Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:25]=[CH:24][C:11]([C:12]([NH:14][C@H:15]3[CH2:17][C@@H:16]3[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:13])=[C:10]([F:26])[CH:9]=2)=[CH:6][C:5]([Br:27])=[CH:4][N:3]=1>CCO>[NH2:1][C:2]1[C:7]([C:8]2[CH:25]=[CH:24][C:11]([C:12]([NH:14][C@@H:15]3[CH2:17][C@H:16]3[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:13])=[C:10]([F:26])[CH:9]=2)=[CH:6][C:5]([Br:27])=[CH:4][N:3]=1
Reactant: Nc1ncc(Br)cc1-c1ccc(C(=O)N[C@H]2C[C@@H]2c2ccccc2)c(F)c1
Solvent: CCO
Product: Nc1ncc(Br)cc1-c1ccc(C(=O)N[C@@H]2C[C@H]2c2ccccc2)c(F)c1

Procedure:
(+/−)-4-(2-amino-5-bromopyridin-3-yl)-2-fluoro-N-((1S,2R)-2-phenylcyclopropyl)benzamide (121 mg) was resolved by chrial chromatography (AD-H column EtOH=60/40, 1 mL/min). The polar compound (Peak1), 4-(2-amino-5-bromopyridin-3-yl)-2-fluoro-N-((1R,2S)-2-phenylcyclopropyl)benzamide, was obtained at 7.41 min (50 mg, 41%) and the less polar compound (Peak2), 4-(2-amino-5-bromopyridin-3-yl)-2-fluoro-N-((1S,2R)-2-phenylcyclopropyl)benzamide, was obtained at 10.26 min (54 mg, 44%). The absolute stereochemistry was assigned based on biochemical data and docking model of the corresponding analogs.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:8][C:9]1[C:10](F)=[CH:11][C:12]2[O:17][CH:16]([C:18]([F:21])([F:20])[F:19])[C:15]([C:22]([O:24]CC)=[O:23])=[CH:14][C:13]=2[CH:27]=1>>[Cl:8][C:9]1[C:10]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:11][C:12]2[O:17][CH:16]([C:18]([F:20])([F:21])[F:19])[C:15]([C:22]([OH:24])=[O:23])=[CH:14][C:13]=2[CH:27]=1
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Reactant: Sc1ccccc1
Product: O=C(O)C1=Cc2cc(Cl)c(Sc3ccccc3)cc2OC1C(F)(F)F

Procedure:
The title compound was prepared from benzenethiol and ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 183, Step 2) via a procedure similar to that described in Example 183, Steps 3 and 4: mp 271.7-274.4° C. 1H NMR (acetone-d6 /300 MHz) 7.86 (s, 1H), 7.60 (m, 6H), 6.29 (s, 1H), 3.74 (q, 1H, J=7.0 Hz). 19F NMR (acetone-d6 /282 MHz) -79.4 (d, J=7.2 Hz). FABLRMS m/z 385 (M-H). ESHRMS m/z 384.9904 (M-H, Calc'd 384.9913). Anal. Calc'd for C17H10ClF3O3S: C, 52.79; H, 2.61; Cl, 9.17; S, 8.29. Found: C, 52.80; H, 2.49; Cl, 9.71; S, 8.37.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]1[N:11]=[N:12][N:13]([CH2:15][CH2:16][F:17])[N:14]=1)(C)(C)C.Cl>C(Cl)Cl>[F:17][CH2:16][CH2:15][N:13]1[N:12]=[N:11][C:10]([CH2:9][CH2:8][NH2:7])=[N:14]1
Reactant: CC(C)(C)OC(=O)NCCc1nnn(CCF)n1
Agent: Cl
Solvent: ClCCl
Product: NCCc1nnn(CCF)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of {2-[2-(2-Fluoro-ethyl)-2H-tetrazol-5-yl]-ethyl}-carbamic acid tert-butyl ester (step 1) (0.025 g, 0.0964 mmol) in DCM (3 ml) is treated with hydrochloric acid (1 ml, 4M in dioxane) and allowed to stir at room temperature for 1 hour. The reaction mixture is concentrated in vacuo to yield the titled compound as a white solid.
Reaction SMILES: Br.Br.C([O:5][C:6]([C@@H:8]([NH:19][C@H:20]([C:22]([N:24]1[C@H:33]([C:34]([OH:36])=[O:35])[CH2:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25]1)=[O:23])[CH3:21])[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:7])C.C(O)(=O)C>[OH-].[Na+]>[C:6]([C@@H:8]([NH:19][C@H:20]([C:22]([N:24]1[C@H:33]([C:34]([OH:36])=[O:35])[CH2:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25]1)=[O:23])[CH3:21])[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]1[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]1)([OH:7])=[O:5]
Reactant: CCOC(=O)[C@H](CCCCC1CCNCC1)N[C@@H](C)C(=O)N1Cc2ccccc2C[C@H]1C(=O)O
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: C[C@H](N[C@@H](CCCCC1CCNCC1)C(=O)O)C(=O)N1Cc2ccccc2C[C@H]1C(=O)O
Reaction time: 1 h
Yield: 76.1 %

