Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[C:5]([NH2:10])[CH:4]=1.[C:11](O)(=O)[CH3:12]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[NH:9][C:11]([CH3:12])=[N:10][C:5]=2[CH:4]=1
Reactant: CC(=O)O
Reactant: COc1ccc(N)c(N)c1
Product: COc1ccc2[nH]c(C)nc2c1

Procedure:
1.95 g (14.11 mmol) 4-methoxy-o-phenylenediamine were refluxed in 30.0 mL acetic acid for 2 h with stirring. The reaction mixture was evaporated down i.vac. The residue was taken up in an aqueous NaHCO3 solution and filtered. The filtrate was extracted with dichloromethane. The organic phase was separated off, dried and evaporated down i.vac.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH2:13][C:14]([N:16]2[CH2:21][CH2:20][O:19][C@:18]([CH2:30][CH2:31][OH:32])([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)[CH2:17]2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CN(C1C=CC=CN=1)C.C(N(CC)CC)C.[CH3:51][C:52]1[CH:57]=[CH:56][C:55]([S:58](Cl)(=[O:60])=[O:59])=[CH:54][CH:53]=1.Cl>C(Cl)Cl.O>[CH3:51][C:52]1[CH:57]=[CH:56][C:55]([S:58]([O:32][CH2:31][CH2:30][C@:18]2([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)[O:19][CH2:20][CH2:21][N:16]([C:14](=[O:15])[CH2:13][C:5]3[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=[C:3]([C:2]([F:1])([F:33])[F:34])[CH:4]=3)[CH2:17]2)(=[O:60])=[O:59])=[CH:54][CH:53]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCO[C@](CCO)(c2ccc(Cl)c(Cl)c2)C1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC[C@@]2(c3ccc(Cl)c(Cl)c3)CN(C(=O)Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CCO2)cc1
Temperature: 2.5 °C
Yield: 60.3 %

Procedure:
To a solution of (2R)-2-[4-{[3,5-bis(trifluoromethyl)phenyl]acetyl}-2-(3,4-dichlorophenyl)morpholin-2-yl]ethanol obtained in Reference Example 1 (3.0 g, 5.7 mmol) in methylene chloride (30 ml) were added dimethylaminopyridine (0.07 g, 0.57 mmol) and triethylamine (1.2 ml, 8.5 mmol) under a nitrogen stream, the resulting mixture was cooled to 0-5° C., and then a solution of 4-methylbenzenesulfonyl chloride (1.3 g, 6.8 mmol) in methylene chloride (10 ml) was further added dropwise at below 10° C. with stirring. After the resulting mixture was stirred at room temperature for 8 hours, to the reaction mixture were added water (30 ml) and concentrated hydrochloric acid (1 ml), and the resulting mixture was partitioned. The separated organic layer was washed with water (30 ml) and evaporated to dryness. The residue obtained was purified by chromatography on a silica gel column and then crystallized from a mixed solvent of toluene (7 ml) and methylcyclohexane (35 ml) under ice-cooling to afford the title compound [2.3 g, yield: 60.3%] as a colorless crystalline solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[Li]CCCC.CN(C)[CH:22]=[O:23]>O1CCCC1>[F:12][C:11]([F:14])([F:13])[C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([CH:22]=[O:23])[CH:3]=1)[NH:9][CH:8]=[CH:7]2
Reactant: CN(C)C=O
Reactant: FC(F)(F)c1cc(Br)c2[nH]ccc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1cc(C(F)(F)F)cc2cc[nH]c12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 84 %

