Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7](OC3CCCCO3)=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]([CH2:28][CH2:29][CH:30]([O:35][SiH](C)C)C(C)(C)C)[CH3:27].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]([CH2:28][CH2:29][CH2:30][OH:35])[CH3:27]
Reactant: CN(CCCCC[C@@H]1Cc2cc(OC3CCCCO3)ccc2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F)CCC(O[SiH](C)C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(CCCO)CCCCC[C@@H]1Cc2ccccc2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F
Reaction time: 2 h
Yield: 97.8 %

Procedure:
2.3 g of 11β-fluoro-7α-{5-[(3-tert-butyldimethylsilyl-oxypropyl)methylamino]pentyl}-3-(tetrahydropyran-2-yloxy)oestra-1,3,5(10)-trien-17-one in 23 ml of tetra-hydrofuran are reacted at room temperature with 6 ml of tetrabutylammonium fluoride solution (1M in tetra-hydrofuran). After 2 hours, the mixture is diluted with ethyl acetate, washed with saturated sodium chloride solution, dried and concentrated in vacuo. Chromatography of the crude product on silica gel using a methylene chloride-methanol gradient affords 1.5 g of 11β-fluoro-7α-{5-[(3-hydroxypropyl)methylamino]-pentyl}oestra-1,3,5(10)-trien-17-one as a foam.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([NH:10][C@H:11]([C:18]([NH:20][C@H:21]([C:32]([NH:34][C@H:35]([C:38]([NH:40][C@H:41]([C:50]([NH:52][C@@H:53]([C:63]([NH:65][C@H:66]([C:71]([NH:73][C@H:74]([C:82]([N:84]1[CH2:93][CH2:92][CH2:91][C@H:85]1[C:86]([NH:88][CH2:89][CH3:90])=[O:87])=[O:83])[CH2:75][CH2:76][CH2:77][NH:78][C:79](=[NH:81])[NH2:80])=[O:72])[CH2:67][CH:68]([CH3:70])[CH3:69])=[O:64])[CH2:54][CH2:55][C:56](=[O:62])[O:57]C(C)(C)C)=[O:51])[CH2:42][C:43]1[CH:48]=[CH:47][C:46]([OH:49])=[CH:45][CH:44]=1)=[O:39])[CH2:36][OH:37])=[O:33])[CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)=[O:19])[CH2:12][C:13]1[N:17]=[CH:16][NH:15][CH:14]=1)=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[OH:6].[CH3:94][C:95]([CH2:97][C:98]([OH:100])=[O:99])=[O:96]>O>[NH2:1][C@H:2]([C:8]([NH:10][C@H:11]([C:18]([NH:20][C@H:21]([C:32]([NH:34][C@H:35]([C:38]([NH:40][C@H:41]([C:50]([NH:52][C@@H:53]([C:63]([NH:65][C@H:66]([C:71]([NH:73][C@H:74]([C:82]([N:84]1[CH2:93][CH2:92][CH2:91][C@H:85]1[C:86]([NH:88][CH2:89][CH3:90])=[O:87])=[O:83])[CH2:75][CH2:76][CH2:77][NH:78][C:79](=[NH:80])[NH2:81])=[O:72])[CH2:67][CH:68]([CH3:70])[CH3:69])=[O:64])[CH2:54][CH2:55][C:56](=[O:57])[OH:62])=[O:51])[CH2:42][C:43]1[CH:48]=[CH:47][C:46]([OH:49])=[CH:45][CH:44]=1)=[O:39])[CH2:36][OH:37])=[O:33])[CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)=[O:19])[CH2:12][C:13]1[N:17]=[CH:16][NH:15][CH:14]=1)=[O:9])[CH2:3][CH2:4][C:5](=[O:6])[OH:7].[CH3:94][C:95]([CH2:97][C:98]([OH:100])=[O:99])=[O:96]
Reactant: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CCC(=O)OC(C)(C)C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CO)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H](N)CCC(=O)O
Agent: CC(=O)CC(=O)O
Solvent: O
Product: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CCC(=O)O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CO)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H](N)CCC(=O)O

