Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]2=[CH:8][CH:9]=[CH:10][N:6]2[NH:5][C:4]([N:12]([CH3:14])[CH3:13])(N)[N:3]=1.[NH2:15][C:16]1[CH:21]=[C:20]([OH:22])[C:19]([CH3:23])=[CH:18][CH:17]=1>C(O)C>[CH3:14][N:12]([CH3:13])[C:4]1[N:3]=[C:2]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([CH3:23])=[C:20]([OH:22])[CH:21]=2)[C:7]2=[CH:8][CH:9]=[CH:10][N:6]2[N:5]=1
Reactant: CN(C)C1(N)N=C(Cl)c2cccn2N1
Reactant: Cc1ccc(N)cc1O
Solvent: CCO
Product: Cc1ccc(Nc2nc(N(C)C)nn3cccc23)cc1O
Temperature: 75 °C
Reaction time: 8 h
Yield: 70.6 %

Procedure:
To a solution of 4-chloro-2-dimethylaminopyrrolo[2,1-f][1,2,4]triazin-2-amine (50 mg, 0.26 mmol) (Tetrahedron, 3037, 52, 1996, José Ma. Quintela, María J. Moreira and Carlos Peinador) in ethanol (2.5 mL) under argon was added 5-amino-o-cresol (35 mg, 0.28 mmol). The reaction mixture was stirred overnight at 75° C. Upon cooling, a solid precipitated which was recrystallized from warm ethanol to provide 52 mg (72%) of the title compound as white solid. MS: [M+H]+=284.2, ESI [M−H]−=282.1; 1H NMR (CDCl3): δ 7.52 (s, 1H), 7.13–6.98 (m, 4H), 6.58 (s, 1H), 3.15 (s, 6H), 2.19 (s, 3H).
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[Br:14][C:15]1[CH:20]=[CH:19][C:18]([C@@H:21]([N:23]2[CH2:29][CH2:28][CH2:27][C@:26]([CH2:36][CH2:37][CH2:38][OH:39])([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[NH:25][C:24]2=[O:40])[CH3:22])=[CH:17][CH:16]=1.CC(O)C>CC(C)=O>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([C@@H:21]([N:23]2[CH2:29][CH2:28][CH2:27][C@:26]([CH2:36][CH2:37][C:38]([OH:3])=[O:39])([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[NH:25][C:24]2=[O:40])[CH3:22])=[CH:17][CH:16]=1
Reactant: CC(C)=O
Reactant: C[C@@H](c1ccc(Br)cc1)N1CCC[C@](CCCO)(c2ccccc2)NC1=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: C[C@@H](c1ccc(Br)cc1)N1CCC[C@](CCC(=O)O)(c2ccccc2)NC1=O
Temperature: 0 °C
Yield: 69 %

Procedure:
A stirred mixture of Jones reagent (0.25 mL) and acetone (2 mL) was cooled in an ice bath and a solution of (S)-1-((S)-1-(4-bromophenyl)ethyl)-4-(3-hydroxypropyl)-4-phenyl-1,3-diazepan-2-one (45 mg, 0.11 mmol) in acetone (6 mL) was added dropwise over 10 min The mixture was stirred in the ice bath for 2 h and i-PrOH (2 mL) was added. The mixture was concentrated under reduced pressure. The residue was taken up in EtOAc (100 mL), washed with water (15 mL) and brine (15 mL), and dried over Na2SO4. Removal of the solvent afforded crude 3-((S)-1-((S)-1-(4-bromophenyl)ethyl)-2-oxo-4-phenyl-1,3-diazepan-4-yl)propanoic acid (33 mg, 69%) which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:16])=[C:4]([NH2:15])[C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.CC(O)=O.[N:21]([O-])=O.[Na+].C([O-])([O-])=O.[Na+].[Na+]>O>[Br:1][C:2]1[C:3]2[NH:16][N:21]=[N:15][C:4]=2[C:5]([N:8]2[CH2:9][CH2:10][N:11]([CH3:14])[CH2:12][CH2:13]2)=[N:6][CH:7]=1
Reactant: O=N[O-]
Reactant: CN1CCN(c2ncc(Br)c(N)c2N)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CN1CCN(c2ncc(Br)c3[nH]nnc23)CC1
Temperature: 10 °C
Reaction time: 1 h
Yield: 88.1 %