Procedure:
To a −78° C. solution of 7-bromo-5-(trifluoromethyl)-1H-indole (8.77 g, 33.2 mmol) in tetrahydrofuran (200 mL), n-BuLi (1.6 M in hexanes, 72.7 mL, 116 mmol) was added slowly. The reaction was warmed to 0° C. and stirred for 15 min. The reaction was recooled to −78° C., treated with dimethylformamide (12.9 mL, 166 mmol), warmed to ambient temperature, and stirred for 30 min. The reaction was quenched by slow addition of 1N hydrochloric acid (50 mL) and was then extracted with ethyl acetate (2×40 mL). The organic layers were dried (magnesium sulfate) and evaporated. The residue was purified by chromatography on silica gel with 15% ethyl acetate/hexanes. The product 5-(trifluoromethyl)-1H-indole-7-carbaldehyde (5.95 g, 27.9 mmol, 84% yield) was obtained as an orange solid. 1H-NMR (CDCl3, 400 MHz) δ 10.28 (bs, 1H), 10.16 (s, 1H), 8.20 (d, J=0.6 Hz, 1H), 7.90 (d, J=0.6 Hz), 7.45 (dd, J=3.2, 2.5 Hz, 1H), 6.72 (dd, J=3.2, 2.4 Hz, 1H).
Reaction SMILES: [NH:1]1[C:6](=S)[CH2:5][S:4][C:3]2[N:8]=[CH:9][CH:10]=[CH:11][C:2]1=2>C(N)(C)C>[CH:2]([NH:1][C:6]1[CH2:5][S:4][C:3]2[N:8]=[CH:9][CH:10]=[CH:11][C:2]=2[N:1]=1)([CH3:11])[CH3:3]
Reactant: S=C1CSc2ncccc2N1
Solvent: CC(C)N
Product: CC(C)NC1=Nc2cccnc2SC1
Reaction time: 0.75 h

Procedure:
1H-Pyrido[2,3-b][1,4]thiazin-2(3H)-thione (0.5 g) was dissolved in 10 ml of isopropylamine and allowed to stand for 45 min at room temperature. Then the excess of the amine was removed in vacuum and the solid residue was dissolved in 25 ml of ethyl acetate I methanol (4:1), treated with charcoal and filtered through a pad of silica. The filter was eluted with 2×10 ml of ethyl acetate/methanol (4:1). The filtrate was evaporated and the slowly crystallizing residue was triturated with 5 ml of ethyl acetate and then with 3 ml of diethyl ether. The crystals were filtered off and dried to give the title compound; m.p. 135°-139° C. (Compound VII).
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11](OC)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19][OH:20].[OH-].[K+]>C1COCC1.CO>[OH:20][NH:19][C:11](=[O:12])[C:10]1[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=1[C:8]#[C:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NO
Reactant: COC(=O)c1ccccc1C#Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(NO)c1ccccc1C#Cc1ccccc1
Temperature: 0 °C
Yield: 42.5 %

Procedure:
In a 100 mL round-bottomed flask was added methyl 2-(phenylethynyl)benzoate 36 (157 mg, 0.665 mmol) in THF (1.33 mL) and MeOH (1.33 mL) and the solution was cooled to 0° C. Then, a 50% aqueous solution of hydroxylamine (2195 mg, 33.2 mmol) was added followed by a 4M aqueous solution of KOH (0.33 mL, 1.329 mmol) and the resulting colorless solution was stirred at 0° C. and allowed to slowly warm to rt for 20 h. The reaction mixture was partitioned between EtOAc and H2O. The aqueous layer was extracted with EtOAc (2×) and the combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The yellow oil was crystallized in Et2O and the filtrate was evaporated and triturated again in Et2O. The solids were combined to afford title compound 37 (67 mg, 43% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.98 (s, 1H), 9.20 (s, 1H), 7.61 (d, J=7.4 Hz, 1H), 7.55-7.43 (m, 814). LRMS (ESI): (calc.) 237.25 (found) 238.2 (MH)+
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([OH:8])=O)(=[O:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([N:31]([CH2:40][C:41]2[CH:50]=[CH:49][C:44]([C:45]([NH:47]O)=[NH:46])=[CH:43][CH:42]=2)[CH:32]2[CH2:38][CH2:37][CH2:36][CH2:35][NH:34][C:33]2=[O:39])(=[O:30])=[O:29])=[CH:24][CH:23]=1.O>CN(C)C=O>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([N:31]([CH2:40][C:41]2[CH:42]=[CH:43][C:44]([C:45]3[N:46]=[C:6]([CH2:5][O:4][C:1](=[O:3])[CH3:2])[O:8][N:47]=3)=[CH:49][CH:50]=2)[CH:32]2[CH2:38][CH2:37][CH2:36][CH2:35][NH:34][C:33]2=[O:39])(=[O:29])=[O:30])=[CH:24][CH:23]=1
Reactant: CC(=O)OCC(=O)O
Reactant: N=C(NO)c1ccc(CN(C2CCCCNC2=O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCc1nc(-c2ccc(CN(C3CCCCNC3=O)S(=O)(=O)c3ccc(Cl)cc3)cc2)no1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 28.1 %

