Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.Br[C:4]1[C:12]2[O:11][C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1.[Li]CCCC.CON(C)[C:25]([C@@H:27]1[CH2:32][CH2:31][CH2:30][N:29]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:28]1)=[O:26]>C1COCC1>[C:13]([C:10]1[O:11][C:12]2[C:4]([C:25]([C@@H:27]3[CH2:32][CH2:31][CH2:30][N:29]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:28]3)=[O:26])=[CH:5][CH:6]=[CH:7][C:8]=2[CH:9]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)c1cc2cccc(Br)c2o1
Reactant: CON(C)C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: N#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)c2cccc3cc(C(C)(C)C)oc23)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 53.7 %

Procedure:
Under protection of N2, a solution of 7-bromo-2-tert-butyl-benzofuran (0.5 g, 1.98 mmol) in anhydrous THF (5 mL) was cooled to −78° C. and 2.5 M n-BuLi solution in hexanes (0.87 mL, 2.18 mmol) was added dropwise slowly. The reaction mixture was stirred at −78° C. for 1 h and a solution of (R)-tert-butyl 3-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (0.65 g, 2.38 mmol) in anhydrous THF (5 mL) was added dropwise slowly. The reaction mixture was warmed to rt and stirred overnight. The mixture was quenched with satd aq NH4Cl (20 mL) and extracted with EtOAc (3×30 mL). The combined organic extracts were dried over Na2SO4. Solvent removal and flash column chromatography afforded (R)-tert-butyl 3-(2-tert-butylbenzofuran-7-carbonyl)piperidine-1-carboxylate (0.41 g, 54%). 1H NMR (CDCl3): 7.83 (d, 1H), 7.19 (d, 1H), 7.26 (t, 1H), 6.440 (s, 1H), 4.1 (d, 1H), 3.75 (s, 1H), 2.83 (t, 1H), 2.27 (d, 1H), 1.82 (d, 1H), 1.590 (m, 4H), 1.426 (s, 9H), 1.406 (s, 9H)
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]([CH2:25][C:26]2[C:31]([CH3:32])=[CH:30][C:29]([CH3:33])=[CH:28][N:27]=2)[CH:15]2[C:24]3[N:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH2:18][CH2:17][CH2:16]2)=[C:9]([CH2:34][OH:35])[CH:8]=1.Cl>CCO.[OH-].[Na+]>[CH3:32][C:31]1[C:26]([CH2:25][N:14]([CH2:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][NH:5][CH2:4][C:3]([OH:36])=[O:2])=[CH:8][C:9]=2[CH2:34][OH:35])[CH:15]2[C:24]3[N:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH2:18][CH2:17][CH2:16]2)=[N:27][CH:28]=[C:29]([CH3:33])[CH:30]=1
Reactant: COC(=O)CNCc1ccc(CN(Cc2ncc(C)cc2C)C2CCCc3cccnc32)c(CO)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cnc(CN(Cc2ccc(CNCC(=O)O)cc2CO)C2CCCc3cccnc32)c(C)c1
Temperature: 90 °C
Reaction time: 16 h
Yield: 77 %

