Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C@H:5]2[O:7][C@H:8]([CH:10]=[O:11])[CH2:9][C@H:4]2[O:3]1.[CH2:13]([Mg]Br)[CH3:14]>C1COCC1>[CH3:1][C:2]1([CH3:12])[O:6][C@H:5]2[O:7][C@H:8]([CH:10]([OH:11])[CH2:13][CH3:14])[CH2:9][C@H:4]2[O:3]1
Reactant: CC1(C)O[C@H]2O[C@H](C=O)C[C@H]2O1
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Product: CCC(O)[C@@H]1C[C@H]2OC(C)(C)O[C@H]2O1
Temperature: -20 °C
Reaction time: 20 h

Procedure:
To a solution of (3aR,5S,6aR)-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxole-5-carbaldehyde (compound 1d, 296 mg, 2 mmol) in THF (20 mL) was added ethyl magnesium bromide (2M in THF, 2 mL, 2 mmol) at −20° C. under argon. After being stirred at −20° C. for 20 hours, the reaction was quenched by saturated NH4Cl solution and extracted with EtOAc (30 mL) three times. The combined organic layers were concentrated in vacuo to afford the crude product of 1-[(3aR,5S,6aR)-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxol-5-yl]propan-1-ol (compound 1e), which was used in next step without further purification. MS obsd. (ESI+) [(M+NH4)+]: 316.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:11][C:12](=[O:18])[CH2:13][NH:14][CH2:15][CH2:16][OH:17])([CH3:10])([CH3:9])[CH3:8].Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>O1CCOCC1.O>[C:7]([O:11][C:12](=[O:18])[CH2:13][N:14]([C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[CH2:15][CH2:16][OH:17])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)CNCCO
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)CN(CCO)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
Potassium carbonate (33.0 g; 0.19 mol) is added to a solution of the product from Example 4 (32.15 g; 0.18 mol) in dioxane (1.0 l) and water (0.5 l). A solution of benzyl chloroformate (27.3 ml; 0.19 mol) in dioxane (0.2 l) is slowly added dropwise at room temperature. The solution is stirred at room temperature for 3.5 h and subsequently concentrated. The residue is taken up in dichloromethane (3.0 l) and extracted by shaking with water (1.0 l). The aqueous phase is re-extracted five times with dichloromethane. The organic phases are combined, dried (magnesium sulphate) and concentrated. Yield: 24.47 g (43%), pale yellow oil.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[C:7]([OH:16])(=[O:15])[C:8]1[C:9](=[CH:11][CH:12]=[CH:13][CH:14]=1)[NH2:10].[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.Cl>O>[CH3:27][C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:10][C:9]2[C:8](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([OH:16])=[O:15])(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccccc1C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(S(=O)(=O)Nc2ccccc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 3.45 g (25 mmol) of sodium carbonate and 1.0 g (7.3 mmol) of anthranilic acid in 50 ml of water at 60° was treated with 2.09 g (10.95 mmol) of p-toluenesulfonyl chloride and held at 70° for 30 min. The reaction mixture was cooled to ambient temperature and acidified with 10% HCl. After standing for 18 hr the product was collected by filtration, washed with water and dried to give N-4-methylphenylsulfonylanthranilic acid as a solid, mp 226-229°.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[C:5]([CH3:15])[C:4]=1[CH:16]=O.COC1C2C(=CC=CC=2)C(OC)=CC=1/[CH:32]=[C:33](\C)/[C:34]([O:36][CH2:37][CH3:38])=[O:35]>>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[C:5]([CH3:15])[C:4]=1/[CH:16]=[C:33](\[CH3:32])/[C:34]([O:36][CH2:37][CH3:38])=[O:35]
Reactant: COc1c(C)c(C=O)c(OC)c2ccccc12
Reactant: CCOC(=O)/C(C)=C/c1cc(OC)c2ccccc2c1OC
Product: CCOC(=O)/C(C)=C/c1c(C)c(OC)c2ccccc2c1OC

Procedure:
Compound 98a was prepared from 34 (0.506 g, 2.20 mmol) as described above for 28a to give 0.541 g (1.42 mmol, 65%) of the product as a colorless oil following flash chromatography (1:19 i-Pr2O:hexanes).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C:10]2=[N:13]O)=[CH:5][CH:4]=1.ClC(Cl)(Cl)C(O)=[O:18]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][CH2:8][CH2:9][NH:13][C:10](=[O:18])[C:11]=2[CH:12]=1
Reactant: O=C(O)C(Cl)(Cl)Cl
Reactant: COc1ccc2c(c1)C(=NO)CCC2
Product: COc1ccc2c(c1)C(=O)NCCC2
Yield: 22.3 %