Procedure:
In 8 ml of 1N aqueous sodium hydroxide is dissolved 0.3 g of (S)-2-[N-[(S)-1-ethoxycarbonyl-5-(4-piperidyl)pentyl]-L-alanyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.dihydrobromide, and the solution is allowed to stand at room temperature for 1 hour. The reaction solution is made acidic with 1 ml of acetic acid, and then purified by Amberlite XAD-2 column chromatography (0.1M aqueous ammonia-5% acetonitrile). The effluent is concentrated under reduced pressure, and lyophilized to give 0.16 g of (S)-2-[N-[(S)-1-carboxy-5-(4-piperidyl)pentyl]-L-alanyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid as a colorless powder.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[N:16]([O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[C:15]([CH3:29])([CH3:28])[CH2:14]2)[N:5]=[C:4]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH:35]2[CH2:40][C:39]([CH3:42])([CH3:41])[N:38]([O:43][CH:44]3[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]3)[C:37]([CH3:51])([CH3:50])[CH2:36]2)[N:3]=1.[OH-].[Na+].Cl[CH2:55][CH:56]([OH:59])[CH2:57][OH:58]>>[O:59]1[CH2:55][CH:56]1[CH2:57][O:58][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[N:16]([O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[C:15]([CH3:29])([CH3:28])[CH2:14]2)[N:5]=[C:4]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH:35]2[CH2:40][C:39]([CH3:42])([CH3:41])[N:38]([O:43][CH:44]3[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]3)[C:37]([CH3:51])([CH3:50])[CH2:36]2)[N:3]=1
Reactant: CC1(C)CC(CCCCNc2nc(Cl)nc(NCCCCC3CC(C)(C)N(OC4CCCCC4)C(C)(C)C3)n2)CC(C)(C)N1OC1CCCCC1
Reactant: OCC(O)CCl
Agent: [Na+]
Agent: [OH-]
Product: CC1(C)CC(CCCCNc2nc(NCCCCC3CC(C)(C)N(OC4CCCCC4)C(C)(C)C3)nc(OCC3CO3)n2)CC(C)(C)N1OC1CCCCC1

Procedure:
The title compound is prepared by the reaction of 2-chloro-4,6-bis[N-(1-cyclohexyloxy-2,2,6,6-tetramethylpiperidin-4-yl)butylamino]-1,3,5-triazine with sodium hydroxide and 3-chloro-1,2-propanediol.
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=2[F:21])[CH:3]=1.[CH2:22]([N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)[C:23]#[CH:24].C(N(CC)CC)C>C1COCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:21][C:13]1[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:12]=1[O:11][C:8]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:3]=[C:2]([C:24]#[C:23][CH2:22][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[S:10][C:9]=12
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(Br)sc23)c(F)c1
Reactant: C#CCN1CCOCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(Oc2ccnc3cc(C#CCN4CCOCC4)sc23)c(F)c1
Temperature: 25 °C
Yield: 78.8 %

