Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)=O.CC(C)=O.[Cl:8][C:9]1[CH:29]=[CH:28][C:12]2[N:13]([CH3:27])[C:14](=[O:26])[CH2:15][N:16]=[C:17]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[C:11]=2[CH:10]=1.CC([O-])(C)C.[K+].[CH3:36][C:37]1[CH:44]=[CH:43][CH:42]=[CH:41][C:38]=1[CH2:39]Br>C1COCC1>[Cl:8][C:9]1[CH:29]=[CH:28][C:12]2[N:13]([CH3:27])[C:14](=[O:26])[CH:15]([CH2:36][C:37]3[CH:44]=[CH:43][CH:42]=[CH:41][C:38]=3[CH3:39])[N:16]=[C:17]([C:18]3[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=3)[C:11]=2[CH:10]=1
Reactant: COc1ccc(C2=NCC(=O)N(C)c3ccc(Cl)cc32)cc1
Reactant: Cc1ccccc1CBr
Agent: CC(C)(C)[O-]
Agent: O=C=O
Agent: [K+]
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(C2=NC(Cc3ccccc3C)C(=O)N(C)c3ccc(Cl)cc32)cc1
Yield: 84.1 %

Procedure:
To a stirred and cooled (dry ice/acetone bath) solution of E1 (0.50 g, 1.59 mmol) in THF (8 mL) was slowly added 1 M KOtBu (2.4 mL, 2.4 mmol, 1.5 eq). The resulting deep red mixture was stirred over dry ice/acetone bath ˜10 min followed by the slow addition of a solution of 2-methylbenzyl bromide (0.46 g, 2.5 mmol, 1.5 eq) in THF (2 mL). After stirring another ˜35 min at −78° C., the reaction mixture was quenched with water and diluted with EtOAc. The organic layer was dried (Na2SO4), filtered and evaporated (rotovap, then high vacuum). Chromatography over silica gel using 20-40% EtOAc/heptane gave 0.56 g (yield of 84%) of the title product. Noting that, when using benzyl chlorides as alkylating agents, tetrabutyl ammonium iodide was added along with the alkylating agent at the low temperature. 1H NMR (300 MHz, CDCl3) δ 2.38 (s, 3H), 3.41 (s, 3H), 3.5-3.65 (m, 2H), 3.74 (dd, 1H), 3.84 (s, 3H), 6.89 (dt, 2H), 7.05-7.15 (m, 3H), 7.25-7.35 (m, 3H), 7.45-7.5 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13]2)[C:9]2[C:4](=[C:5]([O:22][CH3:23])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[F:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1>CN(C)C=O>[ClH:1].[CH3:23][O:22][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([NH:29][C:28]1[CH:30]=[CH:31][C:25]([F:24])=[CH:26][CH:27]=1)[N:11]=[C:10]2[N:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13]1
Reactant: COc1cccc2c(N3CCc4ccccc4C3)nc(Cl)nc12
Reactant: Nc1ccc(F)cc1
Solvent: CN(C)C=O
Product: COc1cccc2c(N3CCc4ccccc4C3)nc(Nc3ccc(F)cc3)nc12
Product: Cl
Yield: 65 %

Procedure:
In accordance with the same procedures as in Example 18, except that to a mixture of 1.5 g of the compound (4.6 mM) prepared in Example 4 and 15 ml of dimethyl-formamide, 0.85 ml of 4-fluoroaniline(9.2 mM) was added, 1.3 g of the title compound was prepared.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH3:12][CH2:13][O-:14].[Na+].[H-].[Na+]>CCO>[CH2:13]([O:14][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1)[CH3:12]
Reactant: CC[O-]
Reactant: O=C(O)Cc1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1ccc(CC(=O)O)cn1
Temperature: 100 °C
Reaction time: 96 h
Yield: 82 %