Procedure:
Following a procedure of Tomita, et. al., J. Chem. Soc. C 1969, 183, 7-methoxytetralone oxime (45.0 g, 0.235 mol) was mixed with solid trichloroacetic acid (150 g), and the resulting suspension heated to ca. 80 C., at which time a violent exotherm ensued, yielding a black solid mixture. The residue was cooled, partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution, and the combined organic layers were concentrated in vacuo. The residue was purified by chromatography over silica gel to yield 10.0 g (22%) of 8-methoxy-2,3,4,5-tetrahydro-1H-2-benzazepin-1-one. An analytical sample was obtained by recrystallization from CH2Cl2 /hexanes to yield colorless crystals: mp. 99°-101° C. (lit. (see above) 100°-101° C.); 1H NMR(CDCl3) d7.35(brs, 1H), 7.30(d, J=3 Hz, 1H), 7.10(d, J=9 Hz, 1H), 6.95(dd, J=3, 9 Hz, 1H), 3.82(s, 3H), 3.10(q, J=6 Hz, 2H), 2.80(t, J=6 Hz, 2H), 1.98(m, 2H),
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:6][C:7]1[CH:14]=[C:13]([F:15])[C:10]([CH:11]=O)=[C:9]([Cl:16])[CH:8]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>ClCCl.O>[Cl:16][C:9]1[CH:8]=[C:7]([OH:6])[CH:14]=[C:13]([F:15])[C:10]=1[CH2:11][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: O=Cc1c(F)cc(O)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Oc1cc(F)c(CN2CCCC2)c(Cl)c1
Yield: 69.8 %

Procedure:
Pyrrolidine (4.65 mL, 56 mmol) was added to a solution of intermediate 17, 4-hydroxy-2-chloro-6-fluorobenzaldehyde (7.5 g, 43 mmol) in dichloromethane (100 mL). The reaction mixture was cooled on ice bath, and sodium triacetoxyborohydride (13.71 g, 65 mmol) was added in portions under stirring. The reaction mixture was intensively stirred for 24 h at RT. Water (100 mL) and concentrated HCl were added to attain pH˜2. The organic layer was separated. The aqueous one was extracted with CH2Cl2 (2×100 mL), then with EtOAc (100 mL). The organic layers were discarded. The aqueous fraction was alkalized with K2CO3 to pH˜10, the obtained crystals were separated by filtration, dried in vacuo, recrystallized from Et2O/hexane mixture (1:1) to give the title compound (7 g, 71%, 30 mmol). LCMS data: 231 and 230 (M+H)+ (calculated for C11H13ClFNO 229.7). 1H NMR data (DMSO-d6): 10.25 (br.s, 1H, OH), 6.66-6.70 (m, 1H, H—Ar), 6.54 (dd, 1H, J1=2.2 Hz, J2=11.3 Hz, H—Ar), 3.58 (d, 2H, J1=2.4 Hz, Ar—CH2); 2.38-2.46 (m, 4H), 1.58-1.68 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([S:7][CH2:8][CH2:9][S:10][CH2:11][CH2:12]SCCCCCC)[NH:4][N:3]=1.[CH2:20](SCCCl)[CH2:21][CH2:22][CH2:23]CC>>[NH2:1][C:2]1[N:6]=[C:5]([S:7][CH2:8][CH2:9][S:10][CH2:11][CH2:12][CH2:20][CH2:21][CH2:22][CH3:23])[NH:4][N:3]=1
Reactant: CCCCCCSCCSCCSc1nc(N)n[nH]1
Reactant: CCCCCCSCCCl
Product: CCCCCCSCCSc1nc(N)n[nH]1
Yield: 86 %