Procedure:
(4-{[(3,5-Dimethyl-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-3-hydroxymethyl-benzylamino)-acetic acid methyl ester (0.140 g, 0.29 mmol) was dissolved in a mixture of EtOH (3 mL) and 3M NaOH (7 mL). The colorless mixture was stirred at 90° C. for 16 hours to give an orange/brown solution. 3M HCl was added until pH 2 followed by the addition of 3M NaOH until the pH 9 and a white precipitate formed. The white solid was removed via suction filtration and the filtrate was extracted with 95:5 (CHCl3/MeOH) (9×30 mL) and the combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. Purification by column chromatography on silica gel (MeCN:MeOH:NH4OH, 6:3:1, v/v/v) afforded (4-{[(3,5-dimethyl-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-3-hydroxymethyl-benzylamino)-acetic acid (0.106 g, 78%) as a pale yellow solid. 1H NMR (CD3OD) δ 1.58 (m, 1H), 2.05 (m, 2H), 2.17 (s+m, 4H), 2.27 (s, 3H), 2.65 (m, 1H), 2.83 (m, 1H), 3.43 (s, 2H), 3.74 (m, 4H), 4.16-4.22 (m, 4H), 4.39 (d, 1H, J=11.1 Hz), 7.11 (m, 1H), 7.25-7.42 (m, 5H), 8.10 (s, 1H), 8.28 (s, 1H). 13C NMR (CD3OD) δ 18.2, 18.9, 22.4, 23.2, 30.5, 52.0, 55.0, 55.1, 59.8, 63.2, 123.4, 130.5, 131.1, 133.1, 133.6, 133.8, 134.7, 135.8, 136.9, 138.7, 140.1, 141.3, 143.7, 146.9, 147.8, 154.5, 158.0, 171.5. HPLC: 97%. ES-MS m/z 475 [M+H]+. Anal. Calcd. for C28H34N4O31.3 H2O: C, 67.53; H, 7.41; N, 11.25. Found: C, 67.65; H, 7.36; N, 11.09.
Reaction SMILES: [C:1]([NH:3][C:4]([NH:12][C:13]1[S:14][C:15]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:16]=2[N:17]=1)=[N:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)#[N:2]>O1CCCC1>[NH:2]=[C:1]1[N:17]2[C:13]([S:14][C:15]3[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:16]=32)=[N:12][C:4]([NH:5][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)=[N:3]1
Reactant: COc1ccc2nc(NC(=Nc3ccccc3)NC#N)sc2c1
Solvent: C1CCOC1
Product: COc1ccc2c(c1)sc1nc(Nc3ccccc3)nc(=N)n12
Reaction time: 1 h
Yield: 100 %

Procedure:
Silica gel (chromatography grade) (20 g) was added to a solution of the product of step (c) (1.2 g) in tetrahydrofuran (50 ml) and the suspension stirred for 1 hour. The mixture was filtered, the filtrate evaporated to dryness and the residue triturated with methanol to yield a white solid. Recrystallisation of the solid from ethanol yielded the title compound (1.2 g) as white crystals, mp 225°-6°.
Reaction SMILES: [CH2:1]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH:12]([S:14]([F:17])(=[O:16])=[O:15])=[CH2:13].[ClH:18].CC(O)C>CN(C=O)C.CC(O)C>[ClH:18].[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([NH:9][CH:13]=[CH:12][S:14]([F:17])(=[O:16])=[O:15])=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C=CS(=O)(=O)F
Reactant: CCCCc1ccc(N)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC(C)O
Product: CCCCc1ccc(NC=CS(=O)(=O)F)cc1
Yield: 67 %

Procedure:
The reaction between 4-butylaniline (3.51 g, 23.5 mmol) and ethenesulfonyl fluoride (3.3 mL, 30 mmol) was carried out in DMF (75 mL) as described in Example 16. There was obtained a dark oily residue which was dissolved in a minimal amount of IPA and treated with 1.1 equivalents of HCl/IPA. The title compound (4.66 g, 67% yield) was obtained as a tan solid, mp 153°-156.5° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([Cl:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]([F:22])([F:21])[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=2)[N:3]=1.[NH2:23][C:24]1[CH:28]=[C:27]([CH3:29])[N:26](C(OC(C)(C)C)=O)[N:25]=1.CC(O)=O>CC(N(C)C)=O>[Cl:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[C:4]([C:13]([F:22])([F:21])[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=1)[N:3]=[C:2]2[NH:23][C:24]1[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=1
Reactant: Fc1ccc(C(F)(F)c2nc(Cl)c3cccc(Cl)c3n2)nc1
Reactant: Cc1cc(N)nn1C(=O)OC(C)(C)C
Solvent: CC(=O)O
Solvent: CC(=O)N(C)C
Product: Cc1cc(Nc2nc(C(F)(F)c3ccc(F)cn3)nc3c(Cl)cccc23)n[nH]1
Temperature: 100 °C
Yield: 16.4 %