Procedure:
190 mg of Glu-His-Trp-Ser-Tyr-D-Glu(OBut)-Leu-Arg-Pro-NH-C2H5 -diacetate were reacted and purified in analogy to Example 1 g). Yield: 148.9 mg. The content of peptide base was 85% as per UV-spectrum. [-α]D22 = -47.8° (c=1, in H2O)
Reaction SMILES: [C:1]1([N:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:23]1([CH2:28][C:29]2[CH:30]=[CH:31][C:32](Br)=[N:33][CH:34]=2)[CH:27]=[CH:26][N:25]=[CH:24]1>>[N:23]1([CH2:28][C:29]2[CH:30]=[CH:31][C:32]([C:11]3[CH:12]=[CH:13][C:8]([N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:9][CH:10]=3)=[N:33][CH:34]=2)[CH:27]=[CH:26][N:25]=[CH:24]1
Reactant: OB(O)c1ccc(N(c2ccccc2)c2ccccc2)cc1
Reactant: Brc1ccc(Cn2ccnc2)cn1
Product: c1ccc(N(c2ccccc2)c2ccc(-c3ccc(Cn4ccnc4)cn3)cc2)cc1

Procedure:
Synthesized using 4-(diphenylamino)phenylboronic acid (364 mg, 1.26 mmol) and 1a (150 mg, 0.63 mmol) according to Method C. Yellow solid. Yield: 140 mg, 0.34 mmol, 55%. 1H NMR (500 MHz, CDCl3): δH (ppm): 5.16, (s, 2H), 6.93 (t, J=1.3 Hz, 1H), 7.06 (tt, J=7.3, 1.3 Hz, 2H), 7.12-7.15 (m, 7H), 7.25-7.29 (m, 4H), 7.45 (dd, J=8.2, 2.2 Hz, 1H), 7.58 (br, s, 1H), 7.65 (dd, J=8.2, 0.6 Hz, 1H), 7.83-7.86 (m, 2H), 8.54 (dd, J=2.5, 0.6 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=48.2, 119.0, 119.8, 122.8, 123.4, 124.9, 127.7, 129.2, 129.3, 130.2, 132.0, 135.7, 137.3, 147.3, 148.5, 149.1, 157.3; MS (ESI): m/z=402.94 [M+H]+.
Reaction SMILES: [N:1]1[NH:2][N:3]=[N:4][C:5]=1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12].[OH-].[Na+].[CH3:15]I>O.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:15][N:3]1[N:2]=[N:1][C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[OH:12])=[N:4]1
Reactant: CI
Reactant: Oc1ccccc1-c1nn[nH]n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: Cn1nnc(-c2ccccc2O)n1
Reaction time: 0.08 h
Yield: 48.6 %

Procedure:
To a stirred solution of 2-(2H-1,2,3,4-tetraazol-5-yl)phenol (0.486 g, 3 mmol) and sodium hydroxide (NaOH) (72 mg, 3 mmol) in water (15 mL) a solution of tetrabutylammonium chloride (83 mg, 0.3 mmol) was added. The mixture was stirred for 5 min, then methyl iodide (0.425 g, 0.187 mL, 3 mmol) was added, and the mixture was stirred for 6 days. The organic layer was then separated, washed with water (2×15 mL), and dried. Evaporation of solvent and flash chromatography on silica gel (ethyl acetate/heptane, 1:1) afforded the subtitle compound (0.257 g, 49%).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:3]=1.[NH2:23][C:24]1[N:29]=[CH:28][C:27](B(O)O)=[CH:26][N:25]=1>>[O:20]1[CH2:21][CH2:22][N:17]([C:4]2[N:3]=[C:2]([C:27]3[CH:26]=[N:25][C:24]([NH2:23])=[N:29][CH:28]=3)[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][N:8]3[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH2:18][CH2:19]1
Reactant: Clc1nc(N2CCOCC2)c2ncn(C3CCCCO3)c2n1
Reactant: Nc1ncc(B(O)O)cn1
Product: Nc1ncc(-c2nc(N3CCOCC3)c3ncn(C4CCCCO4)c3n2)cn1

