Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:14]=[C:13]2[C:8]([C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24](=[O:27])[CH2:25]Br)[CH:18]=3)=[N:10][C:11]([S:15][CH3:16])=[N:12]2)=[C:7]([NH2:28])[C:6]=1[C:29]([NH2:31])=[O:30])([CH3:4])([CH3:3])[CH3:2].[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.O.Cl>C(#N)C.C(Cl)Cl>[C:1]([C:5]1[CH:14]=[C:13]2[C:8]([C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24](=[O:27])[CH2:25][N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)[CH:18]=3)=[N:10][C:11]([S:15][CH3:16])=[N:12]2)=[C:7]([NH2:28])[C:6]=1[C:29]([NH2:31])=[O:30])([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1nc(-c2cccc(NC(=O)CBr)c2)c2c(N)c(C(N)=O)c(C(C)(C)C)cc2n1
Reactant: C1COCCN1
Agent: Cl
Solvent: CC#N
Solvent: O
Solvent: ClCCl
Product: CSc1nc(-c2cccc(NC(=O)CN3CCOCC3)c2)c2c(N)c(C(N)=O)c(C(C)(C)C)cc2n1
Reaction time: 18 h

Procedure:
To a solution of tert-butyl 5-amino-2-methylthio-4-(3-(2-bromoacetamido)-phenyl)-quinazoline-6-carboxamide (example 28a, 88 mg) in acetonitrile was added morpholine (148 l) and the mixture was stirred for 18 h. After this time CH2Cl2 (15 ml) was added and the mixture was washed with sat. aqueous NaHCO3. The organic layer was dried (MgSO4) and concentrated in vacuo. The title compound was purified by chromatography on silica gel using CH2Cl2MeOH=1/0 to 9/1 (v/v) as eluent. The title compound was lyophilized from a mixture of acetonitrile and water containing 1.5 equiv. of HCl.
Reaction SMILES: [CH3:1][C:2]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.[Cr:9]([Cl:13])([O-:12])(=[O:11])=[O:10].[NH+:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CCOCC>C(Cl)Cl>[Cr:9]([Cl:13])([O-:12])(=[O:11])=[O:10].[NH+:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH3:1][C:2]1([CH:7]=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CC1(CO)CCCC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC1(C=O)CCCC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Pyridinium chlorochromate was prepared by following the procedure of E. J. Corey and J. W. Suggs, Tetrahedron Letters, 31, 2647 (1975). A solution of 11.8 g of 1-methylcyclopentanemethanol in 32 ml of anhydrous methylene chloride was added to a stirred suspension of 39.2 pyridinium chlorochromate in 312 ml of methylene chloride under argon. The resultant dark mixture was stirred for 1.5 hours at ambient temperature. A portion of ether was added to the resultant mixture and then the supernatant was decanted. The remaining dark residue was rinsed several times with ether. The combined ether solutions were filtered through a short pad of Florisil. The resultant solution was concentrated by distillation of ether and then the residue was distilled at 110 mm Hg to yield 6.41 g of 1-methylcyclopentanecarboxaldehyde as a colorless oil: bp 98-100°; nmr (CDCl3) δ 1.12 (3H, s), 1.0-2.2 (8H, m) and 9.50 ppm (1H, s).
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:25]2[CH:29]=[C:28]([C:30]3[C:31]([CH3:35])=[N:32][NH:33][CH:34]=3)[C:27]([C:36](OCC)=[O:37])=[N:26]2)[CH2:7][N:6]([C:8]2[CH:13]=[C:12]([F:14])[C:11]([C:15]([NH:17][C@@H:18]([CH3:23])[C:19]([F:22])([F:21])[F:20])=[O:16])=[CH:10][C:9]=2[F:24])[CH2:5]1)#[N:2].[BH4-].[Li+]>C1COCC1>[C:1]([CH2:3][C:4]1([N:25]2[CH:29]=[C:28]([C:30]3[C:31]([CH3:35])=[N:32][NH:33][CH:34]=3)[C:27]([CH2:36][OH:37])=[N:26]2)[CH2:7][N:6]([C:8]2[C:9]([F:24])=[CH:10][C:11]([C:15]([NH:17][C@@H:18]([CH3:23])[C:19]([F:21])([F:22])[F:20])=[O:16])=[C:12]([F:14])[CH:13]=2)[CH2:5]1)#[N:2]
Reactant: CCOC(=O)c1nn(C2(CC#N)CN(c3cc(F)c(C(=O)N[C@@H](C)C(F)(F)F)cc3F)C2)cc1-c1c[nH]nc1C
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1n[nH]cc1-c1cn(C2(CC#N)CN(c3cc(F)c(C(=O)N[C@@H](C)C(F)(F)F)cc3F)C2)nc1CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 1-{3-(cyanomethyl)-1-[2,5-difluoro-4-({[(1S)-2,2,2-trifluoro-1-methylethyl]amino}carbonyl)phenyl]azetidin-3-yl}-3′-methyl-1H,1′H-4,4′-bipyrazole-3-carboxylate (35 mg, 0.062 mmol) in THF (0.5 mL) was added 2.0 M lithium tetrahydroborate in THF (0.12 mL, 0.25 mmol). The reaction mixture was stirred at room temperature overnight. The reaction was quenched with water slowly. The aqueous layer was extracted with ethyl acetate. The organic layer was concentrated. The resulting residue was purified with prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product. 1H NMR (400 MHz, CDCl3) δ 7.79-7.68 (m, 2H), 7.61 (s, 1H), 6.65 (m, 1H), 6.20 (m, 1H), 4.99-4.89 (m, 1H), 4.68 (s, 2H), 4.60 (d, J=8.5 Hz, 2H), 4.45 (dd, J=8.9 and 2.0 Hz, 2H), 3.38 (s, 2H), 2.34 (s, 3H), 1.41 (d, J=7.0 Hz, 3H). LCMS calculated for C23H23F5N7O2 (M+H)+: m/z=524.2. Found: 524.0.
Reaction SMILES: O[CH2:2][CH:3]([CH2:5]O)O.[N+](C1C=CC=CC=1)([O-])=O.S(=O)(=O)(O)O.[NH2:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1.[OH-].[Na+]>O>[N:21]1[C:22]2[C:23](=[CH:24][N:25]=[CH:26][CH:27]=2)[CH:5]=[CH:3][CH:2]=1
Reactant: Nc1ccncc1
Reactant: OCC(O)CO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=[N+]([O-])c1ccccc1
Product: c1cnc2ccncc2c1
Temperature: 0 °C
Yield: 18 %