Procedure:
A 250 mL round bottom flask was charged with 5-bromo-2-(4-methylpiperazin-1-yl)pyridine-3,4-diamine (1.2 g, 4.2 mmol) and CH3COOH (10 mL). To the above was added dropwise a solution of NaNO2 (0.30 g, 4.3 mmol) in water (1 mL) at 10° C. The resulting mixture was stirred at 10° C. for 1 h. Work-up: the reaction mixture was basified to pH 8 by saturated aqueous Na2CO3 and extracted with ethyl acetate (30 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with 10% MeOH in CH2Cl2, to afford 1.1 g (88%) of the product as a white solid. MS m/z: 297 (M+H+).
Reaction SMILES: C(O)(=O)C(O)=O.[C:7]([C:10]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[S:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]1)(=[O:9])[CH3:8].C(=O)([O-])[O-].[K+].[K+].[N:36]#CBr>C(Cl)(Cl)Cl>[C:7]([C:10]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[S:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:15][CH2:14][N:13]([C:16]#[N:36])[CH2:12][CH2:11]1)(=[O:9])[CH3:8]
Reactant: N#CBr
Reactant: CC(=O)C1(c2ccccc2Sc2ccccc2)CCN(C)CC1
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CC(=O)C1(c2ccccc2Sc2ccccc2)CCN(C#N)CC1

Procedure:
A solution of 6.8 g of 4-acetyl-1-methyl-4-(2-phenylthiophenyl)piperidine oxalate, Example 6, in 40 ml of chloroform is added dropwise to a rapidly stirring mixture of 14.7 g of potassium carbonate and 3.7 g of cyanogen bromide in 48.5 ml of chloroform. After total addition, the reaction mixture is successively stirred at reflux for 16 hours, filtered, washed five times with 100 ml portions of water, washed with one 50 ml portion of a saturated sodium chloride solution and dried. The resulting product is purified by chromatography (silica gel column, ether eluant) to provide 4-acetyl-1-cyano-4-(2-phenylthiophenyl)piperidine.
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5]>C(Cl)Cl.CCOCC>[I:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: OCc1ccccc1I
Solvent: CCOCC
Solvent: ClCCl
Product: O=Cc1ccccc1I

Procedure:
Commercially available 2-iodobenzyl alcohol (10.0 g, 42.7 mmol) was dissolved in 200 mL CH2Cl2. Upon completion, the reaction was diluted with 250 mL Et2O. The product was recovered as a brown liquid (10.3 g, 104%). TLC: Rf 0.57 (3:1 hexanes/EtOAc). IR (neat): 3061, 2853, 2745, 1696, 1580, 1561. 1H-NMR (400 MHz, CDCl3): δ 10.07 (s, 1H, C1-H), 7.95 (dd, 1H, J=7.9, 1.0, C4-H), 7.88 (dd, 1H, J=7.7, 1.8, C7-H), 7.47 (td, 1H, J=7.5 0.8, C6-H), 7.29 (td, 1H, J=7.6, 1.8, C5-H). 13C-NMR (100 MHz, CDCl3): δ 195.1, 140.2, 135.1, 134.7, 129.9, 128.4, 100.5. EI-MS m/z (rel int): 232 (M+, 100), 231 ([M−H]+, 40), 203 ([M−CHO]+, 15), 105 ([M−I]+, 3).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][OH:12])=[CH:3][N:2]=1.Cl>CO.[Pt](=O)=O>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH2:11][OH:12])[CH2:3][NH:2]1
Reactant: OCc1cncc2ccccc12
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Product: OCC1CNCc2ccccc21