Procedure:
To a solution of bromide 42 (100 mg, 0.27 mmol) in THF (5 ml) was added 4-(prop-2-ynyl)morpholine (68 mg, 0.54 mmol) [H-W. Tsou, et. al. J. Med. Chem., 2001, 44, 2719-2734], triethylamine (68 mg, 0.67 mmol), CuI (5 mg, 0.03 mmol) and Pd(PPh3)2Cl2 (5.3 mg, 7.56 μmol). The reaction mixture was degassed with nitrogen and refluxed for 2 hrs, cooled to room temperature and adsorbed onto silica. Purification by column chromatography (eluent EtOAc) afforded the title compound 56 as a beige solid (88 mg, 79%). MS (m/z): 397.1 (M+H).
Reaction SMILES: [Na+].[F:2][C:3]([F:16])([F:15])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][S:11]([O-:14])(=[O:13])=[O:12].Cl>CO>[F:16][C:3]([F:2])([F:15])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][S:11]([OH:14])(=[O:13])=[O:12]
Reactant: O=S(=O)([O-])Cc1ccccc1C(F)(F)F
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=S(=O)(O)Cc1ccccc1C(F)(F)F
Temperature: -20 °C
Reaction time: 1.5 h
Yield: 100.6 %

Procedure:
(2-Trifluoromethylphenyl)methanesulfonic acid sodium salt (22.2 g, 84 mmol) was suspended in MeOH (950 mL) and cooled to −20° C. At that temp with continued cooling HCl (g) was bubbled through the mixture for 5 min. The resulting white suspension was stirred at room temperature for 1.5 h, then cooled in an ice-bath. The resulting suspension was filtered and the collected solid allowed to air-dry overnight to afford (2-trifluoromethylphenyl)methanesulfonic acid (20.3 g, ˜100%), a white solid, which was used without further purification
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][N:11]2[N:10]=[C:9]1[CH:18]([NH:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[CH2:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][N:11]2[N:10]=[C:9]1[CH:18]([N:21]([CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[C:33](=[O:34])[C:32]1[CH:36]=[CH:37][C:29]([Cl:28])=[CH:30][CH:31]=1)[CH2:19][CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCC(NC1CCCCC1)c1nn2cccc2c(=O)n1Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCC(c1nn2cccc2c(=O)n1Cc1ccccc1)N(C(=O)c1ccc(Cl)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 12.4 %

Procedure:
3-Benzyl-2-(1-cyclohexylamino-propyl)-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one (Example 28, 26.3 mg, 0.072 mmol) in CHCl3 (1.5 mL) at 25° C. was treated with 4-chlorobenzoyl chloride (43.4 mg, 0.248 mmol) and triethylamine (16.8 mg, 0.166 mmol). The resulting mixture was stirred at 25° C. for 18 h, then concentrated under vacuum and purified by preparative HPLC using a YMC S10 ODS 20×100 mm column affording the desired compound (4.5 mg, 12.4%) as a colorless film: LC/MS 80% at 4.47 min (ESI+) 503 (M++H).
Reaction SMILES: CCN(C(C)C)C(C)C.[NH2:10][CH2:11][C@@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].[Cl:24][CH2:25][C:26](Cl)=[O:27]>C(Cl)Cl>[Cl:24][CH2:25][C:26]([NH:10][CH2:11][C@@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:27]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CN
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CNC(=O)CCl
Reaction time: 1 h

