Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]34[C:12](=[CH:13][C:14](=[O:15])[C:5]=2[NH:4][CH:3]=1)[N:11]([C:16]([C:18]1[NH:26][C:25]2[C:20](=[C:21]5[CH2:32][CH2:31][N:30]([C:33]([C:35]6[NH:43][C:42]7[C:37](=[C:38]8[CH2:49][CH2:48][N:47]([C:50]([NH2:52])=[O:51])[C:39]8=[C:40]([OH:46])[C:41]=7[O:44][CH3:45])[CH:36]=6)=[O:34])[C:22]5=[C:23]([OH:29])[C:24]=2[O:27][CH3:28])[CH:19]=1)=[O:17])[CH2:10][CH:9]3[CH2:8]4.[C:53]([OH:56])(=[O:55])[CH3:54]>>[C:53]([O:56][CH2:8][CH:9]1[CH2:10][N:11]([C:16]([C:18]2[NH:26][C:25]3[C:24]([O:27][CH3:28])=[C:23]([OH:29])[C:22]4[N:30]([C:33]([C:35]5[NH:43][C:42]6[C:41]([O:44][CH3:45])=[C:40]([OH:46])[C:39]7[N:47]([C:50]([NH2:52])=[O:51])[CH2:48][CH2:49][C:38]=7[C:37]=6[CH:36]=5)=[O:34])[CH2:31][CH2:32][C:21]=4[C:20]=3[CH:19]=2)=[O:17])[C:12]2[CH:13]=[C:14]([OH:15])[C:5]3[NH:4][CH:3]=[C:2]([CH3:1])[C:6]=3[C:7]1=2)(=[O:55])[CH3:54]
Reactant: COc1c(O)c2c(c3cc(C(=O)N4CCc5c4c(O)c(OC)c4[nH]c(C(=O)N6CC7CC78C6=CC(=O)c6[nH]cc(C)c68)cc54)[nH]c13)CCN2C(N)=O
Reactant: CC(=O)O
Product: COc1c(O)c2c(c3cc(C(=O)N4CCc5c4c(O)c(OC)c4[nH]c(C(=O)N6CC(COC(C)=O)c7c6cc(O)c6[nH]cc(C)c76)cc54)[nH]c13)CCN2C(N)=O

Procedure:
In The Journal of Antibiotics, 1985, 38, 746, D. G. Martin et al reported that acetic acid adds across the spirocyclopropylcyclohexadienyl (SCPCH) system of CC-1065 to produce the phenolic, acetic acid product (AAP), 7-[[7-[[1-[(acetyloxy)methyl]-1,6-dihydro-5-hydroxy-8-methylbenzo[1,2-b:4,3-b']dipyrrol-3(2H)-yl]carbonyl]-1,6-dihydro-4-hydroxy-5-methoxybenzo[1,2-b:4,3-b']-dipyrrol-3(2H)-yl]carbonyl]-1,6-dihydro-4-hydroxy-5-methoxybenzo[1,2-b:4,3-b']dipyrrole-3(2H)-carboxamide. AAP was tested in vitro and in vivo and found to be less potent than CC-1065 by a factor of 103 to 104 depending upon the particular test system and therefore tended to divert attention from adducts of the SCPCH system as useful antitumor agents or as prodrugs to CC-1065 analogs.
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:21]1[CH:25]=[C:24]([CH2:26][CH2:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=2)[N:23]=[N:22]1.C(N(CC)CC)C>CN(C=O)C>[C:7]([N:21]1[CH:25]=[C:24]([CH2:26][CH2:27][CH2:28][CH2:29][C:30]2[CH:31]=[CH:32][C:33]([OH:36])=[CH:34][CH:35]=2)[N:23]=[N:22]1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccc(CCCCc2c[nH]nn2)cc1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Oc1ccc(CCCCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)nn2)cc1
Reaction time: 8 h

