (1.37 g, 56%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O[CH2:45][C@@H:46]1[NH:50][C:49](=[O:51])[CH2:48][CH2:47]1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[N:15]([CH2:45][C@H:46]4[CH2:47][CH2:48][C:49](=[O:51])[NH:50]4)[N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Reactant: O=C1CC[C@H](CO)N1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1CC[C@H](Cn2nc3c(-c4ccc(Cl)cc4)c(-c4ccc(Cl)cc4)cnn3c2=O)N1
Yield: 60.5 %

Procedure:
The title compound was prepared using 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (50 mg, 0.14 mmol), prepared as described in Example 1, Ph3P (110 mg, 0.42 mmol) and (R)-5-(hydroxymethyl)pyrrolidin-2-one (17 mg, 0.14 mmol) in THF (1.0 mL) and by following the procedure described in Example 2. The title compound, (R)-7,8-bis(4-chlorophenyl)-2-((5-oxopyrrolidin-2-yl)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (38.5 mg, 85%) was obtained as yellow powder. MS M+H=454; 1H NMR (CDCl3) δ 8.15 (1H, s), 7.24-7.36 (6H, m), 7.09 (2H, d, J=10.0 Hz), 6.59 (1H, s), 4.17-4.20 (1H, m), 4.03-4.10 (2H, m), 2.25-2.35 (3H, m), 1.92-2.02 (1H, m).
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=3Br)[CH:15]=2)=[CH:9][C:8]=1[CH3:33])C.[C:35]1([OH:41])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH3:33][C:8]1[CH:9]=[C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:30])([F:29])[F:31])=[CH:24][C:23]=3[O:41][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:15]=2)[CH:11]=[CH:12][C:7]=1[CH2:6][CH2:5][C:4]([OH:3])=[O:34]
Reactant: Oc1ccccc1
Reactant: CCOC(=O)CCc1ccc(Oc2ccc(C)c(Oc3ccc(C(F)(F)F)cc3Br)c2)cc1C
Product: Cc1cc(Oc2ccc(C)c(Oc3ccc(C(F)(F)F)cc3Oc3ccccc3)c2)ccc1CCC(=O)O
Yield: 57 %

Procedure:
The compound of 3-{4-[3-(2-Bromo-4-trifluoromethyl-phenoxy)-4-methyl-phenoxy]-2-methyl-phenyl}-propionic acid ethyl ester is reacted with phenol as in Example 45 to afford 0.256 g (57%) of the title compound. 1H NMR (400 MHz, CDCl3); HRMS (ES+) m/z exact mass calculated for C30H26O5F3 523.1732, found 523.1749.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([O:7][C:8]2[CH:13]=[C:12]([CH3:14])[C:11]([C:15](=[O:17])[CH3:16])=[C:10]([CH3:18])[CH:9]=2)=[CH:5][CH:4]=1.[Br-:21].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(#N)C>[Br:21][CH2:16][C:15]([C:11]1[C:12]([CH3:14])=[CH:13][C:8]([O:7][C:6]2[CH:19]=[CH:20][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:9][C:10]=1[CH3:18])=[O:17]
Reactant: COc1ccc(Oc2cc(C)c(C(C)=O)c(C)c2)cc1
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Product: COc1ccc(Oc2cc(C)c(C(=O)CBr)c(C)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 106.6 %