Procedure:
DIPEA (1.34 ml, 7.5 mmol) was added to a solution of 1,1-dimethylethyl (2S)-2-(aminomethyl)-1-pyrrolidinecarboxylate (1g, 5 mmol) in 50 ml of DCM; then chloroacetyl chloride (0.418 ml, 5.25 mmol) was slowly added and the reaction mixture stirred 1 h before being worked up. DCM was added and the organic phase was washed with a saturated solution of ammonium chloride. The crude was purified by flash chromatography eluting with cyclohexane/ethyl acetate 8/2 affording 1.24 g of the target material.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH2:7][CH:8]([C:13]([O:15][CH3:16])=[O:14])[C:9]([O:11][CH3:12])=[O:10].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([N:30]=[C:31]=[O:32])[CH:27]=[CH:28][CH:29]=1>>[CH3:21][O:20][C:19]1[CH:18]=[CH:17][C:6]([CH2:7][CH:8]([C:9]([O:11][CH3:12])=[O:10])[C:13]([O:15][CH3:16])=[O:14])=[CH:5][C:4]=1[CH2:3][CH2:2][O:1][C:31]([NH:30][C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([O:23][CH3:22])[CH:25]=1)=[O:32]
Reactant: COC(=O)C(Cc1ccc(OC)c(CCO)c1)C(=O)OC
Reactant: COc1cccc(N=C=O)c1
Product: COC(=O)C(Cc1ccc(OC)c(CCOC(=O)Nc2cccc(OC)c2)c1)C(=O)OC

Procedure:
Using dimethyl 2-[3-(2-hydroxyethyl)-4-methoxybenzyl]malonate and 3-methoxyphenylisocyanate, the title compound was obtained in the same manner as described in Example 192b).
Reaction SMILES: [O:1]=[C:2]1[CH2:11][O:10][C:9]2[CH:8]=[C:7]3[NH:12][C:13]([C:15]([O:17]C)=[O:16])=[CH:14][C:6]3=[CH:5][C:4]=2[NH:3]1>O>[O:1]=[C:2]1[CH2:11][O:10][C:9]2[CH:8]=[C:7]3[NH:12][C:13]([C:15]([OH:17])=[O:16])=[CH:14][C:6]3=[CH:5][C:4]=2[NH:3]1
Reactant: COC(=O)c1cc2cc3c(cc2[nH]1)OCC(=O)N3
Solvent: O
Product: O=C1COc2cc3[nH]c(C(=O)O)cc3cc2N1

Procedure:
The title compound is prepared from methyl 6-oxo-1,5,6,7-tetrahydro-8-oxa-1,5-diaza-cyclopenta[b]naphthalene-2-carboxylate according to the method described in Example 8/b. Mp.: 231-237° C. (water).
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([OH:14])=O)[CH:7]=2)[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.ClC(OC)=O.[F:32][C:33]1[CH:34]=[C:35]([CH:37]=[CH:38][C:39]=1[N:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1)[NH2:36]>C(Cl)Cl>[CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:36][C:35]3[CH:37]=[CH:38][C:39]([N:40]4[CH2:41][CH2:42][O:43][CH2:44][CH2:45]4)=[C:33]([F:32])[CH:34]=3)=[O:14])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: Nc1ccc(N2CCOCC2)c(F)c1
Reactant: CCCN(CC1CC1)c1cc(C(=O)O)ncn1
Agent: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(N3CCOCC3)c(F)c2)ncn1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A cooled (0° C.) solution of 6-(cyclopropylmethyl(propyl)amino)pyrimidine-4-carboxylic acid (Intermediate 21, 112 mg; 0.45 mmol) in DCM was treated with diisopropylethylamine (78.4 mL; 0.52 mmol) and methyl chloroformate (36.2 mL; 0.47 mmol). After stirring at 0° C. for 15 minutes, 3-fluoro-4-morpholin-4-yl aniline (Bionet, 132 mg; 0.67 mmol) was added and the mixture stirred for 72 hours. The solvent was evaporated and the compound purified by preparative HPLC to give the title compound as a white solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[OH-].[K+].[CH2:17]([OH:19])[CH3:18]>C(OCC)(=O)C>[CH2:17]([O:19][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH3:18]
Reactant: O=C(O)CCCCCCCCCCBr
Reactant: CCO
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CCOCCCCCCCCCCC(=O)O
Yield: 35 %