Procedure:
To 4,8-dichloro-2-(difluoro(5-fluoropyridin-2-yl)methyl)quinazoline (263 mg, 0.77 mmol) in DMA (2.0 mL) were added tert-butyl 3-amino-5-methyl-1H-pyrazole-1-carboxylate (300 mg, 1.53 mmol) and HOAc (0.102 mL), and the mixture was heated at 100° C. for 5 h. The mixture was allowed to cool to rt and was purified by preparative reverse-phase HPLC (diphenyl column eluting over 40 mins with a gradient of 25 to 80% acetonitrile (containing 0.05% HOAc) and water (containing 0.05% HOAc) to afford 8-chloro-2-(difluoro(5-fluoropyridin-2-yl)methyl)-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine as a colorless solid (51 mg, 16%). 1H NMR (300 MHz, DMSO-d6) δ 12.23 (br s, 1H), 10.87 (br s, 1H), 8.65-8.67 (m, 2H), 8.01-8.08 (m, 3H), 7.61 (dd, J=9, 6 Hz, 1H), 5.94 (s, 1H), 2.17 (s, 3H). LCMS (ESI) m/z 405 (M+H)+.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][NH:6][C:7]1[C:12]([C:13]#[N:14])=[CH:11][CH:10]=[CH:9][N:8]=1)C.C[O-].[Na+]>[Ni].CO>[NH:6]1[C:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:12]=2[CH2:13][NH:14][C:4](=[O:3])[CH2:5]1
Reactant: CCOC(=O)CNc1ncccc1C#N
Agent: [Ni]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1CNc2ncccc2CN1
Temperature: 25 °C
Reaction time: 48 h
Yield: 32 %

Procedure:
Raney nickel (3 g) was added to anhydrous methanol (50 mL) under argon and washed with anhydrous methanol (4×50 mL) (3-Cyanopyridin-2-ylamino)-acetic acid ethyl ester (3.35 g, 16.3 mmol) was dissolved in methanol (50 mL) and added to the Raney nickel slurry. The reaction vessel was purged with argon for 10 min. Sodium methoxide solution (16.3 mmol, 3.75 mL) was added and the argon purge was repeated (5 min). The reaction flask was charged with H2 and stirred at room temperature for 48 h. Dilute HCl (16.3 mL of a 1 M solution) was added and the flask was purged with argon for 30 min. The slurry was filtered through celite and the filter cake was washed with 1:1 methanol/water. The filtrate was concentrated and extracted with ethyl acetate (4×100 mL), dried over MgSO4 and concentrated to afford the title compound as a beige solid (850 mg, 30%). 1H NMR (300 MHz, DMSO-d6) δ 8.07 (t, J=5.2 Hz, 1H), 7.82 (dd, J=4.9, 1.5 Hz, 1H), 7.21 (dd, J=7.1, 1.6 Hz, 1H), 6.69 (t, J=5.0 Hz, 1H), 6.43 (dd, J=7.2, 5.0 Hz, 1H), 4.24 (d, J=5.9 Hz, 2H), 3.91 (d, J=5.1 Hz, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][C:12]([Br:17])=[CH:11][CH:10]=2)=[O:5])[CH3:2].Cl.[CH3:19][O:20][C@@H:21]([CH3:24])[CH2:22][NH2:23].C(N(C(C)C)CC)(C)C>C(O)C>[Br:17][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:15]2[NH:23][CH2:22][C@@H:21]([O:20][CH3:19])[CH3:24]
Reactant: CCOC(=O)c1cnc2ccc(Br)cc2c1Cl
Reactant: CO[C@@H](C)CN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOC(=O)c1cnc2ccc(Br)cc2c1NC[C@H](C)OC
Reaction time: 16 h

Procedure:
Suspend ethyl-6-bromo-4-chloro-quinoline-3-carboxylate (389 g, 1.24 mol) and (2S)-2-methoxypropan-1-amine, hydrochloride (171 g, 1.36 mol, 1.1 eq.) in ethanol (5.84 L). Add diisopropylethylamine (474 mL) and heat the mixture at 50° C. overnight. After 16 hours, cool the reaction to room temperature and concentrate in vacuo. Add methyl tert-butyl ether (2 L) to the residue and stir for 20 min. Filter the precipitate and wash it with methyl tert-butyl ether (2×250 mL). Concentrate the filtrate in vacuo to afford the titled compound in almost quantitative yield. The compound will be used in the next step without further purification. MS (ESI) m/z (M+H)+367.0, 369.0.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:6]1[S:17]([C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18].[NH:27]1[CH:31]=[N:30][N:29]=[N:28]1>>[F:16][C:13]1[CH:14]=[CH:15][C:10]([CH:7]2[N:6]([S:17]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH:5]([CH2:4][CH2:3][CH2:2][N:28]3[N:29]=[N:30][CH:31]=[N:27]3)[CH2:9][CH2:8]2)=[CH:11][CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)N2C(CCCCl)CCC2c2ccc(F)cc2)cc1
Reactant: c1nnn[nH]1
Product: Cc1ccc(S(=O)(=O)N2C(CCCn3ncnn3)CCC2c2ccc(F)cc2)cc1