Procedure:
Glycerol (138.15 g, 1.5 mol) was added dropwise to an ice-cold mixture of "sulfo-mix" (a mixture of nitrobenzene and fuming sulfuric acid, see: Utermohlen, W. P., J. Org. Chem, 1943 8, 544). Addition of 4-aminopyridine (56.46 g, 0.6 mol) was followed by a rapid dropwise addition of water (225 ml), which caused a rise in temperature to 80°; the reaction mixture was allowed to stir until it became homogeneous, and was subsequently heated to 135° for 48 hours. It was then allowed to cool, poured into 1 l ice water, and the pH was adjusted to 13 by the addition of sodium hydroxide pellets. The resulting thick precipitate was removed by filtration, and the filtrate was extracted with methylene chloride (2×2 l). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated to yield a crude product, which was purified by column chromatography (98:2 methylene chloride:methanol). The title product was obtained as an amber oil which crystallized upon standing (13.7 g, 0.11 mol, 18% yield).
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C:9]1([CH2:14][NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23](C)[CH:24]=3)[N:19]=[C:18]([N:27]3[CH2:33][C:32]4[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=4[S:30](=[O:39])(=[O:38])[CH2:29][CH2:28]3)[CH:17]=2)CCOC1)C1C=CC=CC=1.[CH2:47](N)[CH2:48]N>>[O:38]=[S:30]1(=[O:39])[C:31]2[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=2[CH2:33][N:27]([C:18]2[CH:17]=[C:16]([NH:15][CH2:14][CH2:9][NH2:8])[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([CH2:47][CH3:48])[CH:24]=3)[N:19]=2)[CH2:28][CH2:29]1
Reactant: NCCN
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC3(N(Cc4ccccc4)Cc4ccccc4)CCOC3)c2c1
Product: CCc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCCN)c2c1

