Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1.[N+:21]([C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1)([O-:23])=[O:22]>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:33]2[CH2:34][CH2:35][N:30]([C:27]3[CH:26]=[CH:25][C:24]([N+:21]([O-:23])=[O:22])=[CH:29][CH:28]=3)[CH2:31][CH2:32]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1
Reactant: CCOC(=O)Nc1nc2cc(OC)ccc2nc1OC
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Product: COc1ccc2nc(OC)c(NC(=O)N3CCN(c4ccc([N+](=O)[O-])cc4)CC3)nc2c1
Yield: 81 %

Procedure:
Ethyl N-(2,6-dimethoxyquinoxalin-3-yl)carbamate and 1-(4-nitrophenyl)piperazine were reacted by the same way with the example 64 to obtain the titled compound (yield, 81%). 1H NMR (300 MHz, CDCl3): δ 3.57 (s, 4H), 3.75-3.87 (m, 6H), 4.09-4.16 (m, 4H), 6.84 (d, J=9.3 Hz, 2H), 6.91-7.27 (m, 3H), 7.56-7.63 (m, 1H), 8.16 (d, J=9.3 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:12][CH2:11][CH2:10][NH:9][CH2:8][C:7]=2[CH:13]=1.[S:14](Cl)([Cl:17])(=[O:16])=[O:15].COC1C=C2C(CCN(S(Cl)(=O)=O)C2)=CC=1>C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:12][CH2:11][CH2:10][N:9]([S:14]([Cl:17])(=[O:16])=[O:15])[CH2:8][C:7]=2[CH:13]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: COc1ccc2c(c1)CNCCO2
Agent: COc1ccc2c(c1)CN(S(=O)(=O)Cl)CC2
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)CN(S(=O)(=O)Cl)CCO2

Procedure:
This compound was prepared from 1.4 g of 7-methoxy-2,3,4,5-tetrahydro-benzo[f][1,4]-oxazepine, 0.91 mL of sulfuryl chloride and 4.7 mL of triethylamine using the procedure described for 63f. Yield: 0.23 g (oil), EI-MS: 277 (M+).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.[OH-].[Na+].Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>C(O)C.O>[NH2:1][C:2]1[S:3][C:4]([S:7][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[N:5][N:6]=1
Reactant: CCCCCCCBr
Reactant: Nc1nnc(S)s1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCCSc1nnc(N)s1
Temperature: 60 °C
Reaction time: 2 h
Yield: 82.5 %

Procedure:
In 185 ml of ethanol and 185 ml of water, 68.0 g of 2-amino-5-mercapto-1,3,4-thiadiazole and 22.4 g of sodium hydroxide were added. To this mixture, 84.6 g of 1-bromoheptane was added, and the resulting mixture was warmed to 60° C. and stirred for 2 hours. After cooling, water was added and the mixture was filtered. The residue was washed with water, dried under reduced pressure, and recrystallized from an ethanol/hexane mixture. Thus 90.2 g of 2-amino-5-heptylthio-1,3,4-thiadiazole was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][CH:25]=1)[O:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([N:14]=[C:15]([NH:17][C:18]([CH:20]3[CH2:22][CH2:21]3)=[O:19])[N:16]=2)[CH:13]=1)([O-])=O.[Cl-].O[NH3+].CO.Cl>[Zn].O>[NH2:1][C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][CH:25]=1)[O:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([N:14]=[C:15]([NH:17][C:18]([CH:20]3[CH2:22][CH2:21]3)=[O:19])[N:16]=2)[CH:13]=1
Reactant: O=C(Nc1nc2ccc(Oc3cccc([N+](=O)[O-])c3)cn2n1)C1CC1
Agent: Cl
Agent: [Cl-]
Agent: [NH3+]O
Solvent: O
Solvent: CO
Product: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Reaction time: 3 h
Yield: 24.7 %