Procedure:
Compound 6 was prepared using the procedure used for Compound 12, but with 2-chloroethyl hexyl sulfide as the starting material. The yield was 86%. A portion was recrystallized from ligroin/ethyl acetate to obtain a solid, m.p. 76.5°-78° C. Analysis: Calculated for C10H20N4S2 : C, 46.12; H, 7.74; N, 21.51. Found: C, 46.00; H, 7.56; N, 21.56.
Reaction SMILES: [C:1]([C:3]1[CH:42]=[CH:41][C:6]([C:7]([N:9]2[CH2:13][C@H:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C@@H:11]([CH2:20][N:21]([C@@H:29]([C:31]3[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH:34]=[CH:33][CH:32]=3)[CH3:30])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10]2)=[O:8])=[CH:5][CH:4]=1)#[N:2].[N-:43]=[N+:44]=[N-:45].[Na+].Cl.C(N(CC)CC)C>CN(C=O)C>[C:31]1([C@H:29]([N:21]([CH2:20][C@@H:11]2[C@@H:12]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:13][N:9]([C:7](=[O:8])[C:6]3[CH:5]=[CH:4][C:3]([C:1]4[NH:45][N:44]=[N:43][N:2]=4)=[CH:42][CH:41]=3)[CH2:10]2)[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH3:30])[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1
Reactant: C[C@H](c1cccc2ccccc12)N(C[C@H]1CN(C(=O)c2ccc(C#N)cc2)C[C@@H]1c1ccccc1)C(=O)OC(C)(C)C
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@H](c1cccc2ccccc12)N(C[C@H]1CN(C(=O)c2ccc(-c3nnn[nH]3)cc2)C[C@@H]1c1ccccc1)C(=O)OC(C)(C)C
Temperature: 120 °C
Yield: 87.7 %

Procedure:
A 1.5 ml DMF solution of 72 mg of tert-butyl {[(3R,4S)-1-(4-cyanobenzoyl)-4-phenylpyrrolidin-3-yl]methyl}[(1R)-1-(1-naphthyl)ethyl]carbamate was mixed with 153 mg of sodium azide and 304 mg of triethylamine hydrochloride and stirred at 120° C. for 2Hours. By post-treating and purifying this in the standard method, 68 mg of tert-butyl [(1R)-1-(1-naphthyl)ethyl]({(3R,4S)-4-phenyl-1-[4-(1H-tetrazol-5-yl)benzoyl]pyrrolidin-3-yl}methyl)carbamate was obtained as a yellow amorphous substance. EN: 601
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][C:13]([F:16])(F)[F:14])[CH:10]=2)[N:5]=[C:4]([N:17]2[CH2:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[S:20](=[O:29])(=[O:28])[CH2:19][CH2:18]2)[CH:3]=1.[CH2:30]([NH2:34])[CH2:31][CH2:32][NH2:33]>>[F:16][CH:13]([F:14])[O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([N:17]1[CH2:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[S:20](=[O:28])(=[O:29])[CH2:19][CH2:18]1)[CH:3]=[C:2]2[NH:33][CH2:32][CH2:31][CH2:30][NH2:34]
Reactant: NCCCN
Reactant: O=S1(=O)CCN(c2cc(Cl)c3cc(OC(F)(F)F)ccc3n2)Cc2ccccc21
Product: NCCCNc1cc(N2CCS(=O)(=O)c3ccccc3C2)nc2ccc(OC(F)F)cc12

Procedure:
The title compound was prepared in analogy to Example 17-1 in Scheme 6 by using 4-(4-chloro-6-(difluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 17-1 by using 2,4-dichloro-6-(difluoromethoxy)quinoline and 2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide) and propane-1,3-diamine. MS obsd. (ESI+) [(M+H)+] 463, 1H NMR (400 MHz, CD3OD) δ ppm 8.02-8.00 (d, J=7.6 Hz, 1 H), 7.98-7.90 (d, J=2 Hz, 1 H), 7.84-7.82 (d, J=8.4 Hz, 2 H), 7.68-7.64 (t, J=7.6 Hz, 1 H), 7.54-7.50 (m, 1 H), 7.05-6.68 (d, J=73.6 Hz, 2 H), 5.95 (s, 1 H), 5.28 (s, 2 H), 4.48 (s, 2 H), 3.68 (s, 2 H), 3.57-3.54 (t, J=6.8 Hz, 2 H), 3.08-3.04 (t, J=7.6 Hz, 2 H), 2.11-2.04 (m, 2 H).
Reaction SMILES: [F:1][CH2:2][C:3]([OH:11])([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:4][C:5]#[CH:6].N1C=CN=C1.CN(C)C=O.[CH3:22][Si:23]([CH3:26])([CH3:25])Cl>CCCCCC>[F:1][CH2:2][C:3]([O:11][Si:23]([CH3:26])([CH3:25])[CH3:22])([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:4][C:5]#[CH:6]
Reactant: C[Si](C)(C)Cl
Reactant: C#CCC(O)(CF)CCCC
Agent: c1c[nH]cn1
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: C#CCC(CF)(CCCC)O[Si](C)(C)C
Temperature: 0 °C