Procedure:
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro-6-ethylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 2-1 by using 4-chloro-6-ethylquinoline and 2,3,4,5-tetrahydro-1,4-benzothiazepine) and ethane-1,2-diamine. MS obsd. (ESI+) [(M+H)+] 411, 1H NMR (400 MHz, CD3OD) δ ppm 7.98 (d, J=7.6 Hz, 1 H), 7.84 (d, J=7.6 Hz, 1 H), 7.62 (m, 2 H), 7.44 (t, J=8.4 Hz, 2 H), 7.32 (dd, J=1.6, 8.4 Hz, 1 H), 6.03 (s, 1 H), 5.14 (s, 2 H), 4.53 (brs, 2 H), 3.58 (s, 2 H), 3.44 (t, J=6.0 Hz, 2 H), 2.97 (t, J=6.4 Hz, 2 H), 2.72 (q, J=7.6 Hz, 2 H), 1.27 (t, J=7.6 Hz, 3 H).
Reaction SMILES: [K+].[Br-].[F:3][C:4]([F:27])([CH:7]([F:26])[C:8]([F:25])([F:24])[O:9][C:10]([F:23])([F:22])[C:11]([F:21])([F:20])[C:12]([F:19])([F:18])[O:13][C:14]([F:17])([F:16])[F:15])[CH2:5][OH:6].[O-]Cl.[Na+].S(=O)(=O)(O)[OH:32]>CC1(C)N([O])C(C)(C)CCC1.O.CC#N>[F:3][C:4]([F:27])([CH:7]([F:26])[C:8]([F:25])([F:24])[O:9][C:10]([F:22])([F:23])[C:11]([F:20])([F:21])[C:12]([F:18])([F:19])[O:13][C:14]([F:15])([F:16])[F:17])[C:5]([OH:32])=[O:6]
Reactant: OCC(F)(F)C(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)OC(F)(F)F
Reactant: O=S(=O)(O)O
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: [Br-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C(O)C(F)(F)C(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)OC(F)(F)F
Temperature: 25 °C
Yield: 81 %

Procedure:
2.4 mL water, 8 ml MeCN, 0.16 g KBr, TEMPO (0.06 g), and 5 g of 2,2,3,4,4-pentafluoro-4-(1,1,2,2,3,3-hexafluoro-3-trifluoromethoxy-propoxy)-butan-1-ol (prepared according to Zh. Vses. Khim. Ova, 1979, p 656) were placed in a 50 mL glass flask equipped with a dropping funnel and stirrer. 24 ml 15% (wt.) aq. NaOCl buffered to pH 8-9 were added via the dropping funnel in 3 portions over two days while stirring at room temperature. Then concentrated sulphuric acid and water were added to make the reaction mixture acidic (pH=1-2). The reaction mixture was extracted three times with diethyl ether and the combined ether phases were dried over magnesium sulphate. The solvent was evaporated to give a colorless liquid, which was distilled using a water pump (15 mmHg, 75° C.) to give 4.17 g of the acid. Yield: 81%. 1H NMR (CDCl3): 5.2 (dm, J=43 Hz, 1H); 10.2 (s, 1H); 19F NMR (CDCl3): −56.3 (t, J=8.3 Hz, 3F); −78.5 (m, 2F); −84.7 (m, 2F); −86.87 (m, 2F); −130.45 (m, 2F); −117.9 (AB system, J=277 Hz, 1F); −121.6 (AB system, J=277 Hz, 1F); −130.5 (m, 2F); −214.1 (dm, J=43 Hz, J=ca. 11 Hz, 1F).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:27]2([CH3:28])[C@H:12]([C@H:13]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:16]([CH2:17][C@H:18]([CH2:20][CH2:21]2)[OH:19])=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3]>O1CCOCC1>[CH3:3][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:27]2([CH3:28])[C@H:12]([C@H:13]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:16](=[CH:17][C:18](=[O:19])[CH:20]=[CH:21]2)[CH:15]=[CH:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:1]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: C1COCCO1
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Yield: 60.5 %