Procedure:
To a solution of acetoxyacetic acid (0.13 g, 1.10 mmol) in 5 ml dimethylformamide were added 1,1′-carbonyl-diimidazole (0.18 g, 1.10 mmol). The mixture was stirred at room temperature for 10 minutes, heated to 40° C. for a few minutes and cooled to room temperature. 4-{[(4-Chloro-benzenesulfonyl)-(2-oxo-azepan-3-yl)-amino]-methyl}-N-hydroxy-benzamidine (0.45 g, 1.00 mmol) was added and the mixture was stirred at 100° C. for 5 hours and then poured into water. Filtration and chromatography on silicagel with ethylacetate/heptane (3/1) yielded 0.15 g (29%) acetic acid 3-(4-{[(4-chloro-benzenesulfonyl)-(2-oxo-azepan-3-yl)-amino]-methyl}-phenyl)-[1,2,4]oxadiazol-5-ylmethyl ester as white solid, MS: m/e (%)=533.0 (MH+, 100).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:7]([CH2:8][CH2:9][CH2:10][O:11][C:12]2[C:17]([CH3:18])=[CH:16][C:15]([C:19]3[N:20]=[N:21][N:22]([CH3:24])[N:23]=3)=[CH:14][C:13]=2[CH3:25])[N:6]=[CH:5][N:4]=1.Cl[C:27]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[S:28]>C(#N)C.CN(C1C=CN=CC=1)C>[O:29]([C:27]([O:1][CH2:2][C:3]1[N:7]([CH2:8][CH2:9][CH2:10][O:11][C:12]2[C:13]([CH3:25])=[CH:14][C:15]([C:19]3[N:20]=[N:21][N:22]([CH3:24])[N:23]=3)=[CH:16][C:17]=2[CH3:18])[N:6]=[CH:5][N:4]=1)=[S:28])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Cc1cc(-c2nnn(C)n2)cc(C)c1OCCCn1ncnc1CO
Reactant: S=C(Cl)Oc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: Cc1cc(-c2nnn(C)n2)cc(C)c1OCCCn1ncnc1COC(=S)Oc1ccccc1
Temperature: 20 °C
Reaction time: 7 h

Procedure:
To a mixture of 5-hydroxymethyl-1-[3-[4-(2-methyl-tetrazol-5-yl) -2,6-dimethyl-phenoxy]-propyl]-1,2,4-triazole (343 mg, 1 mmol) in 15 ml of acetonitrile was added DMAP (244 mg, 2 mmol) and phenyl chlorothioformate (381 mg, 2.2 mmol). The mixture was stirred at 20° C. for 7 h. An additional phenyl chlorothioformate (1 equiv) was added, and the mixture was stirred for 15 h. The solvent was removed in vacuo and 5-phenoxythiocarbonyloxymethyl-1-[3-[4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxy]-propyl]-1,2,4-triazole was isolated and used without further purification.
Reaction SMILES: [OH:1][CH:2]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)[CH2:3][C:4]([O:6]CC)=[O:5].[OH-].[Li+]>C1COCC1>[OH:1][CH:2]([C:9]1[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=1)[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)CC(O)c1ccc(OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(C(O)CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.7 %