Procedure:
A mixture of N-[6-(3-nitrophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (3.84 g, 11.3 mmol), zinc (5.17 g, 79.1 mmol), hydroxylammonium chloride (3.02 g, 56.5 mmol) and methanol (30 mL) was stirred under refluxing conditions for 3 hr. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethanol (50 mL), and reduced iron (5.00 g, 89.5 mmol), concentrated hydrochloric acid (5 mL) and water (50 mL) were added. The mixture was stirred under refluxing conditions for 1 hr. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was collected by filtration and washed with ethyl acetate to give the title compound (862 mg, 25%) as a white solid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH2:14][CH2:13][N:12]([C:15]4[CH:16]=[N:17][CH:18]=[CH:19][C:20]=4Cl)[C:11]3=[O:22])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[N:23]1([CH2:29][CH2:30][OH:31])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.[OH-].[K+].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.CO.C1(C)C=CC=CC=1>[S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH2:14][CH2:13][N:12]([C:15]4[CH:16]=[N:17][CH:18]=[CH:19][C:20]=4[O:31][CH2:30][CH2:29][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:11]3=[O:22])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: OCCN1CCOCC1
Reactant: O=C1N(c2ccc3ncsc3c2)CCN1c1cnccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: O=C1N(c2ccc3ncsc3c2)CCN1c1cnccc1OCCN1CCOCC1
Yield: 6.6 %

Procedure:
1-Benzothiazol-6-yl-3-(4-chloro-pyridin-3-yl)-imidazolidin-2-one (I-180a: 100 mg, 0.3023 mmol) was refluxed with 2-morpholin-4-yl-ethanol (60 mg, 0.4534 mmol), potassium hydroxide (68 mg, 1.2092 mmol), potassium carbonate (42 mg, 0.3023 mmol), 18-crown-ether (8 mg, 0.0302 mmol) and toluene (3 mL) at 120° C. to afford the crude product. The reaction was monitored by TLC (10% MeOH in chloroform). Purification by column chromatography on silica gel (3.5% methanol in chloroform) followed by hexane wash and ether wash afforded 8.5 mg of the product (6.6% yield).
Reaction SMILES: [Br:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[C:8]1[N:9]=[CH:10][N:11]([NH:13]C(=O)OC)[CH:12]=1.[OH-].[Na+]>>[Br:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[C:8]1[N:9]=[CH:10][N:11]([NH2:13])[CH:12]=1
Reactant: COC(=O)Nn1cnc(-c2cnn(C)c2Br)c1
Agent: [Na+]
Agent: [OH-]
Product: Cn1ncc(-c2cn(N)cn2)c1Br
Temperature: 100 °C