Procedure:
A solution of 706 mg (5.06 mmol) triphenylchloromethane in 5.0 ml DMF was added at 0° C. to a solution of 500 mg (2.30 mmol) 4-(4-1H-[1,2,3]triazol-4-yl-butyl)-phenol and 512 mg (5.06 mmol) triethylamine in 5.0 ml DMF. The mixture was allowed to reach r.t. overnight and solvents were removed in vacuo. After distribution of the residue between water and ethyl acetate, the organic phase was dried (sodium sulphate), solvents distilled off and the residue purified by column chromatography on silica gel (heptane/ethyl acetate 2:1).
Reaction SMILES: [C:1](=[O:36])([O:3][CH2:4][CH:5]1[C:17]2([OH:19])[O:18][N:12]([CH2:13][CH:14]3[CH:16]2[N:15]3[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[C:11]2[C:6]1=[C:7]([OH:35])[CH:8]=[C:9]([CH:30]([O:33][CH3:34])[O:31][CH3:32])[CH:10]=2)[NH2:2]>N1C=CC=CC=1.C(OC(=O)C)(=O)C.CN(C)C1C=CN=CC=1>[C:4]([O:35][C:7]1[CH:8]=[C:9]([CH:30]([O:33][CH3:34])[O:31][CH3:32])[CH:10]=[C:11]2[C:6]=1[CH:5]([CH2:4][O:3][C:1](=[O:36])[NH2:2])[C:17]1([O:19][C:17](=[O:18])[CH3:16])[O:18][N:12]2[CH2:13][CH:14]2[CH:16]1[N:15]2[C:20]([O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:21])(=[O:3])[CH3:5]
Reactant: COC(OC)c1cc(O)c2c(c1)N1CC3C(N3C(=O)OCc3ccccc3)C(O)(O1)C2COC(N)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: COC(OC)c1cc(OC(C)=O)c2c(c1)N1CC3C(N3C(=O)OCc3ccccc3)C(OC(C)=O)(O1)C2COC(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 196.1 %

Procedure:
To a solution of 11-benzyloxycarbonyl-6,9-dihydroxy-4-dimethoxymethyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-8-ylmethyl carbamate (400 mg) in a mixture of pyridine (10 ml) and acetic anhydride (5 ml) was added 4-dimethylaminopyridine (10 mg). The mixture was stirred overnight at ambient temperature and evaporated in vacuo. The residue was subjected to silica gel column chromatography and elution was carried out with a mixture of chloroform and methanol (50:1, v/v). The desired fractions were combined and then evaporated to dryness in vacuo to afford 11-benzyloxycarbonyl-8-carbamoyloxymethyl-4-dimethoxymethyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-6,9-diyl diacetate (458 mg).
Reaction SMILES: IC1C=CC(C)=CC=1S(O)(=O)=[O:10].OOS([O-])=O.[K+].[C:19]1([CH2:25][CH2:26][CH2:27][CH2:28][OH:29])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>[N+](C)([O-])=O>[C:19]1([CH2:25][CH2:26][CH2:27][C:28]([OH:10])=[O:29])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1ccc(I)c(S(=O)(=O)O)c1
Reactant: OCCCCc1ccccc1
Agent: O=S([O-])OO
Agent: [K+]
Solvent: C[N+](=O)[O-]
Product: O=C(O)CCCc1ccccc1
Temperature: 70 °C
Reaction time: 6 h

Procedure:
8.9 mg (0.03 mmol) of 2-iodo-5-methylbenzenesulfonic acid prepared by Preparation Example 2, 2.04 g (3.3 mmol) of powdered Oxone (registered trademark) were added to 3.75 ml of nitromethane, and 450 mg (3 mmol) of 4-phenylbutanol was added dropwise for two hours, and the mixture was heated at 70° C. while being stirred for six hours. The later treatment was carried out in the same way as in Example 1, and then 4-phenylbutanoic acid was obtained. The yield of the obtained 4-phenylbutanoic acid was determined and the result is shown in Table 1.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=2[C:30](O)=[O:31])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:37][NH2:38]>>[N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=2[C:30]([NH:38][CH3:37])=[O:31])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CN
Reactant: O=C(O)c1ccccc1SCc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Product: CNC(=O)c1ccccc1SCc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O

Procedure:
Using the method in Example 172, 2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoic acid (50 mg, 0.10 mmol, 0.20M in DMF) and a saturated solution of methylamine (1.0 ml in DMF) were combined to give 26 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 512 [M+H]+.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.S(Cl)([Cl:14])=O>>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([Cl:14])=[O:11]
Reactant: O=C(O)Cc1ccccc1I
Reactant: O=S(Cl)Cl
Product: O=C(Cl)Cc1ccccc1I