Procedure:
4-(2-Chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)morpholine (4.05 gm) was reacted with 2-aminopyrimidine-5-boronic acid, pinacol ester via General Procedure A to give 4.75 g of 5-(6-morpholino-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-2-yl)pyrimidin-2-amine which was refluxed in the presence of a catalytic amount of dimethylaminopyridine, 4 eq Boc-anhydride and 3 eq triethylamine in 60 mL of acetonitrile. Upon completion, the reaction was cooled, concentrated to dryness and purified via normal phase chromatography to yield 6.11 g of 2-(2-(2-(bis(tert-butoxycarbonyl)amino)pyrimidin-5-yl)-6-morpholino-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-2-yl as a light yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:3]=1[OH:13].[OH-].[K+].[CH3:16]S(C)=O.IC>C(OCC)C>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]([CH3:10])([CH3:12])[CH3:11])[C:3]=1[O:13][CH3:16]
Reactant: Cc1cc(Br)c(O)c(C(C)(C)C)c1
Reactant: CS(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CI
Product: COc1c(Br)cc(C)cc1C(C)(C)C
Temperature: 0 °C
Yield: 82.8 %

Procedure:
A 500 mL three-necked round-bottomed flask was charged with 2-bromo-6-tert-butyl-4-methylphenol (20.0 g, 82.3 mmol), potassium hydroxide (9.7 g, 164.5 mmol) and DMSO (dimethylsulfoxide) (100 mL), and the mixture was chilled to 0° C. After slowly injecting iodomethane (23.4 g, 164.5 mmol) thereto, the resultant mixture was stirred at ambient temperature for 12 hours. The reaction mixture was then poured into ice (200 g), and the resultant mixture stirred for 30 minutes. After adding diethyl ether, the organic layer was isolated and the residue was extracted with diethyl ether. The combined organic layer was dried over magnesium sulfate, and evaporated to remove volatiles. Recrystallization from mixture of hexane and dichloromethane gave 1-bromo-3-tert-butyl-2-methoxy-5-methylbenzene (17.5 g, yield: 82.8%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([NH:11][C:12]1[CH:41]=[CH:40][CH:39]=[CH:38][C:13]=1[C:14]([NH:16][CH2:17][C:18]1[C:19]([NH:31][CH:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[C:20]2[CH:28]=[N:27][N:26]([CH2:29][CH3:30])[C:21]2=[N:22][C:23]=1[CH2:24][CH3:25])=[O:15])=[O:10].[CH3:42][NH:43][CH2:44][CH2:45][OH:46].C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:29]([N:26]1[C:21]2=[N:22][C:23]([CH2:24][CH3:25])=[C:18]([CH2:17][NH:16][C:14](=[O:15])[C:13]3[CH:38]=[CH:39][CH:40]=[CH:41][C:12]=3[NH:11][C:9](=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:43]([CH2:44][CH2:45][OH:46])[CH3:42])[C:19]([NH:31][CH:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)=[C:20]2[CH:28]=[N:27]1)[CH3:30]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1ccccc1NC(=O)CCCCCCCBr
Reactant: CNCCO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1ccccc1NC(=O)CCCCCCCN(C)CCO
Temperature: 60 °C

Procedure:
A solution of 2-[(8-bromooctanoyl)amino]-N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}benzamide (68 mg, 0.11 mmol, e.g. which can be as prepared in Intermediate 46) in N,N-dimethylformamide (5 ml) was treated with 2-(methylamino)ethanol (0.0175 ml, 0.22 mmol, commercially available e.g. from Aldrich) and N,N-diisopropylethylamine (0.038 ml, 0.22 mmol) and heated at 60° C. for 16 hours. The solvent was evaporated and the residue purified by mass directed preparative HPLC (Method A). Fractions containing product were pooled and evaporated to give the title compound (5 mg). LCMS showed MH+=622; TRET=2.15 min.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[N:4][CH:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[CH:22][C:21]=1[OH:35]>>[CH2:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:16][CH2:17][N:8]1[C:6]1[N:7]=[C:2]([C:24]2[CH:23]=[CH:22][C:21]([OH:35])=[C:20]([O:19][CH3:18])[CH:25]=2)[CH:3]=[N:4][CH:5]=1
Reactant: Clc1cncc(N2CCc3ccccc3C2)n1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Product: COc1cc(-c2cncc(N3CCc4ccccc4C3)n2)ccc1O
Yield: 44 %