Procedure:
A mixture of methyl [4-(5-bromo-1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]carbamate (400 mg, 1.33 mmol) and aqueous sodium hydroxide solution (1 M, 1.33 mL, 1.33 mmol) was heated at 100° C. for 18 hours. After cooling, the aqueous mixture was extracted five times with 2-butanol, and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to provide the product as a beige solid. Yield: 310 mg, 1.28 mmol, 96%. 1H NMR (400 MHz, CD3OD) δ 3.89 (s, 3H), 7.46 (d, J=1.2 Hz, 1H), 7.61 (d, J=1.3 Hz, 1H), 7.82 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][S:12][CH:13]=2)=[CH:5][CH:4]=1.[CH3:14][O:15]C(Cl)Cl.C(=O)(O)[O-].[Na+]>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][S:12][CH:13]=2)=[CH:5][C:4]=1[CH:14]=[O:15]
Reactant: COC(Cl)Cl
Reactant: COc1ccc(-c2csnn2)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(-c2csnn2)cc1C=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of 0.99 grams (5.15 mmol) of 4-(4-methoxyphenyl)-1,2,3-thiadiazole (Maybridge Chemical Co.) in 23 mL of anhydrous methylene chloride (CH2Cl2) cooled to 0° C., was treated with 2.3 mL (21.9 mmol) of titanium tetrachloride and stirred for 30 min. The red solution was treated with 0.97 mL (10.7 mmol) of α,α-dichloromethyl methyl ether and allowed to warm to room temperature overnight. The reaction mixture was then poured over 100 mL of saturated aqueous sodium bicarbonate (NaHCO3), the pH was adjusted to 7-8 with solid NaHCO3 and the solution was then extracted with CH2Cl2. The organic layer was dried with magnesium sulfate (MgSO4) and concentrated to a yellow solid. Chromatography on silica gel (20% EtOAc: 80% Hexane) gave the pure title compound as a light yellow solid, 0.35 g (31%).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][C:8](Br)=[CH:9][C:10]=1[N:11]([C@H:21]1[CH2:26][CH2:25][C@H:24]([O:27][CH2:28][CH3:29])[CH2:23][CH2:22]1)[C:12]([C@H:14]1[CH2:19][CH2:18][C@H:17]([CH3:20])[CH2:16][CH2:15]1)=[O:13])=[O:5])C.[OH-].[Li+]>>[C:14]1([C:8]2[S:7][C:6]([C:4]([OH:3])=[O:5])=[C:10]([N:11]([C@H:21]3[CH2:22][CH2:23][C@H:24]([O:27][CH2:28][CH3:29])[CH2:25][CH2:26]3)[C:12]([C@H:14]3[CH2:15][CH2:16][C@H:17]([CH3:20])[CH2:18][CH2:19]3)=[O:13])[CH:9]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]=1
Reactant: CCOC(=O)c1sc(Br)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](OCC)CC1
Agent: [Li+]
Agent: [OH-]
Product: CCO[C@H]1CC[C@H](N(c2cc(C3=CCCCC3)sc2C(=O)O)C(=O)[C@H]2CC[C@H](C)CC2)CC1

Procedure:
The ester from Step II (173 mg, 0.34 mmol) was hydrolysed by lithium hydroxide as previously described (example 3, step VIII) to give 91 mg of 5-cyclohex-1-enyl-3-[(trans-4-ethoxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[C:16]1[NH:17][C:18]2[C:23]([C:24]=1[CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)=[CH:22][CH:21]=[C:20]([C:31]([O:33]C)=[O:32])[CH:19]=2)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH2:35](Br)[CH:36]=[CH2:37]>CN(C=O)C.C1COCC1.CO.[OH-].[Na+]>[CH2:37]([N:17]1[C:18]2[C:23](=[CH:22][CH:21]=[C:20]([C:31]([OH:33])=[O:32])[CH:19]=2)[C:24]([CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]2)=[C:16]1[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][C:10]=1[C:8]([O:7][C:3]([CH3:6])([CH3:4])[CH3:5])=[O:9])[CH:36]=[CH2:35]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3cnccc3C(=O)OC(C)(C)C)[nH]c2c1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CO
Product: C=CCn1c(-c2cnccc2C(=O)OC(C)(C)C)c(C2CCCCC2)c2ccc(C(=O)O)cc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a suspension of NaH (19.5 mg of 60% dispersion in mineral oil, 0.488 mmol) in DMF (2 mL), methyl 2-(4-(tert-butoxycarbonyl)pyridin-3-yl)-3-cyclohexyl-1H-indole-6-carboxylate (100 mg, 0.222 mmol) was added and the reaction mixture was stirred at rt for 10 min. Allyl bromide (0.040 mL, 0.466 mmol) was then added, and the reaction mixture was stirred at rt for 3 hr. It was then quenched by the addition of water and acidified using 1N HCl solution. A yellowish precipitate formed which was collected by filtration to give the crude ester product in sufficient purity to proceed to the next step. This material was then dissolved in a THF/Methanol mixture (3 mL/3 mL) and 2N NaOH solution (2 mL) was added. The reaction mixture was heated at 100° C. under microwave conditions for 15 min. It was then concentrated and the pH was adjusted to 4–5 using 1N HCl solution. This mixture was then extracted using ethyl acetate and the organic layer was dried with MgSO4, filtered and evaporated and the resultant residue was purified using Prep. reverse phase HPLC to afford the title compound as a yellow solid, (50 mg, 44% yield two steps). MS m/z 516(MH+); 1H NMR (500 MHz, CD3OD) □ ppm 1.22–1.48 (m, 13 H) 1.70–2.02 (m, 5 H) 2.15 (m, 1 H) 2.37 (m, 1 H) 3.88 (dd, J=16.63, 5.04 Hz, 1 H) 4.13 (m, 1 H) 4.51 (m, 1 H) 4.76 (m, 1 H) 4.87 (m, 1 H) 5.04–5.21 (m, 3 H) 5.79 (m, 1 H) 5.97 (m, 1 H) 7.58 (d, J=5.80 Hz, 1 H) 7.78 (m, 1 H) 7.90 (d, J=8.24 Hz, 1 H) 8.13 (s, 1 H) 8.50 (s, 1 H) 8.67 (d, J=5.80 Hz, 1 H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=24)[N:15]=[CH:14][N:13]([C@H:23]2[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]2[OH:29])[C:12]3=[O:30])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:36]1[N:37]=[CH:38][S:39][CH:40]=1)CCC>CN(C=O)C.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[OH:29][C@@H:24]1[C@@H:23]([N:13]2[C:12](=[O:30])[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]4=[C:9]([CH2:8][C:5]4[CH:6]=[N:7][C:2]([C:36]5[N:37]=[CH:38][S:39][CH:40]=5)=[CH:3][CH:4]=4)[CH:10]=3)[N:15]=[CH:14]2)[CH2:28][CH2:27][O:26][CH2:25]1
Reactant: O=c1c2cc(Cc3ccc(Cl)nc3)c3ccccc3c2ncn1[C@H]1CCOC[C@@H]1O
Reactant: CCCC[Sn](CCCC)(CCCC)c1cscn1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1c2cc(Cc3ccc(-c4cscn4)nc3)c3ccccc3c2ncn1[C@H]1CCOC[C@@H]1O
Temperature: 50 °C
Reaction time: 6 h