Procedure:
The title compound, colorless oil, MS: m/e=430.5 (M+H+), was prepared in accordance with the general method of example 82b from (2RS,5RS)-2-(3-chloro-propyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine and 1H-tetrazole.
Reaction SMILES: C[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N:11]([S:13]([C:16]2[CH:21]=[CH:20][C:19](F)=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH3:12])[C:3]=1[CH3:23].[OH:24][CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]([C:32]1[CH:40]=[CH:39][C:35]2[O:36][CH2:37][O:38][C:34]=2[CH:33]=1)=[O:31]>>[O:36]1[C:35]2[CH:39]=[CH:40][C:32]([C:30]([NH:29][CH2:28][CH2:27][CH2:26][CH2:25][O:24][C:19]3[CH:20]=[CH:21][C:16]([S:13]([N:11]([CH3:12])[C:4]4[C:3]([CH3:23])=[CH:2][CH:10]=[CH:9][C:5]=4[C:6]([OH:8])=[O:7])(=[O:15])=[O:14])=[CH:17][CH:18]=3)=[O:31])=[CH:33][C:34]=2[O:38][CH2:37]1
Reactant: Cc1ccc(C(=O)O)c(N(C)S(=O)(=O)c2ccc(F)cc2)c1C
Reactant: O=C(NCCCCO)c1ccc2c(c1)OCO2
Product: Cc1cccc(C(=O)O)c1N(C)S(=O)(=O)c1ccc(OCCCCNC(=O)c2ccc3c(c2)OCO3)cc1
Yield: 60 %