Procedure:
To a solution of 1-(4-(4-methoxyphenoxy)-2,6-dimethylphenyl)ethanone (3.80 g, 14.1 mmol) in acetonitrile (28.1 mL) was added tetrabutylammoniumtribromide (TBABr3, 7.46 g, 15.5 mmol). The reaction was stirred at room temperature overnight. The solution was concentrated under reduced pressure, added with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure to give 2-bromo-1-(4-(4-methoxyphenoxy)-2,6-dimethylphenyl)ethanone (5.25 g), which was used directly for the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[O:11][CH:12]([C:14]([OH:16])=[O:15])[CH2:13][C:9]=2[C:8]2[CH2:7][C:6](Br)([CH2:17][CH2:18][CH3:19])[C:5](=[O:21])[C:4]=2[C:3]=1[CH3:22].O.Cl>CS(C)=O>[CH3:1][C:2]1[C:10]2[O:11][CH:12]([C:14]([OH:16])=[O:15])[CH2:13][C:9]=2[C:8]2[CH:7]=[C:6]([CH2:17][CH2:18][CH3:19])[C:5](=[O:21])[C:4]=2[C:3]=1[CH3:22]
Reactant: CCCC1(Br)Cc2c3c(c(C)c(C)c2C1=O)OC(C(=O)O)C3
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Product: CCCC1=Cc2c3c(c(C)c(C)c2C1=O)OC(C(=O)O)C3