Procedure:
To a solution of 6-[(6-chloropyridin-3-yl)methyl]-3-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]benzo[h]quinazolin-4(3H)-one (Example 1, 0.100 g, 0.237 mmol) in 1 mL of DMF under an atmosphere of nitrogen was added 4-(tributylstannyl)-1,3-thiazole (0.111 g, 0.296 mmol), tetrakis(triphenylphosphine)palladium(0) (0.055 g, 0.047 mmol), and copper(I) iodide (0.018 g, 0.095 mmol). The reaction was heated at 50° C. for 15 h, and then at 140° C. for an additional 6 h. The mixture was cooled to rt, diluted with ethyl acetate, and washed with brine and water. The solution was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via preparative reverse phase HPLC to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 471.1478 for [M+H]+ [Calc'd for C26H23N4O3S, [M+H]+=471.1485]: 1H NMR (400 MHz, CD3OD) δ 9.18 (s, 1H), 9.01 (d, J=8.1 Hz, 1H), 8.62 (s, 1H), 8.58 (s, 1H), 8.54 (s, 1H), 8.39 (d, J=8.4 Hz, 1H), 8.32-8.30 (m, 1H), 8.08 (d, J=8.1 Hz, 1H), 7.98 (s, 1H), 7.76-7.68 (m, 2H), 4.72 (s, 2H), 4.72-4.66 (m, 1H), 4.36-4.24 (m, 1H), 4.09-3.99 (m, 2H), 3.53 (t, J=10.1 Hz, 1H), 3.23 (t, J=10.2 Hz, 1H), 2.36-2.34 (m, 1H), 2.00-1.95 (m, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5].[Na+].[I-:13]>CC(C)=O>[I:13][CH2:2][CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5]
Reactant: [I-]
Reactant: OC(CCCl)c1ccccc1
Agent: [Na+]
Solvent: CC(C)=O
Product: OC(CCI)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
(Compound 14) (10.1 g) was dissolved in acetone (200 ml) saturated with NaI. The mixture was refluxed for 12 h and subsequently stirred at RT for 3 days. The mixture was evaporated to dryness and the residue extracted with H2O/ether. The etheral layer separated and washed with H2O and saturated NaCl-solution. Resulting in 12.5 g of 3-iodo-1-phenyl-1-propanol (compound 15).
Reaction SMILES: [NH:1]1[C:5]([CH2:6][C@@H:7]2[CH2:12][C@H:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[C@@H:10]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[NH:9][C:8]2=[O:27])=[N:4][N:3]=[N:2]1.[CH3:28][C:29]([CH3:32])([O-])[CH3:30].[Na+].BrCC1CC1>CN(C=O)C>[NH:4]1[C:5]([CH2:6][C@@H:7]2[CH2:12][C@H:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[C@@H:10]([C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)[N:9]([CH2:28][CH:29]3[CH2:32][CH2:30]3)[C:8]2=[O:27])=[N:1][N:2]=[N:3]1
Reactant: CC(C)(C)[O-]
Reactant: O=C1N[C@H](c2ccc(Cl)cc2)[C@@H](c2cccc(Cl)c2)C[C@H]1Cc1nnn[nH]1
Agent: BrCC1CC1
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1[C@H](Cc2nnn[nH]2)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N1CC1CC1
Temperature: 0 °C