Procedure:
11-bromoundecanoic acid (2.25 g, 8.47 mmol) was added to a solution of potassium hydroxide (2.15 g, 38.3 mmol) in absolute ethanol (20 mL) and refluxed for 7 hrs. After cooling and acidification with HCl, solvent was removed under reduced pressure to give a white solid. The sample was dissolved in ethyl acetate and extracted with water. The organic phase was dried over sodium sulfate, and the solvent was removed under reduced pressure. The product was purified by silica column chromatography in 1% diethyl ether/0.3% formic acid/methylene chloride. Solvent was removed under reduced pressure to yield 11-(ethoxy)undecanoic acid (680 mg, 35%): mp 44-45.5° C.; 1H NMR (300 MHz, CDCl3) δ1.20 (t, 3H, J=7.0, CH3), 1.24-1.40 (bm, 12H, methylene envelope), 1.52-1.68 (bm, 4H, O--CH2 --CH2 ; CH2 --CH2 --COOH), 2.34 (t, 2H, J=7.5, CH2 --COOH), 3.41 (t, 2H, J=6.8, --CH2 --CH2), 3.48 (q, 2H, J=7.0, 0--CH2 --CH3), 10.25 (br, 1H, COOH); 13C NMR (75.4 MHz, CDCL3) δ15.27, 24.75, 26.23, 29.11, 29.26, 29.40, 29.55*, 29.80, 34.12, 66.06, 70.76, 179.71; m/z 231 (M+H+).
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[C:6]([CH3:8])[CH2:5][CH2:4][CH:3]1[CH:9]([CH:11]([CH3:13])[CH3:12])[OH:10].C(O)(C)C.Cl.O>C1(C)C=CC=CC=1>[CH3:8][C:6]12[CH2:5][CH2:4][CH:3]([CH:2]([CH3:1])[CH2:7]1)[CH:9]([CH:11]([CH3:13])[CH3:12])[O:10]2
Reactant: CC1=CC(C)C(C(O)C(C)C)CC1
Agent: Cl
Solvent: CC(C)O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)C1OC2(C)CCC1C(C)C2
Yield: 19.2 %

Procedure:
A solution of 130 grams of 2,4-dimethyl-alpha-isopropyl-3-cyclohexene methanol, 300 grams of isopropyl alcohol and 1000 ml of concentrated HCl is heated 21/2 hours at reflux. The reaction mass is cooled and 1500 ml of H2O and 100 ml of toluene is added with stirring. The aqueous layer is discarded and the organic layer is washed twice with water, neutralizing with aqueous caustic soda on the second wash. The organic layer is distilled through a 48" Vigreux column affording 25 grams of 1,5-dimethyl-3-isopropyl-2-oxabicyclo[2.2.2]octane (b.p. 55° C., 1.8 mm Hg pressure).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([C:10]2[NH:11][C:12](=[O:23])[C:13]3[N:18]([CH3:19])[N:17]=[C:16]([CH2:20][CH2:21][CH3:22])[C:14]=3[N:15]=2)=[CH:8][C:7]([S:24]([N:27]2[CH2:32][CH2:31][N:30]([CH2:33][CH3:34])[CH2:29][CH2:28]2)(=[O:26])=[O:25])=[CH:6][N:5]=1)[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[K+]>N1C=CC=CC=1CO>[CH2:33]([N:30]1[CH2:31][CH2:32][N:27]([S:24]([C:7]2[CH:8]=[C:9]([C:10]3[NH:11][C:12](=[O:23])[C:13]4[N:18]([CH3:19])[N:17]=[C:16]([CH2:20][CH2:21][CH3:22])[C:14]=4[N:15]=3)[C:4]([O:3][CH2:1][C:2]3[CH:7]=[CH:8][CH:9]=[CH:4][N:5]=3)=[N:5][CH:6]=2)(=[O:26])=[O:25])[CH2:28][CH2:29]1)[CH3:34]
Reactant: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)N4CCN(CC)CC4)cnc3OCC)nc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: OCc1ccccn1
Agent: [K+]
Product: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)N4CCN(CC)CC4)cnc3OCc3ccccn3)nc12
Temperature: 110 °C
Reaction time: 18 h
Yield: 14.5 %