Procedure:
To a solution of ethyl 3-hydroxy-3-(4-methoxyphenyl)propanoate (252 mg, 1.1 mmol) in THF (1.1 mL) was added 1 N lithium hydroxide (1.1 mL), and the resulting solution was stirred at room temperature for 3 h. Most of the solvents were removed in vacuo, and 1N hydrochloric acid (1.1 mL) was added. The aqueous layer was extrated with ethyl acetate (x3), and the combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated in vacuo to give the title compound as an off-white solid (200 mg, 91% yield). 1H NMR (400 MHz, CD3OD) δ 2.57-2.63 (m, 1 H) 2.65-2.72 (m, 1 H) 3.29 (s, 8 H) 3.76 (s, 3 H) 4.82 (s, 9 H) 5.01 (dd, J=8.56, 5.29 Hz, 1 H) 6.86 (ddd, J=9.19, 2.77, 2.39 Hz, 2 H) 7.26-7.30 (m, 2 H). HPLC retention time: 1.392 min (method A). MS (ESI) (M+Na)+ 218.92.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[N:13]3[CH:14]=[C:15]([CH2:17][O:18][C:19]4[CH:28]=[CH:27][C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[N:20]=4)[N:16]=[C:12]3[C:11]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[N:10][CH:9]=2)=[CH:4][CH:3]=1.[C:35]([N:42]1[CH2:47][CH:46]=[C:45](B2OC(C)(C)C(C)(C)O2)[CH2:44][CH2:43]1)([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36]>>[O:32]1[CH2:33][CH2:34][N:29]([C:11]2[C:12]3[N:13]([CH:14]=[C:15]([CH2:17][O:18][C:19]4[CH:28]=[CH:27][C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[N:20]=4)[N:16]=3)[C:8]([C:5]3[CH:4]=[CH:3][C:2]([C:45]4[CH2:46][CH2:47][N:42]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:43][CH:44]=4)=[N:7][CH:6]=3)=[CH:9][N:10]=2)[CH2:30][CH2:31]1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Clc1ccc(-c2cnc(N3CCOCC3)c3nc(COc4ccc5ccccc5n4)cn23)cn1
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(-c3cnc(N4CCOCC4)c4nc(COc5ccc6ccccc6n5)cn34)cn2)CC1

Procedure:
Compound 49b was prepared from compound 49a and N-Boc-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester using the methods described in Example 1, Step G. Mass Spectrum (LCMS, ESI pos.) Calcd. For C35H37N7O4: 620.4 [M+H]. found 620.3.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[O:17]C)[C:11]([OH:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.[OH-].[Na+].Cl>C(O)(=O)C>[O:1]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[OH:17])[C:11]([OH:13])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)O)cc1Oc1ccccc1
Agent: Br
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(O)c1ccc(O)c(Oc2ccccc2)c1

Procedure:
A solution of 3-phenoxy-4-methoxybenzoic acid (17.0 g, 0.07 mole), a 48 weight percent aqueous solution of HBr (165 ml, 1.39 mole) and 350 ml of glacial acetic acid was added to a 1-liter, one-necked, round-bottom flask equipped with a reflux condenser, nitrogen inlet adapter and a polytetrafluoroethylene-coated magnetic stir bar. The solution was heated under nitrogen and refluxed for 16 hours. While still hot, the flask was transferred to a rotary evaporator and the volatiles were removed leaving a salmon-colored solid which was added to 200 ml of 1.25N NaOH solution (0.25 mole). Most of the solid dissolved. The insoluble portion was filtered off. The remaining aqueous base solution was added dropwise to a stirred aqueous HCl solution (0.25 mole in 400 ml deionized water) resulting in the precipitation of a salmon-colored solid. The solid was washed in 300 ml of deionized water for 1 hour, filtered, dried at room temperature overnight, and dried under vacuum at 100° C. for 1 hour yielding 3-phenoxy-4-hydroxybenzoic acid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6]CO)=[CH:4][CH:3]=1.[NH:11]1[CH2:15][CH:14]=[CH:13][CH2:12]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:11]([CH2:15][CH3:14])[CH2:12][CH3:13])=[CH:9][CH:10]=1
Reactant: C1=CCNC1
Reactant: OCCc1ccc(Br)cc1
Product: CCN(CC)Cc1ccc(Br)cc1

Procedure:
The procedure of step (i) of Reference Example 2 was repeated, except that 4-bromophenethyl alcohol was used instead of 4-bromobenzylalcohol and various amines were used instead of 2,5-dihydro-1H-pyrrole. The following compounds thus synthesized were used in the Examples.
Reaction SMILES: [C:1]([NH:9]/[C:10](=[CH:15]\[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:18][C:17]=1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)/[C:11]([O:13]C)=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Cl>CO.O>[C:1]([NH:9]/[C:10](=[CH:15]\[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:18][C:17]=1[O:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)/[C:11]([OH:13])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)/C(=C/c1ccc(OCc2ccccc2)cc1OCc1ccccc1)NC(=O)c1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)/C(=C/c1ccc(OCc2ccccc2)cc1OCc1ccccc1)NC(=O)c1ccccc1
Temperature: 60 °C
Yield: 46.3 %