Procedure:
The product of Example 2 (0.30 g, 0.92 mmol) was coupled to N-(4hydroxybutyl)-1,3-benzodioxole-5-carboxamide, prepared according to Example 21, (0.23 g, 0.96 mmol) using the procedure of Example 3 to provide 0.30 g (60% yield) of yellow solid. MP 110° C.; 1H NMR (DMSO-d6): δ 1.66-1.80 (m,CH2, CH2)1.89 (s, CH3), 3.1 (s, CH3), 3.39-3.45 (m, CH2), 4.08 (t, CH2), 6.08 (s, CH2), 6.9 (d, 1 Ar H), 7.04-7.08 (m, 2 Ar H), 7.33-7.45 (m, 5 Ar H), 7.53-7.58 (m, 2 Ar H), 8.39 (t, NH), 12.8 (s, OH). Electrospray Mass Spec: m/z 541.2 (M+H)+.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]([Br:16])=[CH:5][CH2:6][CH:7]([CH:13]([CH3:15])[CH3:14])[C:8]([O:10]CC)=[O:9]>O.C(O)C>[Br:3][C:4]([Br:16])=[CH:5][CH2:6][CH:7]([CH:13]([CH3:14])[CH3:15])[C:8]([OH:10])=[O:9]
Reactant: CCOC(=O)C(CC=C(Br)Br)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)C(CC=C(Br)Br)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
In a mixture of 7 g of water and 20 g of ethanol were dissolved 1.1 g of sodium hydroxide and 4.6 of the ethyl α-(3.3-dibromoallyl)isovalerate obtained above were added to the above solution. The mixture was stirred at room temperature overnight and, then, refluxed for 3 hours. The reaction mixture was then distilled to remove the ethanol and the residue was made acidic by the addition of dilute hydrochloric acid and extracted with diethyl ether. The ethereal layer was dried over anhydrous magnesium sulfate and the low-boiling fraction was distilled off. By the above procedure there were obtained 3.7 g of α-(3,3-dibromoallyl)isovaleric acid, the NMR spectrum of which is shown below [yield: 88% based on ethyl α-(3,3-dibromoallyl)isovalerate].
Reaction SMILES: COC([NH:5][C@H:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([NH:15][C:16]([C:18]3[C:19]([C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=4)=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=3)=[O:17])[CH:12]=2)[CH2:7]1)=O.I[Si](C)(C)C.CO>C(#N)C>[NH2:5][C@H:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([NH:15][C:16]([C:18]3[C:19]([C:25]4[CH:26]=[CH:27][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:29][CH:30]=4)=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=3)=[O:17])[CH:12]=2)[CH2:7]1
Reactant: COC(=O)N[C@@H]1Cc2ccc(NC(=O)c3cccc(C)c3-c3ccc(C(F)(F)F)cc3)cc2C1
Agent: C[Si](C)(C)I
Solvent: CC#N
Solvent: CO
Product: Cc1cccc(C(=O)Nc2ccc3c(c2)C[C@H](N)C3)c1-c1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
(R)-6-methyl-4′-trifluoromethylbiphenyl-2-carboxylic acid (2-methoxycarbonylaminoindan-5-yl)-amide (6.5 g, 13.9 mmol) is dissolved in acetonitrile (325 mL) and cooled to 0° C. under nitrogen. Iodotrimethylsilane (11.1 g, 55.6 mmol) is added dropwise, the mixture is allowed to warm to room temperature and is stirred overnight. Methanol (100 mL) is added and the mixture is stirred for 1 hour and then concentrated in vacuo. The residue is dissolved in ethyl acetate (750 mL) and washed with saturated sodium bicarbonate (2×125 mL), water (125 mL), 5% Na2S2O3 solution (125 mL), water (125 mL), and brine (50 mL). The organic phase is dried over sodium sulfate and concentrated to afford (R)-N-(2-aminoindan-5-yl)-6-methyl-4′-trifluoromethylbiphenyl-2-carboxamide.
Reaction SMILES: [CH3:1][CH2:2][CH2:3]Br.[Br:5][C:6]1[CH:7]=[CH:8][C:9]([F:14])=[C:10]([CH:13]=1)[CH:11]=[O:12]>C(OCC)C.II>[Br:5][C:6]1[CH:7]=[CH:8][C:9]([F:14])=[C:10]([CH:11]([OH:12])[CH2:1][CH2:2][CH3:3])[CH:13]=1
Reactant: CCCBr
Reactant: O=Cc1cc(Br)ccc1F
Agent: II
Solvent: CCOCC
Product: CCCC(O)c1cc(Br)ccc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 93.8 %

Procedure:
To a suspension of Mg (0.236 g, 9.83 mmol) in diethyl ether (10 mL), I2 (1 spatula) was added n-propyl bromide (0.72 g, 0.53 mL, 5.9 mmol) at room temperature. When iodine color disappeared, the remaining n-propyl bromide in ether was added to the reaction mixture and stirred at room temperature for 10 minutes. To this Grignard reagent, 5-bromo-2-fluorobenzaldehyde (1.00 g, 4.92 mmol) in ether was added under cold conditions and stirred at room temperature for 1 hour. The reaction mixture was quenched with NH4Cl solution and extracted with ether. The ether layer was dried over anhydrous Na2SO4, filtered and concentrated to afford 1-(5-bromo-2-fluoro-phenyl)-butan-1-ol (1.14 g, 92.6%). 1H NMR (CDCl3): δ 7.6 (m, 1H), 7.3-7.4 (m, 1H), 6.9 (t, 1H), 5.0 (brs, 1H), 2.0 (brs, 1H), 1.6-1.7 (m, 2H), 1.3-1.5 (m, 2H), 1.0 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]2[C:17]([F:20])([F:19])[F:18])=[C:6]([N+:21]([O-])=O)[CH:5]=1>CO.[Pd]>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]2[C:17]([F:20])([F:18])[F:19])=[C:6]([NH2:21])[CH:5]=1
Reactant: COC(=O)c1ccc(NC2CCCCC2C(F)(F)F)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(NC2CCCCC2C(F)(F)F)c(N)c1
Reaction time: 16 h
Yield: 96.7 %