Procedure:
To a stirred solution of (6-chloro-3-pyridinyl)acetic acid (0.094 g, 0.545 mmol) in EtOH (1.6 mL) was added 3.1 M EtONa in EtOH (0.7 mL, 2.17 mmol) and the reaction mixture was stirred at 100° C. room temperature for 24 hours after which an excess of NaH (60% dispersion in oil) was added together with 1 mL EtOH and heating at 100° C. was continued for 96 h. The solvent was evaporated in vacuo and the residue was taken up into diethyl ether (5 mL). The organic phase was washed with diluted HCl (2×2 mL) and brine (2 mL), dried over MgSO4, filtered, and concentrated in vacuo to provide the title compound (0.081 g, 82%) as a pale brown solid, which was used without further purification. 1H NMR (CDCl3): δ 10.06 (br s, 1H), 8.06 (s, 1H), 7.55 (d, J=9.2 Hz, 1H), 6.72 (d, J=8.4 Hz, 1H), 4.30 (q, J=6.1 Hz, 2H), 3.58 (s, 2H) 1.38 (t, J=8.0, 3H). MS (ESI) (M+H)+=182.
Reaction SMILES: CN1CCOCC1.[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]1[C:23]([OH:25])=O.O.OC1C2N=NNC=2C=CC=1.Cl.[CH2:38]([O:45][C:46]([NH:48][CH2:49][CH2:50][NH2:51])=[O:47])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.Cl.CN(C)CCCN=C=NCC>ClCCl.O>[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]1[C:23]([NH:51][CH2:50][CH2:49][NH:48][C:46](=[O:47])[O:45][CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)=[O:25]
Reactant: NCCNC(=O)OCc1ccccc1
Reactant: O=C(O)[C@@H]1CCCCN1c1nc2ccccc2o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: O
Solvent: CN1CCOCC1
Product: O=C(NCCNC(=O)[C@@H]1CCCCN1c1nc2ccccc2o1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.9 %

Procedure:
N-methylmorpholine (0.47 ml) was added to a solution of (2S)-1-(1,3-benzoxazol-2-yl)-2-piperidinecarboxylic acid (352.6 mg) [see Preparation 3], hydroxybenzotriazole hydrate (338.4 mg), N-benzyloxycarbonyl-1,2-diaminoethane hydrochloride (499.5 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (552.7 mg) in dichloromethane (15 ml). The reaction mixture was stirred at room temperature for 18 hours, after which time the mixture was diluted with water and the organic layer was separated, dried over magnesium sulphate and the solvent removed under reduced pressure. The crude product was purified by coloumn chromatography on silica gel eluting with a solvent gradient of 1:1, changing to 1:9, by volume, hexane:ethyl acetate to afford benzyl N-[2-([(2S)-1-(1,3-benzoxazol-2-yl)-2-piperidinyl]carbonylamino)ethyl]carbamate (550 mg) as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:14][C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[F:21])=[O:5])[CH3:2].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[H-].[Na+].[C:32](OCC)(=O)C>CN(C=O)C.O>[CH2:1]([O:3][C:4]([C:6]1[N:14]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:13]2[C:8](=[N:9][C:10]([CH3:32])=[CH:11][CH:12]=2)[C:7]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[F:21])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]c2cccnc2c1-c1ccccc1F
Reactant: BrCc1ccccc1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(-c2ccccc2F)c2nc(C)ccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 94 %