Procedure:
A solution of 13.32 g (0.05 mol) of 2-iodophenylacetic acid in 75 ml thionyl chloride is refluxed for 2 hours, and the volatiles removed under vacuum. Toluene is added (3 times) and the solvent removed under vacuum after each addition to give 2-iodophenylacetyl chloride as a gum. To the preceding compound (0.05 mol) in a mixture of 100 ml of toluene-dichloromethane (1:1) is added 11 g (0.05 mol) of 2-iodoaniline and (0.10 mol) of diisopropylethylamine. The mixture is stirred at room temperature overnight and the solvent removed. The residue is dissolved in dichloromethane and the solution washed with 1N HCl, saturated sodium bicarbonate, brine and dried (Na2SO4). The solvent is removed and the residue recrystallized from methanol-ether to give 16.0 g of light brown crystals, m.p. 160°-163° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([OH:9])=O)[N:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[Cl:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:49]=[C:50]([NH2:61])[CH:51]=[N:52][C:53]=2[O:54][C@@H:55]([CH3:60])[C:56]([F:59])([F:58])[F:57])=[CH:44][CH:43]=1>CN(C=O)C>[Cl:41][C:42]1[CH:43]=[CH:44][C:45]([C:48]2[CH:49]=[C:50]([NH:61][C:7]([C:3]3[N:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[O:9])[CH:51]=[N:52][C:53]=2[O:54][C@@H:55]([CH3:60])[C:56]([F:57])([F:58])[F:59])=[CH:46][CH:47]=1
Reactant: C[C@H](Oc1ncc(N)cc1-c1ccc(Cl)cc1)C(F)(F)F
Reactant: O=C(O)c1cccnn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H](Oc1ncc(NC(=O)c2cccnn2)cc1-c1ccc(Cl)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.3 %

Procedure:
Pyridazine-3-carboxylic acid (CAN 2164-61-6; 43.1 mg, 347 μmol) was suspended in DMF (1.0 mL). TBTU (112 mg, 347 μmol), ethyldiisopropylamine (102 mg, 131 μl, 789 μmol,) and 5-(4-chloro-phenyl)-6-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-pyridin-3-ylamine (0.100 g, 316 μmol) were added and the reaction mixture was stirred at room temperature for 1 h. The rection mixture was extracted with ethyl acetate and 1M citric acid solution; the organic phase was dried with MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 10 g, 10% to 50% ethyl acetate in heptane) to give 0.11 g (83%) of the title compound as white solid; MS (EI) 423.1 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([CH3:15])[CH:5]([OH:14])[C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)=[O:7].[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.O>O1CCCC1>[CH3:26][C:16]1[CH:21]=[CH:20][C:19]([S:22]([O:14][CH:5]([C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[O:7])[CH:4]([CH3:15])[CH3:3])(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)C(O)C(=O)N1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OC(C(=O)N2CCOCC2)C(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.4 %

Procedure:
Under ice-cooling, to a solution of 60% sodium hydride (136 mg, 3.41 mmol) in tetrahydrofuran (5 mL) is added dropwise a solution of 3-methyl-1-morpholin-4-yl-1-oxobutan-2-ol (426 mg, 2.27 mmol) in tetrahydrofuran (15 mL), and the mixture is stirred at room temperature for 2 hours. To the reaction solution is added p-toluene-sulfonyl chloride (651 mg, 3.42 mmol), and the mixture is stirred at room temperature for 2 hours. After the reaction is completed, water is added to the mixture, and the mixture is extracted with ethyl acetate. This organic layer is washed with water, a saturated aqueous sodium hydrogen carbonate solution, and a saturated brine, and dried over anhydrous magnesium sulfate. The solvent is removed by distillation, and the obtained residue is purified by silica gel column chromatography (chloroform) to give the title compound (701 mg, yield: 90%).
Reaction SMILES: C([O:4][CH:5]([CH2:15][N:16](C(=O)C)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)[C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([NH2:13])=[C:8]([Cl:14])[CH:7]=1)(=O)C>[OH-].[Na+].C(O)C>[NH2:13][C:9]1[C:10]([Cl:12])=[CH:11][C:6]([CH:5]([CH2:15][NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[OH:4])=[CH:7][C:8]=1[Cl:14]
Reactant: CC(=O)OC(CN(CCCCCCOCCc1ccccn1)C(C)=O)c1cc(Cl)c(N)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1c(Cl)cc(C(O)CNCCCCCCOCCc2ccccn2)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.7 %