Procedure:
A solution of 4,5-dimethyl-6-oxo-7-bromo-7-propyl-1,2,7,8-tetrahydro-6H-indeno[5,4-b]furan-2-carboxylic acid (0.70 g., 0.0019 mole) and 1,5-diazabicyclo-[4.3.0]-5-one (0.5 ml.) in dimethylsulfoxide (5 ml.) is stirred at 25°C. in an inert atomsphere for 1 1/2 hours, treated with water (15 ml.) acidified with hydrochloric acid, extracted with ether washed with water and dried over magnesium sulfate. The ether is evaporated at reduced pressure and the crude product crystallized from nitromethane (10 ml.) affording 4,5-dimethyl-6-oxo-7-propyl-1,2-dihydro-6H-indeno[5,4-b]furan-2-carboxylic acid as a red solid which melts at 212°C.
Reaction SMILES: C(OC([NH:8][C:9]([NH:26]C(OC(C)(C)C)=O)=[N:10][C:11]1[CH:16]=[C:15]([C:17]2[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][N:18]=2)[CH:14]=[CH:13][C:12]=1[O:24][CH3:25])=O)(C)(C)C.[ClH:34]>ClCCl.O1CCOCC1>[ClH:34].[ClH:34].[CH3:25][O:24][C:12]1[CH:13]=[CH:14][C:15]([C:17]2[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][N:18]=2)=[CH:16][C:11]=1[NH:10][C:9]([NH2:26])=[NH:8]
Reactant: COc1ccc(-c2cc(C)ccn2)cc1N=C(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc(-c2cc(C)ccn2)cc1NC(=N)N
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of N,N′-bis(tert-butoxycarbonyl)-N″-(2-methoxy-5-(4-methylpyridin-2-yl)phenyl)guanidine (200 mg) in dichloromethane (2 ml) was added a solution of hydrogen chloride in 1,4-dioxane (4N, 4 ml), and the mixture was stirred at room temperature for 24 hours. The solvent was evaporated under reduced pressure. To the residue was added 5% ethanol in ethyl acetate (100 ml), and the resultant precipitate was collected by filtration and dried under reduced pressure to give (2-methoxy-5-(4-methylpyridin-2-yl)phenyl)guanidine dihydrochloride (127 mg).
Reaction SMILES: [CH:1]([C:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[CH:7]=[C:6]([OH:18])[N:5]=1)([CH3:3])[CH3:2].Cl.Cl[CH2:21][C:22]1[C:23]([NH:35][CH2:36][CH3:37])=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([O:32][CH2:33][CH3:34])=[CH:27][CH:26]=2.[Li+].[OH-]>C1COCC1.C(Cl)Cl>[CH2:33]([O:32][C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][CH:27]=1)[N:24]=[C:23]([NH:35][CH2:36][CH3:37])[C:22]([CH2:21][C:7]1[C:8]3[C:13](=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=3)[C:4]([CH:1]([CH3:3])[CH3:2])=[N:5][C:6]=1[OH:18])=[CH:31]2)[CH3:34]
Reactant: COc1cc2cc(O)nc(C(C)C)c2cc1OC
Reactant: CCNc1nc2ccc(OCC)cc2cc1CCl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCNc1nc2ccc(OCC)cc2cc1Cc1c(O)nc(C(C)C)c2cc(OC)c(OC)cc12
Temperature: 160 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 1-isopropyl-6,7-dimethoxyisoquinolin-3-ol SIL 32164 (149 mg, 0.60 mmol) in THF (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added 3-(chloromethyl)-6-ethoxy-N-ethylquinolin-2-amine hydrochloride SLA 41042 (181 mg, 0.68 mmol) at RT followed by a 2 N aq. LiOH solution (0.60 mL, 1.20 mmol) and the mixture was stirred at 160° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with CH2Cl2:MeOH=9:1 (150 mL), washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent EtOAc:MeOH=100:0 to 95:5) followed by a second purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 97:3) provided 16 mg of 4-((6-ethoxy-2-(ethylamino)quinolin-3-yl)methyl)-1-isopropyl-6,7-dimethoxyisoquinolin-3-ol as a brown solid. This free base was dissolved in CH2Cl2 (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.49 M HCl solution in MeOH (1.05 mL) The reaction mixture was stirred for 5 min at RT then concentrated at 40° C. under vacuum to afford 4-((6-ethoxy-2-(ethylamino)quinolin-3-yl)methyl)-1-isopropyl-6,7-dimethoxyisoquinolin-3-ol dihydrochloride 46 as a yellow solid (12 mg, 4% yield).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][C@H:12]([C:31](O)=[O:32])[NH:13][C:14]([O:16][CH2:17][CH:18]1[C:30]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:34][NH:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[CH:39][CH:38]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][C@H:12]([C:31]([N:35]([CH3:34])[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[CH:39][CH:38]=1)=[O:32])[NH:13][C:14]([O:16][CH2:17][CH:18]1[C:30]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: CNCc1ccc(OCc2ccccc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Product: CN(Cc1ccc(OCc2ccccc2)cc1)C(=O)[C@@H](CCCNC(=O)OC(C)(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 33b) from (R)-N5 -(tert.-butoxy-carbonyl)-N2 -(9-fluorenylmethoxycarbonyl)-ornithine and N-methyl-4-(phenylmethoxy)benzenemethanamine in the presence of TBTU in a quantitative yield. Colourless, highly viscous oil, which was used in the following step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])[C:6]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:5]2[S:25]([OH:28])(=O)=[O:26].C(Cl)(=O)C([Cl:32])=O.CN(C)C=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])[C:6]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:5]2[S:25]([Cl:32])(=[O:28])=[O:26]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOC(=O)c1c(S(=O)(=O)O)c2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of the 5-chloro-2-(ethoxycarbonyl)-1-(phenylsulfonyl)-1H-indole-3-sulfonic acid (9.52 g, 21.4 mmol) in 100 mL of dichloromethane at 0° C. was added oxalyl chloride (5.61 mL, 64.3 mmol). Dimethylformamide (0.2 mL) was added, and the reaction was allowed to warm to room temperature. After 24 hours, another portion of oxalyl chloride (3.0 mL) was added, and the reaction was stirred for an additional 16 hours. The mixture was concentrated in vacuo to provide a yellow foam. Proton NMR for the product was consistent with the titled compound. ESI+MS: 426.2 [M−Cl]+.
Reaction SMILES: [NH2:1][C:2](=O)[CH2:3][N:4]1[C:9](=[N:10]S(C2C=CC(C)=CC=2)(=O)=O)[CH:8]=[CH:7][C:6]([O:21][C:22]2[CH:23]=[C:24]([NH:28][C:29]([C:31]3[C:36]([CH3:37])=[CH:35][CH:34]=[CH:33][N:32]=3)=[O:30])[CH:25]=[CH:26][CH:27]=2)=[CH:5]1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O1CCCC1>[NH2:1][C:2]1[N:10]=[C:9]2[CH:8]=[CH:7][C:6]([O:21][C:22]3[CH:23]=[C:24]([NH:28][C:29]([C:31]4[C:36]([CH3:37])=[CH:35][CH:34]=[CH:33][N:32]=4)=[O:30])[CH:25]=[CH:26][CH:27]=3)=[CH:5][N:4]2[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)N=c2ccc(Oc3cccc(NC(=O)c4ncccc4C)c3)cn2CC(N)=O)cc1
Solvent: C1CCOC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Cc1cccnc1C(=O)Nc1cccc(Oc2ccc3nc(N)cn3c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.1 %