Procedure:
To a solution of 4.38 g. of 4-fluoromethyl-4-hydroxy-1-octyne and 4.8 g. of imidazole in 19 ml. of dimethylformamide, cooled in an ice bath under nitrogen is added 4.5 ml. of trimethylchlorosilane via a syringe during a few minutes. The mixture is stirred in the ice bath for 30 minutes and then at room temperature under nitrogen overnight. The solution is poured into hexane, washed with saturated aqueous sodium bicarbonate, water, then brine and dried over anhydrous sodium sulfate. The solvents are removed in vacuo giving the product as a colorless liquid.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl[C:13](=[O:22])[CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19]>ClCCl.O>[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:13](=[O:22])[CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:8][CH:7]=1
Reactant: COC(=O)CCCCC(=O)Cl
Reactant: Fc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: COC(=O)CCCCC(=O)c1ccc(F)cc1
Temperature: -5 °C
Reaction time: 15 h

Procedure:
A suspension of 2.59 g (19.4.10−3 mol) of aluminum chloride in 4 ml of dichloromethane is prepared. It is cooled to −5° C. and a mixture of 0.97 ml (10.3.10−3 mol) of fluorobenzene and 1.31 ml (8.4.10−3 mol) of methyl 6-chloro-6-oxohexanoate in 3 ml of dichloromethane is added gradually, the temperature being maintained between −4 and −7° C. The temperature is then allowed to rise to 20° C. and, after 15 hours, the mixture is hydrolyzed in acidified iced water. It is extracted with dichloromethane and the organic phase obtained is washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The 2 g of crude product recovered in this way are purified by chromatography on silica gel using a petroleum ether/ethyl acetate mixture (96/4) as the eluent to give 1.26 g of the expected product in the form of a white powder (yield=63%).
Reaction SMILES: [CH:1]12[CH2:7][CH:6]1[CH2:5][CH2:4][C@H:3]([C:8]([NH:10][C@H:11]([C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1)[CH3:12])=[O:9])[NH:2]2.[F:23][C:24]([F:34])([F:33])[C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1.C([O-])([O-])=O.[Cs+].[Cs+]>>[F:23][C:24]([F:33])([F:34])[C:25]1[CH:32]=[CH:31][C:28]([CH2:29][N:2]2[C@@H:3]([C:8]([NH:10][C@H:11]([C:13]3[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=3)[CH3:12])=[O:9])[CH2:4][CH2:5][CH:6]3[CH:1]2[CH2:7]3)=[CH:27][CH:26]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCC3CC3N2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCC3CC3N2Cc2ccc(C(F)(F)F)cc2)cc1

Procedure:
The title compound (D143) (10 mg) was prepared according to the general procedure for substituted benzyl amines preparation starting from methyl 4-((1S)-1-((3R)-2-azabicyclo[4.1.0]heptane-3-carboxamido)ethyl)benzoate (diastereoisomers mixture) (D102) (20 mg) and 4-(trifluoromethyl)-benzylbromide (0.012 ml). (Cs2CO3: 1.5 eq; Reaction time: 20 hrs; RT).
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[N:6]=1.[F:16][C:17]1[CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:20]=[CH:19][C:18]=1[C:32]1[CH:33]=[N:34][C:35]([NH2:38])=[N:36][CH:37]=1>>[NH2:38][C:35]1[N:36]=[CH:37][C:32]([C:18]2[CH:19]=[CH:20][C:21]([C:2]3[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=3[O:4][C:5]3[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[N:6]=3)=[CH:22][C:17]=2[F:16])=[CH:33][N:34]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Reactant: Nc1nccc(Oc2ccccc2Br)n1
Product: Nc1ncc(-c2ccc(-c3ccccc3Oc3ccnc(N)n3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 4-(2-bromophenoxy)pyrimidin-2-amine and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C20H15FN6O, 374.13; m/z found, 375.1 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.46 (s, 2H), 7.98-7.94 (d, J=5.8, 1H), 7.53-7.49 (d, J=7.6, 1H), 7.49-7.42 (m, 2H), 7.41-7.36 (m, 1H), 7.36-7.32 (d, J=8.2, 1H), 7.32-7.27 (m, 1H), 7.26-7.14 (d, J=8.0, 1H), 6.13-6.04 (d, J=5.8, 1H).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:10][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:36]([O:43][C:44]1[CH:45]=[CH:46][C:47]([CH2:50]Br)=[N:48][CH:49]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.Cl>O1CCCC1>[CH2:36]([O:43][C:44]1[CH:45]=[CH:46][C:47]([CH2:50][C@H:11]([C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])[CH2:10][C@@H:9]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])=[N:48][CH:49]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: BrCc1ccc(OCc2ccccc2)cn1
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1ccc(OCc2ccccc2)cn1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: -75 °C
Reaction time: 1 h
Yield: 73.1 %