Procedure:
A mixture of α-[[acetyl[6-[2-(2-pyridinyl)ethoxy]hexyl]amino]methyl]-4-amino-3,5-dichlorobenzenemethanol acetate (ester) (130 mg) in sodium hydroxide (5 ml) and ethanol (5 ml) was stirred at room temperature for 18 h. The mixture was heated under reflux for 20 h, cooled, evaporated in vacuo and the aqueous layer extracted with ethyl acetate (2×20 ml). The combined organic extracts were dried and concentrated to give a yellow oil which was triturated in ether/hexane to give the title compound as a white solid (80 mg) m.p. 92°-95°, t.l.c. (System A 80:20:1) Rf 0.44.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[N:11]([CH2:14][CH2:15][CH2:16][F:17])[N:10]=[N:9]2)=[C:4]([F:18])[CH:3]=1.[N+:19]([O-])([OH:21])=[O:20]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:7]([N+:19]([O-:21])=[O:20])=[CH:6][C:5]([N:8]2[C:12](=[O:13])[N:11]([CH2:14][CH2:15][CH2:16][F:17])[N:10]=[N:9]2)=[C:4]([F:18])[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: O=c1n(CCCF)nnn1-c1ccc(Cl)cc1F
Agent: O=S(=O)(O)O
Product: O=c1n(CCCF)nnn1-c1cc([N+](=O)[O-])c(Cl)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 3.1 g (0.011 mole) of 1-(4-chloro-2-fluorophenyl)-1,4-dihydro-4-(3-fluoropropyl)-5H-tetrazol-5-one in 5 ml of concentrated sulfuric acid was added dropwise 0.9 ml (0.011 mole) of 70% nitric acid. Upon completion of addition the reaction mixture was stirred for two hours at ambient temperature then was poured into ice-water. The mixture was extracted with diethyl ether. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was dissolved in methylene chloride and passed through a pad of silica gel. The eluate was concentrated under reduced pressure to yield 2.8 g of 1-(4-chloro-2-fluoro-5-nitrophenyl-1,4-dihydro-4-(3-fluoropropyl)-5H-tetrazol-5-one; m.p. 80°-81° C. The reaction was repeated several times.
Reaction SMILES: [CH3:1][CH:2]([C:7](=[CH:13][CH3:14])[C:8]([O:10]CC)=[O:9])[CH2:3][CH2:4][CH2:5][CH3:6].[OH-].[Na+]>CO.O>[CH3:1][CH:2]([C:7](=[CH:13][CH3:14])[C:8]([OH:10])=[O:9])[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CC=C(C(=O)OCC)C(C)CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC=C(C(=O)O)C(C)CCCC
Yield: 98 %