Procedure:
In a procedure analogous to Example 22, reaction of 2-(6-chloropyrazin-2-yl)-1,2,3,4-tetrahydroisoquinoline and 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol furnished the product (44%).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([C:14]([O:16]C)=[O:15])[N+:12]=2[O-:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO>[C:1]1([C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([C:14]([OH:16])=[O:15])[N+:12]=2[O-:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1cccc(-c2ccccc2)[n+]1[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cccc(-c2ccccc2)[n+]1[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
To a solution of methyl 6-phenylpyridine-2-carboxylate 1-oxide in methanol (2 mL) was added 1N aqueous sodium hydroxide solution (1 mL), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated, 1N hydrochloric acid was added, the precipitate was collected by filtration, and washed with water to give the title compound (120 mg, 90%) as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1I.[CH2:9]([OH:12])[C:10]#[CH:11]>CCN(CC)CC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:11]#[C:10][CH2:9][OH:12]
Reactant: Fc1ccccc1I
Reactant: C#CCO
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe+2]
Solvent: CCN(CC)CC
Product: OCC#Cc1ccccc1F
Temperature: 25 °C
Yield: 86.9 %

Procedure:
To a solution of 2-fluoro-iodobenzene (267 g, 1.2 mol) in Et3N (6L) was added propargyl alcohol (140 g, 2.5 mol, 2 equiv), followed by PdCl2(dppf) (6.1 g, 8.8 mmol, 0.007 equiv), Ph3P (12.5 g, 47.6 mmol, 0.038 equiv) and copper(I) iodide (12.6 g, 66.3 mmol, 0.053 equiv). The resulting mixture was heated at the reflux temperature for 17 h, allowed to cool to room temperature and filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure and purified by vacuum distillation to give 3-(2-fluorophenyl)prop-2-yn-1-ol (156.6 g, 87%) as a deep brown oil: bp 84° C./0.3 mmHg; TLC (CH2Cl2) Rf 0.44; 1H NMR (CDCl3) δ 2.46 (d, J=5.0 Hz, 1H), 4.45 (d, J=5.0 Hz, 1H), 6.94-7.02 (m, 2H), 7.17-7.23 (m, 1H), 7.31-7.37 (m, 1H); GCMS m/z (rel abundance) 151 (MH+, 75%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][CH:14]1[C:19](=[O:20])[CH2:18][CH2:17][CH2:16][N:15]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].[CH:28](=[O:37])/[CH:29]=[CH:30]/[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCCC1>[OH:37][CH:28]([CH:18]1[CH2:17][CH2:16][N:15]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH:14]([CH3:13])[C:19]1=[O:20])/[CH:29]=[CH:30]/[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C/C=C/c1ccccc1
Reactant: CC1C(=O)CCCN1C(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC1C(=O)C(C(O)/C=C/c2ccccc2)CCN1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2.14 mL (15.3 mmol) of N,N-diisopropylamine in 50 mL of tetrahydrofuran at −78° C. was added 7.96 mL (15.6 mmol, 2.5M in hexane) of n-butyl lithium and the mixture was stirred at −78° C. for 10 min. The reaction was warmed to 0° C. and stirred at 0° C. for 15 min. The mixture was cooled down to −78° C. again, and a solution 2.50 g (11.7 mmol) of tert-butyl 2-methyl-3-oxopiperidine-1-carboxylate (Step C) in 5 mL of tetrahydrofuran was added to the mixture slowly. The mixture was stirred at −78° C. for 1 h. Then 1.77 mL (14.9 mmol) of trans-cinnamaldehyde in 5 mL of tetrahydrofuran (pre-cooled to −78° C.) was added to the reaction mixture and the reaction was stirred at −78° C. for 5 h. The reaction was quenched with saturated aqueous sodium bicarbonate solution and extracted with three portions of ether. The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated. Purification by flash chromatography on a Biotage® system (silica gel, eluting with 10% ethyl acetate/hexane to 30% ethyl acetate/hexane) gave the tide compound. LC/MS 368 (M+23).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].FC(F)(F)C1C=C(O)C=CC=1.[Cl:23][C:24]1[CH:25]=[C:26]([OH:30])[CH:27]=[CH:28][CH:29]=1>>[Cl:23][C:24]1[CH:25]=[C:26]([CH:27]=[CH:28][CH:29]=1)[O:30][C:2]1[N:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Oc1cccc(Cl)c1
Reactant: O=C(O)c1cc(F)cnc1Cl
Agent: Oc1cccc(C(F)(F)F)c1
Product: O=C(O)c1cc(F)cnc1Oc1cccc(Cl)c1