Procedure:
1.63 g 3-Nitro-4-(2-trifluoromethyl-cyclohexylamino)-benzoic acid methyl ester were dissolved in 25 ml methanol, 0.03 g of palladium on carbon (10%) were added and the mixture was hydrogenated at 5 bar for 16 h. The catalyst was removed by filtration over celite, the filtrate was concentrated to obtain 1.44 g (97%) of 3-Amino-4-(2-trifluoromethyl-cyclohexylamino)-benzoic acid methyl ester.
Reaction SMILES: C(N(CC)CC)C.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[C:29]([NH:36][CH2:37][C:38]([OH:40])=O)([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].[CH:41]1[C:49]2[C:48]3[CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][C:47]=3[O:46][C:45]=2[CH:44]=[CH:43][C:42]=1[NH2:55]>>[O:40]=[C:38]([NH:55][C:42]1[CH:43]=[CH:44][C:45]2[O:46][C:47]3[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50][C:48]=3[C:49]=2[CH:41]=1)[CH2:37][NH:36][C:29](=[O:30])[O:31][C:32]([CH3:33])([CH3:34])[CH3:35]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: Nc1ccc2oc3c(c2c1)CCCCC3
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC(=O)Nc1ccc2oc3c(c2c1)CCCCC3
Yield: 46.5 %

Procedure:
Following the procedure of Example 30, triethylamine (0.43 mL, 3.1 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.31 g, 1.6 mmol), N-hydroxybenzotriazole (0.22 g, 1.6 mmol), N-Boc-glycine (0.24 g, 1.4 mmol), and 7,8,9,10-tetrahydro-6H-benzo[b]-cyclohepta[d]furan-2-ylamine (0.25 g, 1.2 mmol) provided tert-butyl [2-oxo-2-(7,8,9,10-tetrahydro-6H-benzo[b]cyclohepta[d]furan-2-ylamino)ethyl]carbamate (0.20 g). MS (ESI) m/z 359 ([M+H]+); MS (ESI) m/z 357.2 ([M−H]−).
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([S:13]([NH:16][C:17]2[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:18]=2[O:19][C:20]2[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=2[C:22](O)=[O:23])(=[O:15])=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.B>O1CCCC1>[F:37][C:2]([F:1])([F:38])[C:3]1[CH:4]=[C:5]([S:13]([NH:16][C:17]2[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:18]=2[O:19][C:20]2[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=2[CH2:22][OH:23])(=[O:15])=[O:14])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: O=C(O)c1ccccc1Oc1ccc(C(F)(F)F)cc1NS(=O)(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: B
Solvent: C1CCOC1
Product: O=S(=O)(Nc1cc(C(F)(F)F)ccc1Oc1ccccc1CO)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
2-[2-[3,5-Bis(trifluoromethyl)phenylsulfonamido]-4-trifluoromethylphenoxy]benzoic acid (0.1 g, 0.17 mmol) was dissolved in tetrahydrofuran (5 mL) and stirred under argon at room temperature. A 1M solution of borane (0.5 mL, 0.5 mmol) was added and the mixture was stirred for 16 h. Evaporation of the solvent followed by aqueous workup and flash chromatography (silica gel, ethyl acetate/hexane); and then recrystallization provided the title compound as a white crystalline solid; mp 123°-125° C.
Reaction SMILES: OO.[F:3][C:4]([F:9])([F:8])[C:5]([O-:7])=[O:6].[K+].[F:11][C:12]([F:23])([F:22])[C:13]([O:15]C(=O)C(F)(F)F)=[O:14]>FC(F)(F)C(O)=O>[F:3][C:4]([F:9])([F:8])[C:5]([O:7][O:15][C:13](=[O:14])[C:12]([F:23])([F:22])[F:11])=[O:6]
Reactant: O=C([O-])C(F)(F)F
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: OO
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Product: O=C(OOC(=O)C(F)(F)F)C(F)(F)F