Procedure:
A mixture of methyl (Z)-2-benzoylamino-3-(2,4-dibenzyloxyphenyl)acrylate (1.6 g) and aqueous potassium hydroxide in methanol (35 mL, 15%) is stirred and heated at 60° C. for 6 hours. The reaction mixture is diluted with water (20 mL), acidified to pH 1 by addition of concentrated hydrochloric acid and the resulting solid filtered. Recrystallisation fro ethyl acetate gives (Z)-2-benzoylamino-3-(2,4-dibenzyloxyphenyl)acrylic acid (0.72 g) as a white solid, m.p. 212-213° C. [Elemental analysis:- C,75.2; H,5.28; N,2.83%. Calculated :- C,75.1; H,5.26; N,2.92%].
Reaction SMILES: C([O:5][C:6]([CH2:8][O:9][C:10]([N:12]1[C:21]2[C:16](=[CH:17][C:18]([C:22]([F:25])([F:24])[F:23])=[CH:19][CH:20]=2)[C@@H:15]([N:26]([CH2:39][C:40]2[CH:45]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:43]=[C:42]([C:50]#[N:51])[CH:41]=2)[C:27]2[N:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:29][N:28]=2)[CH2:14][C@H:13]1[CH2:52][CH3:53])=[O:11])=[O:7])(C)(C)C.C(=O)([O-])O.[Na+].C(OCC)(=O)C>Cl.O1CCOCC1>[C:6]([CH2:8][O:9][C:10]([N:12]1[C:21]2[C:16](=[CH:17][C:18]([C:22]([F:25])([F:24])[F:23])=[CH:19][CH:20]=2)[C@@H:15]([N:26]([CH2:39][C:40]2[CH:45]=[C:44]([C:46]([F:47])([F:48])[F:49])[CH:43]=[C:42]([C:50]#[N:51])[CH:41]=2)[C:27]2[N:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:29][N:28]=2)[CH2:14][C@H:13]1[CH2:52][CH3:53])=[O:11])([OH:7])=[O:5]
Reactant: CC[C@@H]1C[C@H](N(Cc2cc(C#N)cc(C(F)(F)F)c2)c2ncc(N3CCOCC3)cn2)c2cc(C(F)(F)F)ccc2N1C(=O)OCC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC[C@@H]1C[C@H](N(Cc2cc(C#N)cc(C(F)(F)F)c2)c2ncc(N3CCOCC3)cn2)c2cc(C(F)(F)F)ccc2N1C(=O)OCC(=O)O
Temperature: 25 °C
Reaction time: 6.5 h