Procedure:
A mixture of the title compound of Example 124 (100 mg, 0.20 mmol) and potassium bis(trimethylsilyl)amide (204 mg, 1.02 mmol) in pyridine-2-methanol (2 ml) was stirred at 110° C. for 18 hours, then cooled. The solvent was removed by Kugelrohr distillation, and the residue was purified by column chromatography on silica gel, using dichloromethane: methanol (95:5) as eluant. This product was triturated with ether to afford the title compound (8 mg, 7%) as a solid.
Reaction SMILES: CB(O)O.[O:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]#[N:22])=[C:16](Br)[CH:15]=1.[C:24]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]#[N:22])=[C:16]([CH3:24])[CH:15]=1
Reactant: N#CCc1ccc(-c2nc3ccccc3o2)cc1Br
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CB(O)O
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: Cc1cc(-c2nc3ccccc3o2)ccc1CC#N
Temperature: 80 °C

Procedure:
A mixture of methane boronic acid (57.6 mg, 0.96 mmol), [4-(1,3-benzoxazol-2-yl)-2-bromophenyl]acetonitrile (example 1) (200 mg, 0.64 mmol), dichlorobis(triphenylphosphine)palladium(II) (22.4 mg, 0.032 mmol), triphenylphosphine (17 mg, 0.064 mmol), and potassium carbonate (177 mg, 1.3 mmol) in degassed DME/H2O (5:1, 12 mL) was heated at 80° C. for 18 h. The mixture was cooled to rt, the two layers were separated and the aqueous layer was extracted with EtOAc (3×). The organics were combined, dried over Na2SO4 and evaporated to dryness to give a brown solid. Purification of the crude solid by flash chromatography on silica gel eluting with a gradient of EtOAc:hexanes (0 to 40 min: 0 to 25% EtOAc) afforded the desired [4-(1,3-benzoxazol-2-yl)-2-methylphenyl]acetonitrile as a yellow solid. 1H NMR (CDCl3, 300 MHz) δ 8.14 (s, 1H), 8.11 (d, 1H), 7.78 (m, 1H), 7.60 (m, 1H), 7.54 (d, 1H), 7.38 (m, 2H), 3.76 (s, 2H), 2.45 (s, 3H). MS (ESI) 249 (M+H)+.
Reaction SMILES: C(OC(NCC1(O)CCNC1)=O)(C)(C)C.Cl[CH2:17][CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([N:28]3[CH:32]=[N:31][N:30]=[CH:29]3)[CH:26]=2)[NH:21][CH:20]=1.[CH2:33]([NH:40][CH2:41][C:42]1([OH:65])[CH2:47][CH2:46][N:45]([CH2:48]CCC2C3C(=CC=C(N4C=NN=C4)C=3)NC=2)CC1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.N1C2C(=CC=CC=2)C=C1>O.CS(C)=O>[CH2:33]([NH:40][CH2:41][C:42]1([OH:65])[CH2:47][CH2:46][N:45]([CH2:17][CH2:18][C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([N:28]4[CH:32]=[N:31][N:30]=[CH:29]4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:48]1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: OC1(CNCc2ccccc2)CCN(CCCc2c[nH]c3ccc(-n4cnnc4)cc23)CC1
Reactant: ClCCc1c[nH]c2ccc(-n3cnnc3)cc12
Agent: CC(C)(C)OC(=O)NCC1(O)CCNC1
Agent: c1ccc2[nH]ccc2c1
Solvent: O
Solvent: CS(C)=O
Product: OC1(CNCc2ccccc2)CCN(CCc2c[nH]c3ccc(-n4cnnc4)cc23)C1