Procedure:
540 mg (1.50 mmol) of di-tert-butyl Boc-glutamate (prepared according to J. Peptide Res. 2001, 58, 338) were dissolved in 6 mL of tetrahydrofuran and cooled to −75° C. 3.45 mL (3.45 mmol) of a 1M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran were added dropwise and the mixture was stirred at −75° C. for another 60 minutes. 460 mg (1.65 mmol) of 5-(benzyloxy)-2-(bromomethyl)pyridine in 5 mL of tetrahydrofuran were then added dropwise, and after stirring 2 hours at −75° C., 3.45 mL of 2N aqueous hydrochloric acid were added, and after stirring another 30 minutes at −75° C., the cooling bath was removed and the mixture was allowed to warm up to room temperature. The mixture was partitioned between dichloromethane and aqueous sodium bicarbonate, and the organic layer was dried over magnesium sulfate and evaporated. The crude residue was purified by column chromatography on silica gel (ethyl acetate in hexane 0%→100%) to give 610 mg of the desired compound as yellowish oil (66% yield).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)[CH2:3]1.[CH:25]([Mg]Cl)([CH3:27])[CH3:26]>C1COCC1>[OH:1][C:2]1([CH:25]([CH3:27])[CH3:26])[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[CH:19][C:20]([C:23]#[N:24])=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[CH2:3]1
Reactant: CC(C)[Mg]Cl
Reactant: N#Cc1ccc(-c2ccc(OCCCN3CCC(=O)C3)cc2)cc1
Solvent: C1CCOC1
Product: CC(C)C1(O)CCN(CCCOc2ccc(-c3ccc(C#N)cc3)cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
The product from Example 154 (147 mg, 0.46 mmol) in dry THF (10 mL) under an atmosphere of nitrogen at 0° C. was treated with a 2.0M solution of isopropylmagnesium chloride (0.92 mmol). After warming to ambient temperature and stirring for 1 hour, the mixture was quenched with 5 mL of cold saturated ammonium chloride solution and then the solution was partitioned between water (50 mL) and dichloromethane (50 mL). The organic layer was washed with brine (50 mL), dried over sodium sulfate and filtered. The filtrate was evaporated under reduced pressure and the residue purified by chromatography (CHCl3:MeOH:NH4OH, 9:1:0.1) to provide the title compound (75% yield).
Reaction SMILES: C[O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[N:6][CH:5]=1.[OH-].[Na+].Cl>CO.O>[CH3:16][N:13]1[CH2:12][CH2:11][N:10]([C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:17])=[O:2])=[CH:5][N:6]=2)[CH2:15][CH2:14]1
Reactant: COC(=O)c1ccc(N2CCN(C)CC2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN1CCN(c2ccc(C(=O)O)cn2)CC1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
A solution of 6-(4-methyl-piperazin-1-yl)-nicotinic acid methyl ester (5.56 g) in MeOH/H2O 1:1 (100 ml) was cooled to 0° C. and treated with NaOH (1.9 g). The reaction mixture was stirred for 45 min at 0° C. and for 5 hrs at r.t., then neutralized with 1N HCl and concentrated. The crude product was used in the next reaction step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[NH:20][C:19]4[CH:21]=[CH:22][C:23]([C:25]([NH2:27])=[O:26])=[CH:24][C:18]=4[N:17]=3)=[CH:12][CH:11]=2)=[CH2:9])=[CH:4][CH:3]=1.N#N>C(O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:11]=[CH:12][C:13]([C:16]3[NH:20][C:19]4[CH:21]=[CH:22][C:23]([C:25]([NH2:27])=[O:26])=[CH:24][C:18]=4[N:17]=3)=[CH:14][CH:15]=2)[CH3:9])=[CH:4][CH:3]=1
Reactant: C=C(c1ccc(Cl)cc1)c1ccc(-c2nc3cc(C(N)=O)ccc3[nH]2)cc1
Agent: N#N
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(c1ccc(Cl)cc1)c1ccc(-c2nc3cc(C(N)=O)ccc3[nH]2)cc1
Yield: 69.8 %