Procedure:
0.50 mg (3.1 mmol) isoquinolin-4-yl-methanol, 75 mg platinum dioxide and 3.2 mL 1N hydrochloric acid solution were hydrogenated in 50 mL methanol for 4 h at RT under a hydrogen atmosphere at 50 psi. The reaction mixture was filtered and the filtrate was concentrated to dryness by rotary evaporation.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][OH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:17][C:18]1[S:22][C:21]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)=[N:20][C:19]=1[CH3:30]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][O:15][CH2:17][C:18]2[S:22][C:21]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[N:20][C:19]=2[CH3:30])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1CCl
Reactant: CC(C)(C)OC(=O)N1CCOC(CO)C1
Product: Cc1nc(-c2ccc(Cl)cc2)sc1COCC1CN(C(=O)OC(C)(C)C)CCO1
Yield: 69 %

Procedure:
Using 4-(tert-butoxycarbonyl)morpholin-2-ylmethanol (217 mg, 1.00 mmol) and 5-chloromethyl-2-(4-chlorophenyl)-4-methylthiazole (258 mg, 1.00 mmol), the same procedure was followed as in Step 5a of Example 5 to give 303 mg (69%) of the desired compound as a yellow oil.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[C:12](O)(=[O:34])/[CH:13]=[CH:14]\[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=[CH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl.O>[CH3:7][O:6][C:5]1[CH:4]=[C:3]([CH:11]=[CH:10][C:8]=1[O:9][C:12](=[O:34])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=[CH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:2]=[O:1]
Reactant: CCCCCCCCCC=CC=CC=CC=CC=C/C=C\C(=O)O
Reactant: COc1cc(C=O)ccc1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCCC=CC=CC=CC=CC=CC=CC(=O)Oc1ccc(C=O)cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.7 %

Procedure:
To a solution of vanillin (330 mg, 2.17 mmol), cis-docosahexaenoic acid (870 mg, 2.65 mmol) and catalytic amount of 4-(dimethylamino)pyridine in dichloromethane (15 mL) was added a solution of N,N′-dicyclohexylcarbodiimide (720 mg, 3.50 mmol) in DCM (5 mL) for 5 min at ice cold temperature. The mixture was stirred at rt for 16 h and diluted with water. DCM layer was separated and the aqueous layer was extracted with DCM (3×100 mL). The combined DCM layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and the residue was chromatographed over silica gel column using hexane-ethyl acetate (95:5) mixture as an eluent to give the product as an oil (800 mg, 80%). 1H NMR (400 MHz, CDCl3) δ 9.94 (1H, s, —CHO), 7.49 (1H, d, J=1.6 Hz, H-2), 7.47 (1H, dd, J=8.0, 1.6 Hz, H-6), 7.20 (1H, d, J=8.0 Hz, H-5), 5.30-5.48 (12H, m, H-4′, 5′, 7′, 8′, 10′, 11′, 13′, 14′, 16′, 17′, 19′, 20′, 3.89 (3H, s, —OCH3), 2.80-2.88 (10H, m, H-6′, 9′, 12′, 15′, 18′), 2.58-2.67 (2H, m, H-2′), 2.22-2.25 (2H, m, H-21′), 2.05-2.11 (2H, m, H-3′), 0.97 (3H, t, J=7.4 Hz, H-22′).
Reaction SMILES: [C:1]1([CH3:32])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[C:11]2[C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[Br:33]N1C(=O)CCC1=O>O1CCCC1.O>[C:1]1([CH3:32])[CH:2]=[CH:3][C:4]([S:7]([N:10]2[C:11]([C:22]3[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:29])=[O:30])=[CH:24][CH:23]=3)=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:13]=[C:14]2[Br:33])(=[O:8])=[O:9])=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(S(=O)(=O)n2ccc(-c3ccc(F)cc3)c2-c2ccc(S(C)(=O)=O)cc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2c(Br)cc(-c3ccc(F)cc3)c2-c2ccc(S(C)(=O)=O)cc2)cc1
Reaction time: 5 h
Yield: 87 %