Procedure:
The title compound was prepared from 3-(t-butyloxycarbonylamino) methyl-3-hydroxypyrrolidine and 1-chloro-2-[5-(1,2,4-triazol-4-yl)-1H-indol-3-yl]ethane (prepared from 2-[5-(1,2,4-triazol-4-yl)-1H-indol-3-yl]ethanol), followed by deprotection and functionalisation as described for 4-(benzylamino)methyl-4-hydroxy-1-(3-[5-(1,2,4-triazol-4-yl)-1H-indol-3-yl]propyl)piperidine. mp>56° C. MS, ES+, m/z=417 for (M+H)+ ; δ (360 MHz, D6 -DMSO) 1.60-1.68 (1H, m, CH), 1.80-1.88 (1H, m, CH), 2.40-2.76 (8H, m, 4×CH2N), 2.84 (2H, t, J=7 Hz, CH2 -indole), 3.72 (2H, s, NHCH2Ar), 4.56 (1H, s, OH), 7.17-7.36 (7H, m, Ar--H), 7.47 (1H, d, J=8 Hz, Ar--H), 7.78 (1H, d, J=2 Hz, Ar--H), 9.01 (2H, s, triazole-H), 11.07 (1H, s, indole-NH). (Found: C, 67.40; H, 6.68; N, 19.54. C24H28N6O.0.5 H2O requires C, 67.74; H, 6.87; N, 19.75%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH:6]=[O:7].[BH4-].[Na+].O>>[O:2]([C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH2:6][OH:7])[CH3:1]
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: COc1cc(CO)cc(OC)c1OC
Temperature: 25 °C
Yield: 92.72 %

Procedure:
3,4,5-trimethoxybenzaldehyde (15 g, 76.45 mmol) and anhydrous alcohol (200 ml) were placed in a 250 ml three-necked flask, and were dissolved at 40° C. Sodium borohydride (1.48 g, 38.23 mmol) was added to the solution. The resulting mixture was heated to reflux for 45 minutes, and monitored by TLC. When the reaction is completed, cooling it to room temperature, deionized water (10 ml, 555.8 mol) was added to quench the reaction. After suction filtering, the filter residue was washed by anhydrous alcohol (20 ml), the combined filtrate was concentrated in rotatory evaporater to dry, dichlormethane (100 ml) was added to dissolve the crude product. The organic layer was washed with sodium hydroxide solution (50 ml) twice and with deionized water (50 ml) twice, and a proper amount of anhydrous magnesium sulfate was added to dry it overnight. After filtering, washing the filter residue with dichlormethane (20 ml). The combined filtrate was concentrated in a rotatory evaporator to afford 3,4,5-trimethoxyl benzyl alcohol, 14.05 g of colorless oily product, yield: 92.72%
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[O:17][CH:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:15]C3)=[N:8][CH:9]=1)([O-:3])=[O:2].C1(C2C[S:37]C3C=C(O)C=CC=3O2)C=CC=CC=1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:20]=[CH:19][C:18]3[O:17][CH:16]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:15][S:37][C:13]=3[CH:12]=2)=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Reactant: Oc1ccc2c(c1)SCC(c1ccccc1)O2
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)SCC(c2ccccc2)O3)nc1

Procedure:
5-Nitro-2-(2-phenyl-2,3-dihydrobenzo[1,4]oxathiin-6-yloxy)pyridine was prepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) using 269 mg 2-phenyl-2,3-dihydrobenzo[1,4]oxathiin-6-ol. The product was recrystallised from ethanol. 1H NMR (400 MHz, CDCl3) δ: 9.07 (d, 1H, J 2.8 Hz), 8.47 (dd, 1H, J 9.1, 2.8 Hz), 7.43 (m, 4H), 7.37-7.41 (m, 1H), 7.02 (d, 1H, J 9.1 Hz), 6.99 (d, 1H, J 8.9 Hz), 6.95 (d, 1H, J 2.8 Hz), 6.82 (dd, 1H, J 8.9, 2.8 Hz), 5.21 (dd, 1H, J 9.7, 1.9 Hz), 3.31 (dd, 1H, 13.2, 9.7 Hz), 3.11 (dd, 1H, 13.2, 1.9 Hz).