Procedure:
A solution of bis(trifluoroacetyl) peroxide in trifluoroacetic acid was prepared by addition of H2O2 (95%, 1.61 g, 45.0 mmol H2O2) dropwise into a well-stirred solution of potassium trifluoroacetate (6.8 mg, 0.045 mmol) in freshly distilled bis(trifluoroacetic) anhydride (21 g, 100 mmol) at 0° C. A 31% (mol) solution of bis(trifluoroacetyl) peroxide in the trifluoroacetic acid was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9]O.CC(C)(O)[C:13]#[N:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC=CC=1.CCCCCC>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:13]#[N:14]
Reactant: OCCc1ccccc1Br
Reactant: CC(C)(O)C#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: c1ccccc1
Product: N#CCCc1ccccc1Br
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of commercially available 2-(2-bromophenyl)ethanol (1 eq.) in Benzene (0.064M) at room temperature was added acetone cyanohydrin (1.5 eq), 1-1′(Azodicarbonyl)dipiperidine (1.5 eq) then dropwise over 5 min triphenyl phosphine (1.5 eq). The mixture was stirred at room temperature for 12 h, diluted with hexane (0.03M) and filtered on pad of silica gel. Fractions containing the desired material were combined and concentrated. A second purification by column chromatography on silica gel (Combi-Flash by ISCO), eluting with Hex/EtOAc (0 to 30%, in 30 min) afforded the desired compound as a colorless oil.
Reaction SMILES: [CH2:1]([C:5]1[C:9]([C:10]([F:13])([F:12])[F:11])=[C:8]([C:14]([OH:16])=O)[O:7][N:6]=1)[CH:2]([CH3:4])[CH3:3].N1C=CC=CC=1.[F:23]C1N=C(F)N=C(F)N=1>ClCCl>[CH2:1]([C:5]1[C:9]([C:10]([F:13])([F:12])[F:11])=[C:8]([C:14]([F:23])=[O:16])[O:7][N:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: Fc1nc(F)nc(F)n1
Reactant: CC(C)Cc1noc(C(=O)O)c1C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)Cc1noc(C(=O)F)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.5 %

Procedure:
To a mixture of 3-isobutyl-4-(trifluoromethyl)isoxazole-5-carboxylic acid (0.200 g, 0.843 mmol) and pyridine (0.082 mL, 1.01 mmol) in dichloromethane (8 mL) at room temperature was added 2,4,6-trifluoro-1,3,5-triazine (cyanuric fluoride) (0.085 mL, 1.01 mmol). The reaction mixture was stirred at room temperature overnight. The heterogeneous reaction was diluted with dichloromethane, washed with an ice-cold solution of 0.5N aqueous hydrochloric acid (2×), and the organic layer was collected. The aqueous layer was back-extracted with dichloromethane, and the combined organic layers were dried anhydrous sodium sulfate and concentrated to afford 3-isobutyl-4-(trifluoromethyl)isoxazole-5-carbonyl fluoride (0.130 g, 0.544 mmol, 65% yield) as a yellow solid. The product had an HPLC ret. time=2.51 min. (corresponding to the methyl ester)−Column: CHROMOLITH® SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:8]=[CH:9][C:10]3[N:14]=[N:13][N:12]([O:15][CH2:16][CH2:17][CH2:18][C:19]([O:21]CC)=[O:20])[C:11]=3[CH:24]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[OH-].[Na+].Cl>C(O)C>[N:1]1([CH2:6][C:7]2[CH:8]=[CH:9][C:10]3[N:14]=[N:13][N:12]([O:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[C:11]=3[CH:24]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCOC(=O)CCCOn1nnc2ccc(Cn3ccnc3)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCCOn1nnc2ccc(Cn3ccnc3)cc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 71 %

Procedure:
A mixture of 3.2 parts of ethyl 4-[[6-(1H-imidazol-1-ylmethyl)-1H-benzotriazol-1-yl]oxy]butanoate, 25 parts of a sodium hydroxide solution 1N and 20 parts of ethanol was stirred for 1.5 hours at room temperature. 25 Parts of hydrochloric acid solution 1N were added and the whole was concentrated to a volume of about 20 parts. The precipitated product, which was formed during concentration, was filtered off, washed with water, 2-propanol and 1,1'-oxybisethane and dried, yielding 2.1 parts (71%) of 4-[[6-(1H-imidazol-1-ylmethyl)-1H-benzotriazol-1-yl]oxy]butanoic acid; mp. 170.5° C. (compound 236).