Procedure:
3-(2-Fluoro-phenyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid ethyl ester A5 (0.02 g, 0.07 mmol) was diluted with DMF (1 mL). To the resulting solution was added benzyl bromide (0.1 mmol) and sodium hydride (0.077 mmol). The resulting suspension was stirred at room temperature for 14 hours, then ethyl acetate (50 mL) and water (20 mL) were added to the reaction mixture and layers were separated. The organic layer was sequentially washed with aqueous saturated sodium bicarbonate solution (10 mL), water (10 mL) and saturated brine (10 mL). The separated organic solution was dried (magnesium sulfate), filtered and concentrated in vacuo to provide a crude residue which was purified using flash chromatography to provide 1-Benzyl-3-(2-fluoro-phenyl)-5-methyl-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid ethyl ester A6 (94% yield). MS: 389.2 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[N:8]=[CH:9][CH:10]=[N:11][C:12]=2[C:13]([C:16]2[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=2[Cl:27])=[CH:14][CH:15]=1)=O)C.[NH2:28][C:29]1[N:34]=[CH:33][C:32]([CH2:35][N:36]([CH3:42])[CH2:37][CH2:38][N:39]([CH3:41])[CH3:40])=[CH:31][CH:30]=1.C[Al](C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.CO.C(Cl)Cl>[CH3:40][N:39]([CH3:41])[CH2:38][CH2:37][N:36]([CH2:35][C:32]1[CH:31]=[CH:30][C:29]([NH:28][C:4]([C:6]2[C:7]3[N:8]=[CH:9][CH:10]=[N:11][C:12]=3[C:13]([C:16]3[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=3[Cl:27])=[CH:14][CH:15]=2)=[O:3])=[N:34][CH:33]=1)[CH3:42]
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2Cl)c2nccnc12
Reactant: CN(C)CCN(C)Cc1ccc(N)nc1
Agent: C[Al](C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(CN(C)CCN(C)C)cn3)c3nccnc23)c1F
Temperature: 80 °C
Reaction time: 5 h

Procedure:
The title compound was prepared in analogy to the procedure described in Example 115 but using 8-(2-chloro-6-fluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 144.1), N-(6-amino-pyridin-3-ylmethyl)-N,N′,N′-trimethyl-ethane-1,2-diamine (prepared as described in Example 26 but using N,N,N′-trimethyl-ethane-1,2-diamine in Step 26.2 and purified by column chromatography), 2 equiv of trimethyl aluminum, stirring the reaction mixture for 5 h at 80° C., pouring it onto a saturated aqueous solution of NaHCO3 and DCM. The title compound: ESI-MS: 553.1 [M+H]+; tR=3.43 min (System 1); TLC: Rf=0.06 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: [Br-].[CH2:2]([O:9]CCC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:3]1C=CC=C[CH:4]=1.[H-].[Na+].[CH2:34]1[CH2:44][C:42](=O)[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:35]1.O>O1CCCC1>[OH:9][CH2:2][CH2:3][CH2:4][CH:42]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:35][CH2:34][CH2:44]1
Reactant: O=C1CCCc2ccccc21
Reactant: c1ccc(COCCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: OCCCC1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(3-Benzyloxypropyl)triphenylphosphoniumbromide (1.00 g) was dissolved in tetrahydrofuran (10 ml), sodium hydride (162 mg) was added under ice-cooling, and the mixture was stirred at room temperature for 1 hr. α-Tetralone (1.36 ml) was added to the reaction mixture, and the mixture was stirred at 75° C. for 48 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. To a solution of the obtained residue in ethyl acetate (10 ml) was added 10% palladium carbon (200 mg), and the mixture was stirred under a hydrogen atmosphere at room temperature for 18 hr. The reaction container was purged with nitrogen, the solution was filtered, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography to give the object product (140 mg) as a colorless oil.
Reaction SMILES: [CH3:1][C@:2]12[C@@H:11]3[CH2:12][CH2:13][C@@H:14]4[C:16]([CH2:18][C@@:10]3([CH2:15]4)[CH2:9][CH2:8][C@@H:7]1[C@@:6]([C:20]([OH:22])=[O:21])([CH3:19])[CH2:5][CH2:4][CH2:3]2)=[CH2:17].C(Cl)(C(Cl)=O)=O.[CH:29]1([NH2:35])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>C(Cl)Cl.CN(C=O)C>[CH:29]1([NH-:35])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.[CH3:1][C@:2]12[C@@H:11]3[CH2:12][CH2:13][C@@H:14]4[C:16]([CH2:18][C@@:10]3([CH2:15]4)[CH2:9][CH2:8][C@@H:7]1[C@@:6]([C:20]([OH:22])=[O:21])([CH3:19])[CH2:5][CH2:4][CH2:3]2)=[CH2:17]
Reactant: NC1CCCCC1
Agent: C=C1C[C@@]23CC[C@H]4[C@@](C)(CCC[C@@]4(C)C(=O)O)[C@@H]2CC[C@H]1C3
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: [NH-]C1CCCCC1