Procedure:
Cholesterol (19.3 gms) and dichlorodicyanoquinone (38 gms) in dry dioxan (500 ml) were heated under reflux for 22 hrs. The mixture was then cooled, filtered and the filtrate evaporated to dryness. Chromatography of the residue on alumina and elution with benzene/hexane followed by elution with benzene afforded the trienone as a pale oil (11.5 gms) which solidified on standing. Physical properties of this material were appropriate.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:21][NH:22][CH2:23][CH2:24][CH:25]1[O:30][CH2:29][CH2:28][NH:27][CH2:26]1>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:27]4[CH2:28][CH2:29][O:30][CH:25]([CH2:24][CH2:23][NH:22][CH3:21])[CH2:26]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: CNCCC1CNCCO1
Product: CNCCC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CCO1

Procedure:
By the use of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 2-(2-methylaminoethyl)morpholine, the reaction is similarly carried out as Example 11 to give 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-[2-(2-methylaminoethyl)morpholino]-4-oxoquinoline-3-carboxylic acid 1/4 hydrate, melting at 243°-251° C. with decomposition.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][NH:4][C:3]1=[O:9].[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=1[SH:18]>>[CH3:1][N:2]1[C:7](=[O:8])[C:6]2[NH:10][C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=3[S:18][C:5]=2[NH:4][C:3]1=[O:9]
Reactant: Cn1c(=O)cc[nH]c1=O
Reactant: Cc1ccc(N)c(S)c1
Product: Cc1ccc2c(c1)Sc1[nH]c(=O)n(C)c(=O)c1N2

Procedure:
Employing the procedure of Example 1, parts A and B with 3-methylpyrimidine-2,4(1H, 3H)-dione and 2-amino-5-methylbenzenthiol yielded the title compound.
Reaction SMILES: N(OC(C)(C)C)=O.N[C:9]1[CH:10]=[C:11]([C:16]([F:19])([F:18])[F:17])[CH:12]=[CH:13][C:14]=1[Br:15].[CH3:20][S:21]SC>C(Cl)(Cl)Cl>[Br:15][C:14]1[CH:13]=[CH:12][C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[S:21][CH3:20]
Reactant: Nc1cc(C(F)(F)F)ccc1Br
Reactant: CSSC
Agent: CC(C)(C)ON=O
Solvent: ClC(Cl)Cl
Product: CSc1cc(C(F)(F)F)ccc1Br

Procedure:
t-Butyl nitrite (3 ml) was added to a mixture of 3-amino-4-bromobenzotrifluoride (4 g) and dimethyl disulphide (15 ml) in chloroform. The mixture was warmed until reaction started when t-butyl nitrite (11 ml) and a solution of 3-amino-4-bromobenzotrifluoride (16 g) in chloroform were added simultaneously. The resultant mixture was stirred for 24 hours, washed with water, hydrochloric acid (2M), water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was distilled to give 4-bromo-3-(methylsulphenyl)benzotrifluoride (16.4 g) as a yellow oil, b.p. 84°-88° C. at 2 mm Hg.
Reaction SMILES: Cl[CH2:2][O:3][CH3:4].[CH2:5]([O:7][C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([I:17])[C:15]=1[OH:16])[CH:11]=[O:12])[CH3:6].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:5]([O:7][C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([I:17])[C:15]=1[O:16][CH2:2][O:3][CH3:4])[CH:11]=[O:12])[CH3:6]
Reactant: CCOc1cc(C=O)cc(I)c1O
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc(C=O)cc(I)c1OCOC