Procedure:
Ethyl (2-hexyl)but-2-enoate (12 g, 0.06M) in methanol (150 ml) was treated with sodium hydroxide (15 g, 0.375M) in water (100 ml) under reflux for 6 hours. The solvents were then removed in vacuo and the residue taken up in water and extracted with dichloromethane. The aqueous phase was separted, acidified in pH1 with concentrated hydrochloric acid and extracted with dichloromethane. The extract was dried over sodium sulphate and concentrated in vacuo to an oil which was distilled in vacuo to afford E and Z (2-hexyl)but-2-enoic acid (10.1 g, 0.06M) as the main fraction (b.p. 100°-110° C. at 0.5 mm Hg) (Found: C, 68.2; H, 10.4. C10H18O2 +0.5H2O requires: C, 68.5; H, 9.7%); δ(CDCl3) 0.88 (3H, m, CH3); 1.3 (8H, m, (CH2)4); 1.84 and 2.04 (3H, each m, each CH3CH); 2.32 (2H, t, J=8 Hz, CH2) 6.14 and 6.94 (1H, each q, each J=8 Hz, CH).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@H:21]([CH2:24][C:25](=[O:27])[CH3:26])[CH2:22][CH3:23])[C:11](=[O:28])[C@:10]([CH2:30][C:31]([OH:33])=[O:32])([CH3:29])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[BH4-].[Na+]>CCOCC.CO>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@H:21]([CH2:24][CH:25]([OH:27])[CH3:26])[CH2:22][CH3:23])[C:11](=[O:28])[C@:10]([CH2:30][C:31]([OH:33])=[O:32])([CH3:29])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@@H](CC(C)=O)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: CC[C@@H](CC(C)O)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-5-oxohexan-3-yl)piperidin-3-yl)acetic acid (24 mg, 0.049 mmol; Example 130) in ether (0.40 mL) and MeOH (0.10 mL) was added sodium borohydride (9.26 mg, 0.245 mmol) at 0° C. Then the reaction was allowed to warm to rt. After being stirred at rt for 1 h, the reaction was quenched (10% citric acid) and extracted (2×EtOAc). The combined organic layer was washed (sat. aq. NaCl solution), dried (Na2SO4), and concentrated under reduced pressure. Purification by RP-HPLC (30 to 70% MeCN/H2O (0.1% TFA), a gradient elution) provided the title compound as the more polar isomer.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C@H:7]2[CH2:8][C@@H:3]1[CH2:4][CH2:5][C@H:6]2[CH2:9][CH2:10][OH:11].C([OH:15])C>O.C(O)(=O)C.[O-2].[O-2].[O-2].[Cr+6]>[CH3:1][C:2]1([CH3:12])[C@H:7]2[CH2:8][C@@H:3]1[CH2:4][CH2:5][C@H:6]2[CH2:9][C:10]([OH:15])=[O:11]
Reactant: CCO
Reactant: CC1(C)[C@H]2CC[C@@H](CCO)[C@@H]1C2
Agent: [Cr+6]
Agent: [O-2]
Solvent: O
Solvent: CC(=O)O
Product: CC1(C)[C@H]2CC[C@@H](CC(=O)O)[C@@H]1C2
Temperature: 15 °C
Reaction time: 8 h

Procedure:
A solution of chromium trioxide (42.6 g CrO3, 426 mmol) in water (40 mL) was diluted with acetic acid (350 mL). The solution was cooled to 15° C. and the product from Example 4A (27 g, 160 mmol) was added dropwise. The solution was left to stand at room temperature overnight. Ethanol (20 mL) was added to destroy the excess of CrO3. The mixture was heated at 50° C. for 15 minutes and then concentrated under reduced pressure. The residue was suspended in water, acidified to pH 2 and extracted 3 times with ether. The ethereal solution was concentrated and the residue was dissolved in hexanes. The organic solution is decanted from the green tar and concentrated under reduced pressure. The residue was dissolved in 10% aqueous NaOH and neutral impurities were extracted with ether (discarded). The aqueous phase was acidified to pH 2 and extracted with hexanes, dried with Na2SO4, concentrated, cooled and filtered to give 10.9 g of title compound (crystals melting point: 50-53° C.).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[CH:20]=[CH:19][C:8]2[C:9](=[O:18])[C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[CH:12]=[CH:13][C:7]=2[CH:6]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC.O1CCCC1>[O:18]=[C:9]1[C:8]2[CH:19]=[CH:20][C:5]([CH2:4][CH2:3][OH:2])=[CH:6][C:7]=2[CH:13]=[CH:12][C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]1=2
Reactant: COC(=O)Cc1ccc2c(=O)c3ccccc3ccc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=c1c2ccccc2ccc2cc(CCO)ccc12
Reaction time: 3 h

Procedure:
0.45 G. of methyl(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)acetate is dissolved in 10 ml. of ether/tetrahydrofuran (1:1) and excess lithium aluminum hydride is added. After 3 hours, excess hydride is destroyed by addition of water and the mixture is extracted with ether. The extract is dried and to it is added 2.0 g. of manganese dioxide. The mixture is left for 4 days and then filtered through celite and evaporated. The residue is recrystallized from hexane to afford 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)ethan1-ol (m.p. 73°-75°C).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([CH:11]=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[F:13][C:14]1[CH:15]=[C:16]([C:29]2[C:30]([S:35]([NH:38][CH3:39])(=[O:37])=[O:36])=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:17]=[CH:18][C:19]=1B1OC(C)(C)C(C)(C)O1>>[F:13][C:14]1[CH:15]=[C:16]([C:29]2[C:30]([S:35]([NH:38][CH3:39])(=[O:37])=[O:36])=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:17]=[CH:18][C:19]=1[C:2]1[CH:3]=[C:4]2[C:10]([CH:11]=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CNS(=O)(=O)c1ccccc1-c1ccc(B2OC(C)(C)C(C)(C)O2)c(F)c1
Reactant: O=Cc1c[nH]c2ncc(Br)cc12
Product: CNS(=O)(=O)c1ccccc1-c1ccc(-c2cnc3[nH]cc(C=O)c3c2)c(F)c1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 88 using 5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde and 3′-fluoro-N-methyl-4′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-2-sulfonamide. MS (ESI): mass calcd. for C21H16FN3O3S, 409.09; m/z found, 410.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].[F:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1>>[F:21][C:22]1[CH:27]=[C:26]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]3=[O:20])[CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Reactant: OB(O)c1cccc(F)c1
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3cccc(F)c3)ccn2c1=O
Yield: 80.4 %