Procedure:
The compound obtained in Example 22 above (37 mg) was dissolved in 4N HCl/dioxane (2 ml) and stirred at room temperature for 6.5 hours. A saturated sodium hydrogen carbonate aqueous solution and ethyl acetate were added to the reaction mixture and the organic layer was separated, washed with a saturated brine, dried over magnesium sulfate and concentrated in vacuo. The resulting residue was purified by column chromatography (silica gel; chloroform:methanol=1:0→17:3) to give the titled compound (26 mg). MS (m/z): 693 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[CH:40]=[CH:39][C:29]2=[N:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:36]=3[C:37](=[O:38])[N:28]2[N:27]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[CH:40]=[CH:39][C:29]5=[N:30][C:31]6[CH:32]=[CH:33][CH:34]=[CH:35][C:36]=6[C:37](=[O:38])[N:28]5[N:27]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Reactant: O=c1c2ccccc2nc2ccc(Cl)nn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4ccc5nc6ccccc6c(=O)n5n4)cc3CC[C@@H]12
Yield: 59.4 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2-chloro-10H-pyridazino[6,1-b]quinazolin-10-one (107 mg, 0.46 mmol) and 1 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (0-10% methanol/ethyl acetate eluent gradient) to give 103 mg (62%) of the title compound as an amorphous foam. mp 110°-114°. FDMS: m/e=456. α[D]589 =+54.77 (c=0.49, chloroform).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@@H:12](O)[CH3:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.S(Br)([Br:17])=O>ClCCl>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C@@H:12]([Br:17])[CH3:13])[CH:3]=1
Reactant: O=S(Br)Br
Reactant: C[C@H](O)c1cc(Br)cc(C(F)(F)F)c1
Solvent: ClCCl
Product: C[C@H](Br)c1cc(Br)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-1-(3-bromo-5-(trifluoromethyl)phenyl)ethanol (150 mg, 0.56 mmol) in dichloromethane (3 mL) at 0° C. was added thionyl bromide (0.086 mL, 1.12 mmol). The ice bath was removed and stirring continued for 1 h. The reaction was warmed to reflux and held there for 1 h. The reaction was treated with a second portion of thionyl bromide (0.086 mL, 1.12 mmol) and the reaction held at reflux for 2 h. The reaction was cooled to 0° C., quenched by addition of water, and diluted with pentane. The organics were washed with water (2×), then brine, dried over magnesium sulfate, and concentrated. Column chromatography (100% hexanes) gave 78 mg (42%). 1H NMR (500 MHz, CDCl3) δ ppm 7.76 (s, 1H), 7.68 (s, 1H), 7.60 (s, 1H), 5.12 (q, J=7.0 Hz, 1H), 2.03 (d, J=7.0 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ ppm 146.4, 133.5, 132.9 (q, J=32.6 Hz), 128.4 (q, J=3.8 Hz), 123.0, 123.0 (q, J=273 Hz), 122.6 (q, J=3.8 Hz), 46.1, 26.6.
Reaction SMILES: [CH2:1]([NH2:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[C:11](Cl)(=[O:16])[CH2:12][CH2:13][CH2:14][CH3:15]>C(OCC)C>[CH2:1]([NH:10][C:11](=[O:16])[CH2:12][CH2:13][CH2:14][CH3:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCCN
Reactant: CCCCC(=O)Cl
Solvent: CCOCC
Product: CCCCCCCCCNC(=O)CCCC

Procedure:
2 mole nonylamine are reacted with 1 mole valeroyl chloride in diethyl ether, the suspension is filtered off with suction, the filtrate is evaporated and N-nonyl-valeric acid amide is thus obtained quantitatively; m.p. 29°-31° C. Reduction with 1.65 mole lithium aluminium hydride in diethyl ether gives a colourless oil in a yield of 78% of theory; b.p. 142°-146° C./16 mm.Hg. The addition of this N-nonyl-N-pentylamine to methyl acrylate (oil; yield 96% of theory) and subsequent saponification with 1N aqeuous sodium hydroxide solution gives a yield of 64% of theory of pasty 3-(N-nonyl-N-pentylamino)-propionic acid which is reacted analogously to Example 3 to give the diphosphonic acid; yield 87% of theory; m.p. 168°-176° C.; Mrel =0.14.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:12]=[C:11]2[C:7]([N:8]=[CH:9][N:10]2[C@@H:13]2[CH2:17][C@H:16]([CH2:18][OH:19])[CH:15]=[CH:14]2)=[C:6](Cl)[N:5]=1.[CH:21]([OH:24])([CH3:23])[CH3:22]>>[NH2:3][C:4]1[N:12]=[C:11]2[C:7]([N:8]=[CH:9][N:10]2[C@@H:13]2[CH2:17][C@H:16]([CH2:18][OH:19])[CH:15]=[CH:14]2)=[C:6]([O:24][CH:21]([CH3:23])[CH3:22])[N:5]=1
Reactant: CC(C)O
Reactant: Nc1nc(Cl)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Agent: [H-]
Agent: [Na+]
Product: CC(C)Oc1nc(N)nc2c1ncn2[C@H]1C=C[C@@H](CO)C1
Temperature: 75 °C

Procedure:
A flask was charged with sodium hydride (60% oil dispersion, 240 mg, ~6 mmol) which was washed with hexanes before the addition of isopropanol (20 mL) and (±)-cis-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopentene-1-methanol (0.318 g, 1.19 mmol) from Example 4. This solution was heated at 75° C. for 2 hours before being allowed to cool to room temperature and neutralized by addition of 1.0 N HC1. The solution was concentrated and the residue was placed on a silica gel column which was eluted with 10% methanol-chloroform. Crystallization from ethanol:water 1:1 yielded off-white crystals (265 mg, 77%), m.p. 188-191° C.