Procedure:
Kaurenoic acid can be dissolved in dry CH2Cl2 and treated with 10 equivalents of (COCl)2 followed by two drops of DMF. When the reaction stops bubbling, the CH2Cl2 solvent and (COCl)2 can be evaporated under vacuum and the reaction residue can be redissolved in dry benzene and then treated with 5 equivalents of cyclohexylamine to yield N-cyclohexylamide derivative of kaurenoic acid.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[CH:26]=[CH:25][N:24]=[C:23]3[C:18]=2[C:19]2[CH:31]=[CH:30][C:29]([C:32]([O:34]C)=[O:33])=[CH:28][C:20]=2[C:21](=[O:27])[NH:22]3)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-].O>C1COCC1>[C:1]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17]2[CH:26]=[CH:25][N:24]=[C:23]3[C:18]=2[C:19]2[CH:31]=[CH:30][C:29]([C:32]([OH:34])=[O:33])=[CH:28][C:20]=2[C:21](=[O:27])[NH:22]3)=[CH:14][CH:15]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc2c(c1)c(=O)[nH]c1nccc(Nc3ccc(NC(=O)c4ccccc4)cc3)c12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(c1)c(=O)[nH]c1nccc(Nc3ccc(NC(=O)c4ccccc4)cc3)c12
Yield: 56.7 %