Procedure:
2-(3-Chloro-phenoxy)-5-fluoro-nicotinic acid was prepared in analogy to Example 1, Step 1, replacing 2-chloro-nicotinic acid with 2-chloro-5-fluoro-nicotinic acid ([CAS RN 38186-88-8]) and 3-trifluoromethyl-phenol with 3-chloro-phenol ([CAS RN 108-43-0]). 1H NMR (400 MHz, DMSO): δ7.09 (dd, J=8.4 Hz, J=1.6 Hz, 1H), 7.24-7.25 (m, 2H), 7.44 (t, J=8.4 Hz, 1H), 8.19 (dd, J=8.1 Hz, J=3.2 Hz, 1H), 8.37 (d, J=3.2 Hz, 1H), 13.60 (s, 1H). 19F NMR (376.5 MHz, DMSO): −134.4. MS (ISN): 266.0 [M−H]−.
Reaction SMILES: Br[C:2]1[C:10]2[NH:9][C:8]3[CH:11]4[CH2:17][CH2:16][N:14]([CH2:15][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1)[CH2:13][CH2:12]4.[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1/[CH:26]=[CH:27]/B1OC(C)(C)C(C)(C)O1>>[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1/[CH:26]=[CH:27]/[C:2]1[C:10]2[NH:9][C:8]3[CH:11]4[CH2:17][CH2:16][N:14]([CH2:15][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1)[CH2:13][CH2:12]4
Reactant: CC1(C)OB(/C=C/c2ccc(F)cc2F)OC1(C)C
Reactant: Brc1cccc2c3c([nH]c12)C1CCN(CC1)C3
Product: Fc1ccc(/C=C/c2cccc3c4c([nH]c23)C2CCN(CC2)C4)c(F)c1

Procedure:
A suspension of the product of Example 1B (100 mg, 0.34 mmol) and trans-2-(2,4-difluorophenyl)vinylboronic acid pinacol ester (101 mg, 0.38 mmol; Aldrich) was processed as described in Example 4 to provide the title compound: 1H NMR (400 MHz, methanol-d4) δ ppm 1.98-2.19 (m, 4 H), 3.03-3.17 (m, 3 H), 3.21-3.28 (m, 2 H), 4.24 (s, 2 H), 6.93-7.05 (m, 3 H), 7.25 (d, J=7.6 Hz, 1 H), 7.30 (d, J=16.2 Hz, 1 H), 7.37 (d, J=7.3 Hz, 1 H), 7.63 (d, J=16.5 Hz, 1 H), 7.79-7.88 (m, 1 H); MS (DCI) m/z 351 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:22])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][CH3:21])[CH:14]=1.[CH:23](=O)[CH:24]([CH3:26])[CH3:25].[BH3-]C#N.[Na+].NC1C=CC=CC=1>CCOC(C)=O.[Cl-].[Cl-].[Zn+2].[BH3-]C#N.[Na+].[Cl-].[Cl-].[Zn+2].CO.C1COCC1>[CH2:20]([O:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[O:12][CH2:11][C:10]([NH:9][C:3]1[CH:4]=[CH:5][C:6]([OH:8])=[CH:7][C:2]=1[NH:1][CH2:23][CH:24]([CH3:26])[CH3:25])=[O:22])[CH3:21]
Reactant: CCOc1cccc(OCC(=O)Nc2ccc(O)cc2N)c1
Reactant: CC(C)C=O
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: Nc1ccccc1
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1cccc(OCC(=O)Nc2ccc(O)cc2NCC(C)C)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 93.6 %