Procedure:
Chloro(methoxy)methane (6.27 mL) was added to a mixture of 3-ethoxy-4-hydroxy-5-iodobenzaldehyde (16.1 g), potassium carbonate (15.2 g), and DMF (120 mL), and the resultant mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The obtained organic layer was washed with water and saturated saline and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (12.1 g).
Reaction SMILES: [CH:1]1([CH:6]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[C:22](=[O:23])[CH2:21][O:20][C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[N:18]3)=[CH:12][CH:11]=2)[C:7](O)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH:34]([CH2:38][CH2:39][C:40]([O:42][CH3:43])=[O:41])[CH2:33]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C>[CH:1]1([CH:6]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[C:22](=[O:23])[CH2:21][O:20][C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[N:18]3)=[CH:12][CH:11]=2)[C:7]([NH:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH:34]([CH2:38][CH2:39][C:40]([O:42][CH3:43])=[O:41])[CH2:33]2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C(c1ccc(CN2N=C(c3ccccc3)OCC2=O)cc1)C1CCCC1
Reactant: COC(=O)CCC1CCCC(N)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCC1CCCC(NC(=O)C(c2ccc(CN3N=C(c4ccccc4)OCC3=O)cc2)C2CCCC2)C1

Procedure:
A solution of 590 mg (1.5 mmol) of cyclopentyl{4-[(5-oxo-2-phenyl-5,6-dihydro-4H-1,3,4-oxadiazin-4-yl)methyl]phenyl}acetic acid (enantiomer 2; Example 77A), 400 mg (1.8 mmol) of methyl 3-(3-aminocyclohexyl)propanoate hydrochloride (mixture of isomers), 1.05 ml (6.0 mmol) of N,N-diisopropylethylamine and 857 mg (2.26 mmol) of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) in 13 ml of DMF was stirred at room temperature overnight. After the reaction had ended, the reaction mixture was poured onto ice-water, whereupon the target compound precipitated in the form of white crystals. After filtration, the crystals obtained were washed three times with water and then dried overnight at 40° C. in a vacuum drying cabinet. This gave 830 mg (1.58 mol, 98% of theory) of the title compound as a mixture of diastereomers.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.Br[CH2:23][CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH3:35]>>[OH:1][CH:2]1[CH:7]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:23][CH2:24][CH2:25][CH2:26][O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])=[CH:12][CH:13]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1
Reactant: COc1ccccc1OCCCCBr
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)C(O)C1
Product: COc1ccccc1OCCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1

Procedure:
Analogously to Method F, 5.86 g of tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidin-1-carboxylate and 6.33 g of 1-(4-bromobutoxy)-2-methoxybenzene are reacted. The title compound is obtained as a solid. Rf=0.12 (1:2 EtOAc-heptane); Rt=5.15.
Reaction SMILES: [C:1]1([NH:11][C:12]([N:14]2[CH2:19][CH2:18][NH:17][C@H:16]([C@@H:20]([NH:22][C:23]3[N:28]=[C:27]([N:29]4[C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=5[N:31]=[CH:30]4)[CH:26]=[CH:25][N:24]=3)[CH3:21])[CH2:15]2)=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH:38](=O)[CH3:39].C([BH3-])#N.[Na+]>>[CH2:38]([N:17]1[CH2:18][CH2:19][N:14]([C:12](=[O:13])[NH:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[CH2:15][C@H:16]1[C@@H:20]([NH:22][C:23]1[N:28]=[C:27]([N:29]2[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[N:31]=[CH:30]2)[CH:26]=[CH:25][N:24]=1)[CH3:21])[CH3:39]
Reactant: CC=O
Reactant: C[C@H](Nc1nccc(-n2cnc3ccccc32)n1)[C@@H]1CN(C(=O)Nc2cccc3ccccc23)CCN1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCN1CCN(C(=O)Nc2cccc3ccccc23)C[C@H]1[C@H](C)Nc1nccc(-n2cnc3ccccc32)n1