Procedure:
A solution of 1-(4-toluenesulfonyl)-2-(4-methylsulfonylphenyl)-3-(4-fluorophenyl)pyrrole (10.0 g, 0.021 mole) in 100 ml tetrahydrofuran was cooled in an ice bath and treated with N-bromosuccinimide (3.8 g, 0.021 mole) and stirred for five hours. The mixture was diluted with one liter of water and the resulting solid was collected by filtration, washed with water and dried. The crude product was recrystallized from ethyl acetate/hexane to yield 10.0 g (87% yield); m.p. 207°-207.5°.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][NH2:15])=[C:10]([F:16])[CH:9]=1.C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][NH:15][C:3](=[O:4])[N:2]([CH3:6])[CH3:1])=[C:10]([F:16])[CH:9]=1
Reactant: CN(C)C(=O)Cl
Reactant: NCc1ccc(Br)cc1F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)NCc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
N,N-Dimethylcarbamoyl chloride (101 μL, 1.1 mmol) was added to a solution of 1-(4-bromo-2-fluorophenyl)methanamine (0.204 g, 1.0 mmol) and triethylamine (148.1 μL, 1.10 mmol) in methylene chloride (5 mL) at 0° C., followed by 4-dimethylaminopyridine (0.012 g, 0.1 mmol). After 10 min, the ice-water bath was removed and the mixture was stirred overnight at RT. The mixture was washed with water and brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue (253 mg, 91.9%) was directly used in next step without further purification. LCMS: (M+H)=276.9/274.9.
Reaction SMILES: Cl.[CH2:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2[CH:34]=[CH:33][C:17]([CH2:18][NH:19][C:20]3[CH:32]=[CH:31][C:23]4[O:24][C:25]([CH3:30])([CH3:29])[O:26][C:27](=[O:28])[C:22]=4[CH:21]=3)=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5].[O:35]1[C:39]2[CH:40]=[CH:41][C:42]([C:44](Cl)=[O:45])=[CH:43][C:38]=2[O:37][CH2:36]1>>[CH2:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]#[C:13][C:14]2[CH:34]=[CH:33][C:17]([CH2:18][N:19]([C:20]3[CH:32]=[CH:31][C:23]4[O:24][C:25]([CH3:30])([CH3:29])[O:26][C:27](=[O:28])[C:22]=4[CH:21]=3)[C:44]([C:42]3[CH:41]=[CH:40][C:39]4[O:35][CH2:36][O:37][C:38]=4[CH:43]=3)=[O:45])=[CH:16][CH:15]=2)=[CH:10][CH:11]=1)[CH2:3][CH2:4][CH3:5]
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Reactant: CCCCc1ccc(C#Cc2ccc(CNc3ccc4c(c3)C(=O)OC(C)(C)O4)cc2)cc1
Agent: Cl
Product: CCCCc1ccc(C#Cc2ccc(CN(C(=O)c3ccc4c(c3)OCO4)c3ccc4c(c3)C(=O)OC(C)(C)O4)cc2)cc1

Procedure:
The titled compound was prepared following the procedure K using 6-({4-[(4-butylphenyl)ethynyl]benzyl}amino)-2,2-dimethyl-4H-1,3-benzodioxin-4-one hydrochloride and 1,3-benzodioxole-5-carbonyl chloride as a pale yellow oil (94%). M+ (ESI): 588.3. HPLC, Rt: 5.69 min (Purity: 99.4%).
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([OH:9])([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4].[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[BH4-].[Na+]>[OH-].[Na+]>[CH2:10]([NH:1][C@@H:2]([C:6]([OH:9])([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(O)[C@H](N)C(=O)O
Reactant: O=Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(O)[C@H](NCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.5 %