Procedure:
A 500 mL 3-neck flask fitted with a stir-bar, addition funnel, and an Ar inlet was charged with aniline 64 (9.20 g, 30.4 mmol), THF (100 mL), and MeOH (30 mL). To the resultant solution was added isobutyraldehyde (3.07 g, 3.89 mL, 42.6 mmol), and the mixture stirred 10 min at rt. Meanwhile, in a 250 mL flask fitted with a stir-bar and septum with an Ar inlet, NaCNBH3 (1M in THF, 43 mL, 43 mmol) was added to MeOH (80 mL). ZnCl2 (1M in Et2O, 21 mL, 21 mmol) was next added forming a cloudy mixture which was stirred for 10 min. The mixture was then added to the above aniline solution. The reaction stirred overnight at rt. Another 1.0 mL isobutyraldehyde was added, followed by a second portion of 25% of the original amount of the NaCNBH3/ZnCl2 mixture as made previously. The mixture stirred at rt overnight. Another 0.5 mL of isobutyraldehyde was then added, and the mixture stirred overnight again. The cloudy solution was diluted with EtOAc (300 mL) and washed with saturated NaHCO3 (2×250 mL) and brine (150 mL). The solution was filtered through phase separation paper and concentrated to 12.1 g of a dark oil. The crude oil was chromatographed on silica gel with the product eluting with 25-33% EtOAc in hexanes. The product fractions were concentrated to give 10.2 g of 65b as a tan solid (85%). 1H NMR (300 MHz, CDCl3): δ 7.84 (s, 1H), 7.24 (m, 1H), 6.97 (d, 1H), 6.64-6.52 (m, 3H), 6.16 (d, 1H), 6.09 (dd, 1H), 4.67 (s, 2H), 4.05 (qt, 2H), 2.77 (d, 2H), 1.78 (nonet, 1H), 1.43 (t, 3H), 0.92 (d, 6H) ppm. HPLC analysis (10:10:80 H2O:A1:MeOH) showed a purity of 98% with a retention time of 4.3 min.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]([C:7]([F:10])([F:9])[F:8])([CH3:6])[CH2:4][OH:5].C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl.O>[F:1][C:2]([F:11])([F:12])[C:3]([CH3:6])([C:7]([F:9])([F:8])[F:10])[CH2:4][O:5][S:21]([CH3:20])(=[O:23])=[O:22]
Reactant: CC(CO)(C(F)(F)F)C(F)(F)F
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(COS(C)(=O)=O)(C(F)(F)F)C(F)(F)F
Yield: 101.7 %

Procedure:
To 2,2-bis(trifluoromethyl)propanol (4.34 g, 22.1 mmol) in DCM (100 mL) at 0° C. add with stirring triethylamine (6.2 mL, 44 mmol) followed by methanesulfonyl chloride (2.6 mL, 33 mmol). After 15 min at 0° C. dilute with water and extract three times with EtOAc. Dry over anhydrous Na2SO4 and concentrate in vacuo to give the crude desired intermediate as a yellow oil (6.16 g, 100%).
Reaction SMILES: [Si:1]([O:8][C@@H:9]([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH2:10][OH:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C>C(Cl)Cl>[Si:1]([O:8][C@@H:9]([CH2:12][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)[CH:10]=[O:11])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@H](CO)CC1CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)O[C@H](C=O)CC1CCCCC1
Reaction time: 0.33 h