Procedure:
The title compound was prepared from (S,S)-2-[1-(4-(N-naphth-1-yl-carbamoyl)-piperazin-2-yi)-ethylamino]-4-[benzimidazol-1-yl]pyrimidine (EXAMPLE 36, Step C; 9 mg), acetaldehyde (5 mg), and sodium cyanoborohydride (2.3 mg) according to the procedure described in Example 14, Step G. Mass spectrum (ESI) 521.5 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][C:5]1([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[O:10])[CH2:8][CH2:7][CH2:6]1.[BH4-].[Na+]>>[CH3:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][C:5]1([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[OH:10])[CH2:6][CH2:7][CH2:8]1
Reactant: Cc1ccccc1CC1(C(=O)c2ccccn2)CCC1
Agent: [BH4-]
Agent: [Na+]
Product: Cc1ccccc1CC1(C(O)c2ccccn2)CCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 15 %

Procedure:
To a solution of Example 253B (0.19 g, 0.0007 mol) was added NaBH4 (0.03 g, 0.84 mmol) in small portions at 0° C. The minxture was stirred at 0° C. for 1 hour, and concentrated. The residure was purified by Prep. TLC on silica gel and eluted with petroleum ether/EtOAc (5:1) to give the title compound (total yiled for 3 steps 15%). MS: m/z 268 (M+H); 1H NMR (400 MHz, CDCl3) δ 8.58 (d, J=4.8 Hz, 1H), 7.66 (m, 1H), 7.23 (m, 5H), 4.94 (s, 1H), 4.63 (b, 1H), 2.79 (d, J=14.0 Hz, 1H), 2.27 (d, J=14.0 Hz, 1H), 2.17 (m, 2H), 2.12 (s, 3H), 1.90 (m, 2H), 1.56 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[C:14]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][S:20][C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)=[CH:13][C:5]2[C:6]([CH3:12])([CH3:11])[O:7][C:8](=[O:10])[NH:9][C:4]=2[C:3]=1[Br:28].[OH:29]O>>[Br:1][C:2]1[C:14]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][S:20]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)=[O:29])=[CH:13][C:5]2[C:6]([CH3:11])([CH3:12])[O:7][C:8](=[O:10])[NH:9][C:4]=2[C:3]=1[Br:28]
Reactant: Cc1ccc(SCCCCOc2cc3c(c(Br)c2Br)NC(=O)OC3(C)C)cc1
Reactant: OO
Product: Cc1ccc(S(=O)CCCCOc2cc3c(c(Br)c2Br)NC(=O)OC3(C)C)cc1

Procedure:
Prepared analogously to Example 2 from 7,8-dibromo-6-[4-(4-methyl-phenylmercapto)-butoxy]-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [F:1][C:2]1[C:9]([CH:10]=O)=[CH:8][CH:7]=[C:6]([I:12])[C:3]=1[C:4]#[N:5].[CH:13]([NH2:16])([CH3:15])[CH3:14].C([BH3-])#N.[Na+].[OH-].[Na+]>CO.CC(O)=O>[F:1][C:2]1[C:9]([CH2:10][NH:16][CH:13]([CH3:15])[CH3:14])=[CH:8][CH:7]=[C:6]([I:12])[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(I)ccc(C=O)c1F
Reactant: CC(C)N
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)NCc1ccc(I)c(C#N)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.5 %