Procedure:
A mixture of (S)-2-amino-3-hydroxy-3-methylbutanoic acid (18.6 g, 140 mmol), aqueous NaOH solution (2 mol/L, 70 mL) and benzaldehyde (14.56 g, 137 mmol) was stirred at 25° C. for 1 hour and cooled to 0° C. Then to the mixture was added sodium borohydride (3 g, 80 mmol) portion wise with the temperature maintained below 10° C. Then the mixture was warmed to 25° C. and stirred for another 12 hours. The aqueous layer was washed with DCM (30 mL×3) and the organic layer was discarded. The aqueous layer was cooled to 5° C., and adjusted to pH 1-2 with con. HCl. The mixture was stirred at 5° C. for 4 hours, and filtered to give the title compound as a white solid (18.8 g, 60%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:22])[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=3[F:21])[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].O>CN(C)C=O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:22])[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=3[F:21])[C:8](=[O:12])[N:9]2[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CBr
Reactant: O=c1[nH]c2cc(Br)ccc2c(=O)n1Cc1ccc(Br)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cn1c(=O)n(Cc2ccc(Br)cc2F)c(=O)c2ccc(Br)cc21
Temperature: 0 °C

Procedure:
To a solution of 7-bromo-3-(4-bromo-2-fluorobenzyl)-1,2,3,4-tetrahydro-2,4-dioxoquinazoline (2.80 g) in N,N-dimethylformamide (56 ml) was added sodium hydride (60% in mineral oil, 334 mg) with stirring at 0° C. under an atmosphere of nitrogen and the mixture was stirred at room temperature for 1 hour. To this mixture was added ethyl bromoacetate (0.85 ml) dropwise and the mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure to give a residue, which was poured into water and extracted with ethyl acetate. The extract was washed with water and dried. Removal of the solvent followed by recrystallization from isopropyl either gave ethyl 2-[7-bromo-3-(4-bromo-2-fluorobenzyl)-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-1-yl]acetate (3.11 g).
Reaction SMILES: [OH:1][C:2]1([C:29]2[S:33][C:32](S(C)(=O)=O)=[N:31][CH:30]=2)[CH2:7][CH2:6][CH:5]([N:8]2[CH2:11][CH:10]([NH:12][C:13]([CH2:15][NH:16][C:17](=[O:28])[C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)=[O:14])[CH2:9]2)[CH2:4][CH2:3]1.[CH:38]([O:41][Na])([CH3:40])[CH3:39]>>[OH:1][C:2]1([C:29]2[S:33][C:32]([O:41][CH:38]([CH3:40])[CH3:39])=[N:31][CH:30]=2)[CH2:7][CH2:6][CH:5]([N:8]2[CH2:11][CH:10]([NH:12][C:13]([CH2:15][NH:16][C:17](=[O:28])[C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:25])[F:27])[CH:19]=3)=[O:14])[CH2:9]2)[CH2:4][CH2:3]1
Reactant: CS(=O)(=O)c1ncc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)s1
Reactant: CC(C)O[Na]
Product: CC(C)Oc1ncc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)s1

Procedure:
The title compound was prepared as a white solid from N-({1-[4-hydroxy-4-(2-methanesulfonyl-thiazol-5-yl)-cyclohexyl]-azetidin-3-ylcarbamoyl}-methyl)-3-trifluoromethyl-benzamide (less polar isomer, 47a),and i-PrONa (prepared in situ from IPA and 95% NaH) using the procedure described in Example 52.
Reaction SMILES: [CH3:1][N:2]([CH3:47])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]4[NH:23][C:24]([C:26]5[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][N:33]([CH3:35])[CH3:34])[CH:27]=5)=[CH:25][C:18]=34)=[CH:15][N:14]([CH2:36][CH2:37][N:38](C)[C:39](=O)OC(C)(C)C)[N:13]=2)=[CH:8][CH:7]=1)=[O:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:34][N:33]([CH2:32][C:28]1[CH:27]=[C:26]([C:24]2[NH:23][C:19]3=[N:20][CH:21]=[CH:22][C:17]([C:16]4[C:12]([C:9]5[CH:8]=[CH:7][C:6]([NH:5][C:3](=[O:4])[N:2]([CH3:47])[CH3:1])=[CH:11][CH:10]=5)=[N:13][N:14]([CH2:36][CH2:37][NH:38][CH3:39])[CH:15]=4)=[C:18]3[CH:25]=2)[CH:31]=[CH:30][CH:29]=1)[CH3:35]
Reactant: CN(C)Cc1cccc(-c2cc3c(-c4cn(CCN(C)C(=O)OC(C)(C)C)nc4-c4ccc(NC(=O)N(C)C)cc4)ccnc3[nH]2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCCn1cc(-c2ccnc3[nH]c(-c4cccc(CN(C)C)c4)cc23)c(-c2ccc(NC(=O)N(C)C)cc2)n1