Procedure:
(9.32 mmol) of (S)-2-t-butyldimethylsilyloxy-3-cyclohexylpropyl alcohol [prepared as described in step (iii) above] in 12 ml of methylene chloride was added dropwise over a period of 5 minutes. The resulting mixture was then stirred for 20 minutes at the same temperature, after which 6.5 ml (46.6 mmol) of triethylamine were added. The mixture was then allowed to stand for 7 minutes, and the cooling bath was removed. After a further 10 minutes, the reaction was stopped by adding an aqueous solution of ammonium chloride. The reaction mixture was then extracted with diethyl ether. The extract was washed twice with water and once with a saturated aqueous solution of sodium chloride. The organic phase was dried over anhydrous magnesium sulfate, and the solvent was then removed by distillation under reduced pressure, to give 2.55 g (a quantitative yield) of the title aldehyde compound as a colorless oil.
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([CH:10]=[O:11])/[C:7](=[N:12]/[C:13](=[O:23])[C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[O:21][CH3:22])/[S:6]1)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>C1COCC1>[C:1]([N:5]1[CH:9]=[C:8]([CH2:10][OH:11])/[C:7](=[N:12]/[C:13](=[O:23])[C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[O:21][CH3:22])/[S:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(Cl)cc1C(=O)/N=c1\sn(C(C)(C)C)cc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sn(C(C)(C)C)cc1CO
Yield: 100.6 %

Procedure:
The product from Example 21A (50 mg, 0.14 mmol) in THF (10 mL) was treated with sodium borohydride (21 mg, 0.57 mmol) at −40° C. for 1 hr, quenched with saturated NH4Cl, extracted with EtOAc (2×), dried over MgSO4, filtered and concentrated to afford 50 mg of the title compound. 1H NMR (500 MHz, CDCl3) δ ppm 1.67 (s, 9H) 3.93 (s, 3H) 4.88 (s, 2H) 6.94 (d, J=8.85 Hz, 1H) 7.37 (dd, J=8.85, 3.05 Hz, 1H) 8.05 (s, 1H) 8.08 (d, J=2.75 Hz, 1H); MS (DCI/NH4+) m/z 355 (M+H)+.
Reaction SMILES: [Na].[C:2]([O:12][CH2:13][CH3:14])(=[O:11])[CH2:3][C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=O.Cl.[Cl:16][C:17]1[CH:18]=[CH:19][C:20]2[N:26]=[C:25]([NH:27][NH2:28])[CH2:24][N:23]=[C:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:21]=2[CH:35]=1>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]2[N:26]=[C:25]([NH:27][N:28]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][C:2]([O:12][CH2:13][CH3:14])=[O:11])[CH2:24][N:23]=[C:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:21]=2[CH:35]=1
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Reactant: CCOC(=O)CC(=O)C(=O)OCC
Agent: Cl
Agent: [Na]
Product: CCOC(=O)CC(=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1)C(=O)OCC
Reaction time: 1.5 h

Procedure:
An aqueous solution of 1.26 g. (0.006 mole) of diethyl oxalacetate sodium salt was acidified with hydrochloric acid and extracted with methylene chloride. The extract was dried over sodium sulfate and evaporated to dryness in vacuo. The resulting oil in 30 ml. of methanol under N2 was mixed with 0.812 g. (0.003 mole) of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine and allowed to stand at room temperature for 1.5 hours. The solution was evaporated in vacuo, dissolved in methylene chloride, washed with dilute sodium hydroxide and dried over magnesium sulfate. After filtration the solution was evaporated in vacuo giving 7-chloro-2-[[1,2-bis-(ethoxycarbonyl)ethylidene]hydrazino]-5-phenyl-3H-1,4-benzodiazepine as an oil. Nmr confirmed the structure. Nmr (CDCl3) δ 1.20 and 1.22 (2 t's, 6, CH2CH3), 4.13 (q, 6, CH2CH3), 4.48 (broad s, 2, 3--CH2), between 6.93 and 7.83 (m's, 8, arom H's).