Procedure:
A mixture of N-(3-{[1-(2-amino-2-oxoethyl)-6-{[(4-methylphenyl)sulfonyl]imino}-1,6-dihydropyridin-3-yl]oxy}phenyl)-3-methylpyridine-2-carboxamide (9.68 g, 18.2 mmol), trifluoroacetic anhydride (30 mL) and tetrahydrofuran (250 mL) was stirred at room temperature for 2 hr. The reaction solution was concentrated under reduced pressure, ethanol (200 mL) and 4M aqueous sodium hydroxide solution (60 mL) were added to the residue, and the mixture was stirred at room temperature for 19 hr. The reaction solution was concentrated under reduced pressure, and ethyl acetate was added to the residue. The mixture was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH silica gel, 0%→100% ethyl acetate-hexane) to give the title compound (4.52 g, 69%) as a pale-yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:11])=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][CH:15]=1>>[Cl:1][C:2]1[C:3](=[O:11])[N:4]([CH2:18][C:17]2[CH:20]=[CH:21][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: COc1ccc(CBr)cc1
Reactant: O=[N+]([O-])c1cnc(O)c(Cl)c1
Product: COc1ccc(Cn2cc([N+](=O)[O-])cc(Cl)c2=O)cc1

Procedure:
The title compound was prepared in analogy to the procedure described for step W2 but using 3-chloro-2-hydroxy-5-nitropyridine and 4-methoxybenzyl bromide. The reaction was quenched with a saturated aqueous solution of sodium bicarbonate. The residue was purified by trituration in EtOAc. tR: 0.98 min (LC-MS 4); ESI-MS: 295.2 [M+H]+ (LC-MS 4).
Reaction SMILES: C(N(CC)CC)C.[C:8]1(=[O:14])[O:13][C:11](=[O:12])[CH2:10][CH2:9]1.[N+:15]([C:18]1[CH:29]=[C:28]2[C:21]([NH:22][CH:23]=[C:24]2[CH2:25][CH2:26][NH2:27])=[CH:20][CH:19]=1)([O-])=O>CN(C1C=CN=CC=1)C.ClCCl>[CH3:8][O:13][C:11]([NH:15][C:18]1[CH:29]=[C:28]2[C:21](=[CH:20][CH:19]=1)[NH:22][CH:23]=[C:24]2[CH2:25][CH2:26][NH:27][C:11](=[O:12])[CH2:10][CH2:9][C:8]([OH:13])=[O:14])=[O:12]
Reactant: O=C1CCC(=O)O1
Reactant: NCCc1c[nH]c2ccc([N+](=O)[O-])cc12
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)Nc1ccc2[nH]cc(CCNC(=O)CCC(=O)O)c2c1
Reaction time: 4 h