Procedure:
A flask containing a solution of 2-{4-[1-(4-chloro-phenyl)-vinyl]-phenyl}-1H-benzoimidazole-5-carboxylic acid amide (Example 41, 30 mg, 0.08 mmol) in 1:1 ethanol/ethyl acetate (6.0 mL) was charged with N2 and evacuated (3×). Palladium on carbon (10 wt %) was added to the solution, and the flask was charged with H2 and evacuated (3×), and then maintained at ˜1 atm H2 for 2.5 h. The flask was evacuated and then charged with N2. The reaction mixture was filtered through a pad of Celite®, which was washed with ethanol (50 mL), ethyl acetate (50 mL) and then methanol (2×50 mL). The filtrate was concentrated under reduced pressure. Purification of the residue by chromatography (silica gel, 1% methanol saturated with ammonia/9% methanol/CH2Cl2) afforded the title compound (21 mg, 68%). TLC (silica, 1% methanol, saturated with ammonia/9% methanol/CH2Cl2): Rf=0.35. MS (ESI+): mass calculated for C22H18ClN3O, 375.1, m/z found, 376.1 [M+H]+. 1H NMR (500 MHz, CD3OD): δ 8.16 (br s, 1H), 8.04 (d, J=8.4 Hz, 2H), 7.81 (d, J=8.3 Hz, 1H), 7.62 (br s, 1H), 7.43 (d, J=8.3 Hz, 2H), 7.30–7.26 (m, 4H), 4.27–4.24 (m, 1H), 1.67 (d, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[C:7]([OH:14])=[C:6]([NH:15][S:16]([C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=2[O:26][CH3:27])(=[O:18])=[O:17])[CH:5]=1.Br[CH2:30][CH2:31]Br>>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]([C:10]([F:11])([F:13])[F:12])[C:7]2[O:14][CH2:31][CH2:30][N:15]([S:16]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=3[O:26][CH3:27])(=[O:18])=[O:17])[C:6]=2[CH:5]=1)=[O:28]
Reactant: COC(=O)c1cc(NS(=O)(=O)c2cc(Cl)ccc2OC)c(O)c(C(F)(F)F)c1
Reactant: BrCCBr
Product: COC(=O)c1cc2c(c(C(F)(F)F)c1)OCCN2S(=O)(=O)c1cc(Cl)ccc1OC

Procedure:
The title compound, MS (ISP)=569.0 (M−H)−, was produced in analogy with example 36, steps 1-4. Step 1 was performed using 3-(5-chloro-2-methoxy-benzenesulfonylamino)-4-hydroxy-5-trifluoromethyl-benzoic acid methyl ester (example 40, step 2) and 1,2-dibromoethane, yielding 4-(5-chloro-2-methoxy-benzenesulfonyl)-8-trifluoromethyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid methyl ester, which was hydrolyzed in step 2 to afford 4-(5-chloro-2-methoxy-benzenesulfonyl)-8-trifluoromethyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid. This was reacted with ethyl 4-aminobenzoate in step 3 to produce 4-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-8-trifluoromethyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic acid ethyl ester, which was hydrolyzed in step 4.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[F:11][C:12]1([F:19])[CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>>[F:11][C:12]1([F:19])[CH2:18][CH2:17][CH2:16][N:15]([C:2]2[N:6]([CH3:7])[N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:14][CH2:13]1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Reactant: FC1(F)CCCNCC1
Product: Cn1ncc([N+](=O)[O-])c1N1CCCC(F)(F)CC1
Yield: 100 %

Procedure:
Reaction of 5-chloro-1-methyl-4-nitro-1H-pyrazole and 4,4-difluoroazepane gave 4,4-difluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepane as a white solid (0.41 g, 100%). 1H NMR (400 MHz, CDCl3) δ 8.04 (s, 1H), 3.79 (s, 3H), 3.39-3.23 (m, 4H), 2.35-2.20 (m, 4H), 2.00-1.92 (m, 2H)