Procedure:
Methyl 8-(3-fluoro-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A from methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.34 mmol) and 3-fluoro-phenyl-boronic acid (71 mg, 0.51 mmol). Purification by flash silica column chromatography (DCM:MeOH) (1:0 to 94:6) afforded the title compound as a yellow solid (96 mg, 77%).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:17])[N:9]([CH3:16])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][CH:15]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[F:18].[I:19]I>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:17])[N:9]([CH3:16])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[I:19])[C:6]=2[CH:5]=[CH:4][C:3]=1[F:18]
Reactant: CN1Cc2cncn2-c2ccc(F)c(Cl)c2C1=O
Reactant: II
Solvent: CN(C)C=O
Product: CN1Cc2c(I)ncn2-c2ccc(F)c(Cl)c2C1=O

Procedure:
6.08 g (22.8 mmol) of 7-chloro-8-fluoro-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one was stirred at 100° for 4 hours with 20 g (79.5 mmol) of iodine in 50 ml of N,N-dimethylformamide. The reaction mixture was evaporated, the residue was taken up in methylene chloride and water, decolorized with sodium thiosulphate and neutralized with sodium bicarbonate. The aqueous phase was separated and extracted four times with methylene chloride. The combined organic phases were dried over magnesium sulphate, evaporated and the residue was chromatographed on silica gel while eluting with ethyl acetate/hexane (1:1). There was obtained 7-chloro-8-fluoro-4,5-dihydro-3-iodo-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 218°-219°.
Reaction SMILES: C(O[C:4](=[O:15])[CH:5](P(OCC)(OCC)=O)[CH3:6])C.C([Li])CCC.[CH:21]1([NH:26][C:27]2[C:32]([CH:33]=O)=[CH:31][N:30]=[C:29]([S:35][CH3:36])[N:28]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[CH:21]1([N:26]2[C:27]3[N:28]=[C:29]([S:35][CH3:36])[N:30]=[CH:31][C:32]=3[CH:33]=[C:5]([CH3:6])[C:4]2=[O:15])[CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Reactant: CSc1ncc(C=O)c(NC2CCCC2)n1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1ncc2cc(C)c(=O)n(C3CCCC3)c2n1
Temperature: -40 °C
Yield: 36.5 %

Procedure:
2-(Diethoxy-phosphoryl)-propionic acid ethyl ester (15.24 g, 64 mmol) was dissolved in tetrahydrofuran (100 mL) to which n-butyl lithium (47.7 mL, 119 mmol, 2.5 M in hexanes) was slowly added at −70° C. 4-Cyclopentylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde (15 g, 63 mmol) was dissolved in tetrahydrofuran (70 mL) then added to the reaction mixture allowing the reaction to warm to −40° C. After 3 hours the reaction was warmed to room temperature, poured into cold 1 N citric acid and extracted with diethyl ether. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated to give a yellow oil which was purified by silica gel chromatography. The resulting oil was dissolved to 1,8-diazabicyclo[5.4.0]undec-7-ene (75 mL) and heated to 150° C. for 4 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (350 mL), washed with 5% HCl and brine, dried over MgSO4, then filtered and concentrated in vacuo The remaining residue was diluted with diethyl ether and the precipitated solid was filtered off to give 8-cyclopentyl-6-methyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one as a white solid (6.33 g, 31.3%). 1H NMR δ (400 MHz, CDCl3) 8.52 (s, 1H), 7.39 (d, J=1.2 Hz, 1H), 5.96 (m, 1H), 2.59 (s, 3H), 2.30 (m, 2H), 2.19 (d, J =1.2 Hz, 3H), 2.07 (m, 2H), 1.86 (m, 2H), 1.67 (m, 2H).