Procedure:
To 1,1-dimethylethyl {2-[3-(4-{[(dimethylamino)carbonyl]amino}phenyl)-4-(2-{3-[(dimethylamino)methyl]phenyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]ethyl}methylcarbamate (1.05 g, 1.65 mmol) was added 25% TFA in CH2Cl2 (25 mL).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.Cl.[CH2:18]([O:20][C:21](=[O:31])[C@H:22]([CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[NH2:23])[CH3:19]>>[CH2:18]([O:20][C:21](=[O:31])[C@@H:22]([NH:23][C:12](=[O:14])[C:11]1[CH:10]=[CH:9][C:8]([N:5]2[CH2:4][CH2:3][C:2](=[O:1])[CH2:7][CH2:6]2)=[CH:16][CH:15]=1)[CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH3:19]
Reactant: O=C1CCN(c2ccc(C(=O)O)cc2)CC1
Reactant: CCOC(=O)CC[C@H](N)C(=O)OCC
Agent: Cl
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(N2CCC(=O)CC2)cc1)C(=O)OCC

Procedure:
The title compound was prepared from 4-(4-oxo-piperidin-1-yl)-benzoic acid (which was obtained in Example 151) and L-glutamic acid diethyl ester hydrochloride according to the procedure of Example 154 as a yellowish gum; 1H NMR (300 MHz, CDCl3) δ 1.22 (t, J=7.1 Hz, 3 H), 1.31 (t, J=7.1 Hz, 3 H), 2.10–2.50 (m, 4 H), 2.57 (t, J=6.1 Hz, 4 H), 3.73(t, J=6.1 Hz, 4 H), 4.10–4.30(m, 4 H), 4.70–4.85(m, 1 H), 6.90 (d, J=7.5 Hz, 1 H), 7.08(d, J=8.9 Hz, 2 H), 7.78(d, J=8.9 Hz, 2 H); MS (ES) m/z: 405.3 (MH+).
Reaction SMILES: [Li+].[CH3:2]CC[CH2-].[CH3:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Br:15])[CH:10]=1)=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[Br:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([C:7]([CH3:2])=[CH2:6])[CH:10]=1
Reactant: CC(=O)c1cccc(Br)c1
Reactant: [CH2-]CCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C(C)c1cccc(Br)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
Methyltriphenylphosphonium bromide (35.7 g, 97.9 mmoles, 1.3 equiv) is suspended in tetrahydrofuran (100 mL) and cooled to 0° C. N-Butyllithium (2.5M in hexanes, 27.0 g, 97.7 mmoles, 39.2 mL, 1.3 equiv) is added slowly to the mixture via an addition funnel. The resulting solution is stirred for 1 h at 0° C. A solution of 3-bromoacetophenone (15.0 g, 75.3 mmoles, 10.0 mL, 1.0 equiv) in tetrahydrofuran (50 mL) is added slowly via an addition funnel. The resulting mixture is warmed to room temperature and stirred for 3 h. The reaction is cooled to 0° C. and quenched with saturated aqueous ammonium chloride solution. The layers are partitioned in a separatory funnel and the aqueous phase is extracted with hexanes. The combined organic phase is dried over anhydrous sodium sulfate, filtered, and allowed to stand overnight at room temperature. The organic phase is decanted from a precipitate and concentrated under reduced pressure. The resulting solid is diluted with hexanes and filtered. The precipitate is washed with hexanes. The filtrate is concentrated and the resulting mixture is purified by silica gel flash column chromatography (hexanes) to give the title compound (83% yield): 1H NMR (CDCl3, 400 MHz) δ 7.59 (t, 1H, J=1.72 Hz), 7.40-7.36 (m, 2H), 7.18 (t, 1H, J=8 Hz), 5.36 (s, 1H), 5.12-5.10 (m, 1H), 2.13-3.11 (m, 3H).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[CH:6]=[CH:7][C:8]=1[CH3:9].C(N(CC)CC)C.CS([Cl:28])(=O)=O>C(Cl)Cl>[Cl:28][CH2:2][C:3]1[CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: Cc1ccc(-c2ccc(C)c(CO)c2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(-c2ccc(C)c(CCl)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-hydroxymethyl-4,4'-dimethylbiphenyl (1.3 g) and triethylamine (0.8 g) in methylene chloride (50 ml) was cooled to 0° C., and methanesulfonyl chloride (0.84 g) in methylene chloride was added dropwise. The mixture was allowed to warm to room temperature, and was stirred overnight. Ice/water was then added, the organic layer separated, the aqueous layer washed with methylene chloride, the organic layer washed with brine, dried over sodium sulfate, and the solvent evaporated under reduced pressure, to yield 3-chloromethyl-4,4'-dimethylbiphenyl as an oil.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=O.[CH3:8][NH:9][CH3:10].[BH4-].[Na+]>CO>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:9]([CH3:10])[CH3:8]
Reactant: O=Cc1ncc[nH]1
Reactant: CNC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN(C)Cc1ncc[nH]1
Temperature: 50 °C