Procedure:
A solution of Example 220A (1.00 g, 3.6 mmol) in MeOH (15 mL) was treated with isopropylamine (0.31 mL, 3.6 mmol) and sodium cyanoborohydride (227 mg, 3.6 mmol), and the mixture was stirred overnight at rt. HOAc (1 mL) was added and the reaction was stirred for 5 h, then treated with 1N NaOH and extracted with EtOAc. The extracts were washed with brine, dried (MgSO4) and concentrated. The residue was purified by flash chromatography on silica gel eluting with 8% MeOH/CH2Cl2 to give the desired product (372 mg). MS (ESI(+)) m/e 318.9 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[C:6]([CH3:18])=[C:7]([N+:15]([O-:17])=[O:16])[C:8](O)=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)(=[O:4])=[O:3].O.P(Cl)(Cl)([Cl:22])=O>CN(C)C1C=CC=CC=1>[Cl:22][C:8]1[C:7]([N+:15]([O-:17])=[O:16])=[C:6]([CH3:18])[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][C:9]=1[N+:11]([O-:13])=[O:12]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1c(S(C)(=O)=O)cc([N+](=O)[O-])c(O)c1[N+](=O)[O-]
Solvent: O
Solvent: CN(C)c1ccccc1
Product: Cc1c(S(C)(=O)=O)cc([N+](=O)[O-])c(Cl)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a slurry of 4-(methylsulfonyl)-2,6-dinitro-m-cresol (4.9 g.) in phosphorus oxychloride (21 ml.), N,N-dimethylaniline is added at such a rate that the temperature does not exceed 34° C. When the addition is complete and the initial exotherm has subsided, the mixture is heated to 60°-65° C. and held there for 10 minutes. The reaction mixture is carefully decomposed by pouring into an ice and water mixture. The desired product as a precipitated solid (4.49 g.) is collected and recrystallized from benzene-pet ether to give a solid with m.p. of 174°-175° C. Analysis: Calcd. for C8H7ClN2O6S: C, 32.59; H, 2.37; N, 9.50; S, 10.86; Cl, 12.05. Found: C, 32.62; H, 2.37; N, 9.39; S, 10.65; Cl, 12.25.
Reaction SMILES: O=[C:2]1[CH:6]([C:7]([O:9]CC)=[O:8])[CH2:5][CH2:4][NH:3]1.F[B-](F)(F)F.C[O+](C)C.[C:21]([NH:24][NH2:25])(=O)[CH3:22]>ClCCl>[CH3:22][C:21]1[N:3]2[CH2:4][CH2:5][CH:6]([C:7]([OH:9])=[O:8])[C:2]2=[N:25][N:24]=1
Reactant: CC(=O)NN
Reactant: CCOC(=O)C1CCNC1=O
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: Cc1nnc2n1CCC2C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.1 %

Procedure:
Dissolved commercially available ethyl 2-oxopyrrolidine-3-carboxylate (2.50 g, 15.91 mmol) in 30 mL dichloromethane in 50 mL round bottom flask. To this solution was added trimethyloxonium tetrafluoroborate (2.59 g, 17.5 mmol) as a solid and rinsed with 20 mL dichloromethane. The resulting mixture was stirred at room temperature for two h and LC/MS indicated that the intermediate methyl 5-methoxy-3,4-dihydro-2H-pyrrole-4-carboxylate had formed. At this point, acetohydrazide (1.18 g, 15.91 mmol) was introduced as a solid to the mixture and the resulting solution was stirred at room temperature for 3 h. The solution was then concentrated under vacuum to remove all dichloromethane and the residue was then taken up in 100 mL n-butanol which was heated to reflux in an oil bath set at 120° C. overnight. The solution was cooled to room temperature and concentrated under vacuum. The residue was purified via sixteen 1500 μm silica gel preparative plates eluting with 90:10 dichloromethane: methanol solvent system. The product was extracted from the silica gel using 85:15 dichloromethane:methanol which afforded the title compound (454 mg, 11%). 1H NMR (500 MHz DMSO-d6) δ: 4.16-4.06 (m, 1H), 4.00-3.88 (m, 1H), 2.85-2.78 (m, 1H), 2.29 (s, 3H), 1.55 (dt, J=6.7, 13.9 Hz, 2H), 1.32 (dt, J=6.7, 14.0 Hz, 2H), 0.88 (t, J=7.5 Hz, 3H). LC-MS: m/z (ES)=196 (MH)+.