Procedure:
Triethylamine (12 mmol), DMAP (0.6 mmol), and succinic anhydride (9 mmol) are added to a solution of 5-nitrotryptamine (6 mmol) in dichloromethane (25 mL). The mixture is stirred 4 h, the solvent removed in vacuo, and the residue chromatographed on silica gel using 10% methanol-chloroform with 1% acetic acid as eluent. The product is then hydrogenated and transformed to the carbamic acid methyl ester as in the previous examples. Purified product is obtained by reverse-phase HPLC as above.
Reaction SMILES: [CH2:1]([S:3]([NH:6][C@@H:7]([CH:11]([CH3:13])[CH3:12])[C:8]([OH:10])=O)(=[O:5])=[O:4])[CH3:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.Cl.[OH:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][NH2:39])=[CH:33][C:32]=1[O:40][CH3:41].Cl>O1CCCC1>[OH:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][NH:39][C:8](=[O:10])[C@@H:7]([NH:6][S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])[CH:11]([CH3:13])[CH3:12])=[CH:33][C:32]=1[O:40][CH3:41]
Reactant: COc1cc(CCN)ccc1O
Reactant: CCS(=O)(=O)N[C@H](C(=O)O)C(C)C
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CCS(=O)(=O)N[C@H](C(=O)NCCc1ccc(O)c(OC)c1)C(C)C
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
5.1 g of (S)-2-(ethylsulfonylamino)-3-methyl-butyric acid and 5.7 ml of N-methylmorpholine are cooled in 200 ml of tetrahydrofuran, with stirring, to −20° C. 3.15 ml of chloroformic acid isobutyl ester are added dropwise thereto. Stirring is then carried out for 30 min, during which the reaction temperature is increased to −10° C. Cooling is then carried out to −20° C. again and 5.0 g of 2-(4-hydroxy-3-methoxyphenyl)-ethylamine hydrochloride are introduced. The reaction mixture is allowed to warm to room temperature and is stirred for a further 24 hours. The reaction mixture is introduced into 300 ml of 2N hydrochloric acid. It is extracted twice with 500 ml of ethyl acetate each time. The organic phases are washed twice with 100 ml of saturated sodium chloride solution each time, combined, dried over magnesium sulfate and concentrated. The residue is purified by flash-chromatography on silica gel using a mixture of ethyl acetate/n-hexane 3:1, yielding (S)-2-(ethylsulfonylamino)-3-methyl-butyric acid N-[2-(4-hydroxy-3-methoxyphenyl)ethyl]-amide in the form of a colourless oil.
Reaction SMILES: [C:1]([C:3]1[C:11]2[NH:10][C:9](=[O:12])[C:8](=[O:13])[NH:7][C:6]=2[S:5][CH:4]=1)#[N:2].S(Cl)([Cl:17])(=O)=O>C(O)(=O)C>[Cl:17][C:4]1[S:5][C:6]2[NH:7][C:8](=[O:13])[C:9](=[O:12])[NH:10][C:11]=2[C:3]=1[C:1]#[N:2]
Reactant: O=S(=O)(Cl)Cl
Reactant: N#Cc1csc2[nH]c(=O)c(=O)[nH]c12
Solvent: CC(=O)O
Product: N#Cc1c(Cl)sc2[nH]c(=O)c(=O)[nH]c12
Yield: 37.3 %

Procedure:
Chlorination of 7-cyanothieno(2,3-b]pyrazine-2,3(1H,4H)-dione (386 mg, 2 mmol) in acetic acid (50 ml) with sulfuryl chloride (250 pl, 3.1 mmol) was performed following the procedure outlined in example 5 (Method G) to give 170 mg (37%) of the title compound. M.P.>250° C. 1H-NMR (DMSO-D6, δ): 12.25 (br.s, 1H), 12.8 (br.s, 1H).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[P:12](=[S:20])([NH2:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15].C(N(CC)CC)C>O>[C:4]1(=[O:6])[N:19]([P:12](=[S:20])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]12
Reactant: CCOP(N)(=S)OCC
Reactant: O=C1OC(=O)c2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Product: CCOP(=S)(OCC)N1C(=O)c2ccccc2C1=O
Temperature: 67 °C

Procedure:
A mixture of 222 g (1.5 moles) phthalic anhydride, 84.5 g (0.5 moles) O,O-diethyl phosphoramidothioate and 151 g (1.5 moles) triethylamine in 800 mls light petroleum (bP 60°-80° C.) was stirred and heated at 67° C. for 5.75 hours. Two hundred and eighty mls of water were added to the vigourously stirred system. After several minutes the mixture was allowed to stand and the hot organic layer was separated and cooled to 0°-5° C. to give the desired compound, O,O-diethyl phthalimidophosphonothioate, as a colorless solid, m.p. 75°-81° C. (97.5 purity by GLC). The yield was calculated to be 55% from the O,O-diethyl phosphoramidothioate. A further 4% yield of the desired compound was obtained by filtering the cooled aqueous layer.