Procedure:
To a two-necked round-bottomed flask equipped with a reflux condenser and a pressure-equalizing addition funnel, was added 2-imidazolecarboxaldehyde (6 g, 62.5 mmol) in MeOH (60 mL). To this suspension (ambient temperature) was added a solution of dimethylamine (40% aqueous, 60 mL) at a fast dropping rate (20 min). After the addition was complete, solid sodium borohydride (7 g, 186.8 mmol,) was CAUTIOUSLY added portionwise over 45 min. Foaming occurred after each portion, and the internal temperature was allowed to maintain ˜50° C. without external cooling. The reaction mixture was then heated to 65° C. for 3 h and allowed to cool to ambient temperature for overnight. The reaction contents were concentrated in vacuo and the resultant residue was taken up in EtOAc (2×30 mL) washed with brine and with CHCl3 (4×100 mL). The EtOAc extract was discarded. The CHCl3 extract was dried over (NaSO4), filtered, and concentrated in vacuo to give 3.7 g of the desired product as a waxy solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:6]([S:16]([C:19]1[CH:24]=[CH:23][C:22]([O:25]C)=[C:21]([F:27])[CH:20]=1)(=[O:18])=[O:17])[CH:5]2[CH3:28].C1CCCCC=1.B(Br)(Br)Br.ClCCl>>[F:27][C:21]1[CH:20]=[C:19]([S:16]([N:6]2[CH:5]([CH3:28])[C:4]3[C:13](=[CH:14][CH:15]=[C:2]([F:1])[CH:3]=3)[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]2=3)(=[O:17])=[O:18])[CH:24]=[CH:23][C:22]=1[OH:25]
Reactant: COc1ccc(S(=O)(=O)N2c3ccccc3-c3ccc(F)cc3C2C)cc1F
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: C1=CCCCC1
Product: CC1c2cc(F)ccc2-c2ccccc2N1S(=O)(=O)c1ccc(O)c(F)c1
Yield: 79.4 %

Procedure:
The title compound was prepared from 8-fluoro-5-[(3-fluoro-4-methoxyphenyl)sulfonyl]-6-methyl-5,6-dihydrophenanthridine (0.50 g, 1.3 mmol), cyclohexene (2.3 mL, 22 mmol), and 1 M boron tribromide in dichloromethane (7.5 mL, 7.5 mmol) according to the procedure and in the same manner as described in Example 47, Step b. The crude product was purified by flash column chromatography on silica gel, eluting with a mixture of ethyl acetate-hexane (1:4), followed by trituration from hexane, to yield 2-fluoro-4-[(8-fluoro-6-methylphenanthridin-5(6H)-yl)sulfonyl]phenol as a homogeneous solid (0.40 g, 82%), m.p. 191° C.;