Procedure:
A solution of (3S,5R,6S)-3-((1H-tetrazol-5-yl)methyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one (Example 60, Step A) (65 mg, 0.162 mmol) in DMF (1.6 mL) was cooled to 0° C. and sodium tert-butoxide (31.1 mg, 0.323 mmol) was added. The reaction mixture was stirred at 0° C. for ten minutes before adding (bromomethyl)cyclopropane (78 μL, 0.808 mmol). The reaction mixture was warmed to room temperature and stirred for 16 hours, quenched with saturated ammonium chloride and diluted with water and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the organic layers were combined, washed with 1M LiCl, sat. aq. NaCl solution, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by reversed phase preparatory HPLC (column:
Reaction SMILES: B(Br)(Br)Br.C([O:12][C:13]1[CH:27]=[CH:26][C:16]2[C:17]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[N:18][S:19][C:15]=2[CH:14]=1)C1C=CC=CC=1.O>C(Cl)Cl>[CH:20]1([C:17]2[C:16]3[CH:26]=[CH:27][C:13]([OH:12])=[CH:14][C:15]=3[S:19][N:18]=2)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: c1ccc(COc2ccc3c(C4CCCCC4)nsc3c2)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Oc1ccc2c(C3CCCCC3)nsc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 40.3 %

Procedure:
A solution of boron tribromide 1M in CH2Cl2 (11.9 ml, 11.9 mmoles) was slowly added to a solution of 6-benzyloxy-3-cyclohexyl-1,2-benzisothiazole (3.5 g, 10 mmoles) in CH2Cl2 (50 ml) at 0° C. The mixture was stirred at room temperature for 15 min and poured into water. The precipitate was filtered, dried and crystallised from EtOH to give pure 3-cyclohexyl-1,2-benzisothiazol-6-ol (940 mg, 40.3%). mp 190° C.
Reaction SMILES: [CH3:1][NH2:2].CO[C:5]([C:7]1[N:8]=[C:9]([CH:12]([OH:37])[CH2:13][CH:14]([N:18]([CH3:36])[C:19](=[O:35])[CH:20]([NH:25][C:26]([CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][N:29]2[CH3:34])=[O:27])[CH:21]([CH3:24])[CH2:22][CH3:23])[CH:15]([CH3:17])[CH3:16])[S:10][CH:11]=1)=[O:6]>C1COCC1.CO>[OH:37][CH:12]([C:9]1[S:10][CH:11]=[C:7]([C:5](=[O:6])[NH:2][CH3:1])[N:8]=1)[CH2:13][CH:14]([N:18]([CH3:36])[C:19]([CH:20]([NH:25][C:26]([CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][N:29]1[CH3:34])=[O:27])[CH:21]([CH3:24])[CH2:22][CH3:23])=[O:35])[CH:15]([CH3:16])[CH3:17]
Reactant: CCC(C)C(NC(=O)C1CCCCN1C)C(=O)N(C)C(CC(O)c1nc(C(=O)OC)cs1)C(C)C
Reactant: CN
Solvent: C1CCOC1
Solvent: CO
Product: CCC(C)C(NC(=O)C1CCCCN1C)C(=O)N(C)C(CC(O)c1nc(C(=O)NC)cs1)C(C)C
Temperature: 100 °C
Yield: 51.9 %

Procedure:
In a sealed tube, 10.0 mL of a 2.0 M solution of methylamine (5.00 mmol) in THF was added to a 0.02 M solution of 23 (27.0 mg, 0.0529 mmol) in MeOH (2.50 mL). The reaction solution was heated to 100° C. for 21 h. After the solution cooled to rt, the solvent was removed under reduced pressure. Reverse-phase HPFC (20:80 to 100:0 MeCN/H2O) followed by lyophilization provided compound 25 (14.0 mg, 52%) as an amorphous solid. The 1H NMR corresponds to a 6:1 mixture of rotamers, with the major isomer reported. [α]D23=−2.9 (c=1.0, MeOH). 1R: 1070, 1499, 1551, 1646, 2876, 2961 cm−1. 1H NMR (500 MHz, MeOD): δ 0.83 (d, 3H, J=6.5 Hz), 0.90 (t, 3H, J=7.5 Hz), 0.966 (d, 3H, J=6.5 Hz), 0.974 (d, 3H, J=6.5 Hz), 1.15-1.25 (m, 1H), 1.25-1.32 (m, 1H), 1.48-1.66 (m, 4H), 1.72 (d, 2H, J=10.5 Hz), 1.81-1.99 (m, 3H), 2.00-2.10 (m, 1H), 2.16 (s, 3H), 2.19-2.37 (m, 1H), 2.53-2.58 (m, 1H), 2.87-2.94 (m, 1H), 2.92 (s, 3H), 3.17 (s, 3H), 4.16-4.58 (br s, 1H), 4.64 (dd, 1H, J=2.3, 10.3 Hz), 4.72 (d, 1H, J=9.0 Hz), 8.06 (s, 1H). 13C NMR (125 MHz, MeOD) δ 11.1, 16.1, 20.5, 20.6, 24.4, 25.9, 26.3, 26.4, 31.3, 31.7, 37.8, 38.8, 44.8, 55.4, 56.7, 70.0, 70.6, 124.2, 151.0, 164.4, 175.3, 175.7, 179.4. HRMS (FAB) calcd for C25H44N5O4S (M+H): 510.3114. Found: 510.3098.
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:16][CH2:17][CH:18]([OH:28])[C:19]2[N:20]=[C:21]([C:24]([F:27])([F:26])[F:25])[S:22][CH:23]=2)[CH3:15])=[CH:9][CH:8]=1)([O:3]C)=O.[NH3:29]>>[NH2:29][C:1]([CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH:14]([NH:16][CH2:17][CH:18]([OH:28])[C:19]2[N:20]=[C:21]([C:24]([F:27])([F:26])[F:25])[S:22][CH:23]=2)[CH3:15])=[CH:11][CH:12]=1)=[O:3]
Reactant: COC(=O)COc1ccc(CC(C)NCC(O)c2csc(C(F)(F)F)n2)cc1
Reactant: N
Product: CC(Cc1ccc(OCC(N)=O)cc1)NCC(O)c1csc(C(F)(F)F)n1

Procedure:
Prepared analogously to Example 14 by reaction of N-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine with concentrated ammonia followed by purification of the base on a silica gel column using methylene chloride/methanol=9:1 as eluant.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[CH3:19][O:20][C:21]1[C:26]([O:27][CH3:28])=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:25]3[CH:24]=[CH:23][CH:22]=[C:21]([O:20][CH3:19])[C:26]=3[O:27][CH3:28])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: COc1cccc(B(O)O)c1OC
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Product: CCCNC(=O)c1nnc2c(-c3cccc(OC)c3OC)cccc2c1N
Yield: 87.7 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (100 mg, 0.33 mmol) and 2,3-dimethoxyphenyl boronic acid (148 mg, 0.97 mmol) were reacted to afford the title compound (106 mg, 89.5% yield) as a pale-yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.55 (br, 1H), 7.89 (d, J=8.1 Hz, 1H), 7.78 (dd, J=7.1 Hz, J′=1.5 Hz, 1H), 7.71 (t, J=7.6 Hz, 1H), 7.15 (t, J=7.9 Hz, 1H), 6.99 (m, 2H), 3.92 (s, 3H), 3.53 (s, 3H), 3.45 (q, J=6.7 Hz, 2H), 1.65 (m, J=7.2 Hz, 2H), 0.99 (t, J=7.4 Hz, 3H) MS APCI, m/z=367 (M+H) HPLC 1.86 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH2:16])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[F:18][C:19]([F:40])([F:39])[C:20]1[C:25]([C:26](O)=[O:27])=[CH:24][N:23]=[C:22]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)[N:21]=1.C(OC(C1C(C(F)(F)F)=NC(C2C=CC(C(F)(F)F)=CC=2)=NC=1)=O)C>>[CH2:1]([O:3][C:4](=[O:17])[C:5]([CH3:7])([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][NH:16][C:26]([C:25]2[C:20]([C:19]([F:40])([F:18])[F:39])=[N:21][C:22]([C:29]3[CH:30]=[CH:31][C:32]([C:35]([F:37])([F:38])[F:36])=[CH:33][CH:34]=3)=[N:23][CH:24]=2)=[O:27])=[CH:13][CH:14]=1)[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CN)cc1
Reactant: O=C(O)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1C(F)(F)F
Agent: CCOC(=O)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1C(F)(F)F
Product: CCOC(=O)C(C)(C)Oc1ccc(CNC(=O)c2cnc(-c3ccc(C(F)(F)F)cc3)nc2C(F)(F)F)cc1

Procedure:
In analogy to the procedures described in example 26B] and 26C, 2-(4-aminomethyl-phenoxy)-2-methyl-propionic acid ethyl ester [PCT Int. Appl. (2002), WO 2002/096895A1] was reacted with 4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid (prepared by saponification from 4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid ethyl ester (example 107B]) in analogy to example 53B]) to give 2-methyl-2-[4-({[4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carbonyl]-amino}-methyl)-phenoxy]-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8](C(=O)C3C=CC=CC=3)[CH:9]=[CH:10][C:5]2=[CH:4][CH:3]=1.O.[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:20]1([C:2]2[N:7]=[C:6]3[NH:8][CH:9]=[CH:10][C:5]3=[CH:4][CH:3]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C(c1ccccc1)n1ccc2ccc(Br)nc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: c1ccc(-c2ccc3cc[nH]c3n2)cc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
A solution of 6-bromo-1-benzoyl-1H-pyrrolo[2,3-b]pyridine (0.19 g, 0.64 mmol) obtained in Example A47, Step 1 in 1,2-dimethoxyethane (5.0 mL) was successively added with water (2.0 mL), phenylboronic acid (0.16 g, 0.64 mmol), and sodium carbonate (0.20 g, 1.9 mmol). After the inside of the reaction vessel was replaced with argon, the reaction mixture was added with tetrakis(triphenylphosphine)palladium(0) (0.074 g, 0.064 mmol), and the mixture was stirred overnight at 110° C. in a sealed tube. The reaction mixture was extracted with ethyl acetate, and then the organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluted with chloroform/methanol (99:1→99:5)) to obtain 6-phenyl-1H-pyrrolo[2,3-b]pyridine (0.10 g, 80%).