Procedure:
267 (220 mg, 0.47 mmol) and LiOH (56 mg, 2.37 mmol) were suspended in THF (2 mL) and H2O (2 mL) and stirred overnight at room temperature. The THF was removed, the mixture was diluted with H2O, and acidified to pH=5 with 1M HCl. The crude product was purified via HP-LC to provide 268 (120 mg, 56% yield) as a white solid. LC-MS (M+H=451, obsd.=451).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Br:5][C:6]1[CH:7]=[N:8][N:9]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:10]=1.CCN(CC)CC>C(Cl)Cl>[Br:5][C:6]1[CH:7]=[N:8][N:9]([CH:11]2[CH2:16][CH2:15][N:14]([C:1](=[O:3])[CH3:2])[CH2:13][CH2:12]2)[CH:10]=1
Reactant: CC(=O)Cl
Reactant: Brc1cnn(C2CCNCC2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(n2cc(Br)cn2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Acetyl chloride (312 μl, 4.35 mmol) is added dropwise, under stirring at 0° C., to a solution of 4-(4-Bromo-pyrazol-1-yl)-piperidine (as obtained in preparation 89, 1 g, 4.34 mmol), Et3N (1.824 ml, 13.04 mmol) in CH2Cl2. The cooling bath is then removed and the reaction mixture stirred at RT for an additional 1 h. The mixture is then diluted with de-ionized water and the phases are separated. The organic phase is washed several times with de-ionized water and the aqueous layer re-extracted with CH2Cl2. The combined organic layers are washed with brine, dried over Na2SO4, filtered and the filtrate is concentrated in vacuo. The residue is used without further purification in the next step, and afford the title compound as yellow solid, Rt=0.786 min (Acquity HPLC BEH C18, 2.1×50 mm, 1.7 micron, detection 215 nM, 0.1 min 2% CH3CN in H2O, 2% to 100% CH3CN in H2O in 1.5 min, 0.4 min 100% CH3CN+0.1% TFA, flow rate 1.0 ml/min); MS: 272 (M+1, 79Br)+
Reaction SMILES: [Na].[NH2:2][C:3]1[C:8]([C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:17][C:18]([OH:20])=[O:19].CN(C)C=O.[CH2:26](I)[CH3:27]>O>[NH2:2][C:3]1[C:8]([C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:17][C:18]([O:20][CH2:26][CH3:27])=[O:19]
Reactant: CCI
Reactant: Nc1c(CC(=O)O)cccc1C(=O)c1ccccc1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1cccc(C(=O)c2ccccc2)c1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2.5 g. (0.009 mole) of the sodium salt of 2-amino-3-benzoylphenylacetic acid in 25 ml. of dry dimethylformamide was treated with 5.0 g. (0.035 mole) of ethyl iodide. The mixture was stirred two hours at room temperature using a magnetic stirrer. The mixture was diluted with water and the aqueous solution extracted several times with ethyl ether. The combined extracts were washed with water, dried over sodium sulfate and concentrated under vacuum to a yellow solid. The solid was recrystallized from absolute ethanol to give 1.7 gms. (61.0%) of yellow needles which melted at 77°-78° C.
Reaction SMILES: [CH3:1][N:2]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:3]1[N:8]=[C:7]([NH2:9])[N:6]=[C:5]([C:10]2[N:14]=[C:13](C(Cl)(Cl)Cl)[O:12][N:11]=2)[N:4]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[F:32][C:33]([F:44])([F:43])[CH2:34][O:35][CH2:36][CH:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>CN(C=O)C>[CH3:1][N:2]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:3]1[N:8]=[C:7]([NH2:9])[N:6]=[C:5]([C:10]2[N:14]=[C:13]([N:40]3[CH2:39][CH2:38][CH:37]([CH2:36][O:35][CH2:34][C:33]([F:32])([F:43])[F:44])[CH2:42][CH2:41]3)[O:12][N:11]=2)[N:4]=1
Reactant: CN(c1ccccc1)c1nc(N)nc(-c2noc(C(Cl)(Cl)Cl)n2)n1
Reactant: FC(F)(F)COCC1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(c1ccccc1)c1nc(N)nc(-c2noc(N3CCC(COCC(F)(F)F)CC3)n2)n1
Reaction time: 0.08 h
Yield: 18 %

Procedure:
2-N-methyl-2-N-phenyl-6-[5-(trichloromethyl)-1,2,4-oxadiazol-3-yl]-1,3,5-triazine-2,4-diamine (prepared in an analogous manner to Intermediate 60, 0.110 g, 0.285 mmol) was added to a mixture of potassium carbonate (0.071 g, 0.518 mmol) in DMF (2 mL) at room temperature and the mixture was stirred for 5 min. 4-[(2,2,2-trifluoroethoxy)methyl]piperidine hydrochloride (Intermediate 179, 0.060 g, 0.259 mmol) was added to the reaction mixture and stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure, dissolved in water and extracted with EtOAc. The combined organic extracts was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude compound was purified by FCC (EtOAc:heptane 1:1) and preparative HPLC, Method A, to afford the title compound (22.1 mg, 18%).
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[CH:6][C:5]([NH2:9])=[C:4]([O:10][CH3:11])[CH:3]=1.[CH3:12][C:13]1(C)[C:17](C)(C)OB(C(C)=C)O1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.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>[Cl:1][C:2]1[C:7]([C:13]([CH3:17])=[CH2:12])=[CH:6][C:5]([NH2:9])=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: COc1cc(Cl)c(I)cc1N
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
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: C=C(C)c1cc(N)c(OC)cc1Cl
Temperature: 25 °C
Yield: 24.8 %

Procedure:
A mixture of 4-chloro-5-iodo-2-methoxybenzenamine (1.0 g, 3.53 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (889 mg, 5.29 mmol), Pd(PPh3)4 (363 mg, 0.353 mmol), Na2CO3 (1.12 g, 10.6 mmol) in DME (10 mL) and water (3 mL) was stirred at reflux under argon for 6 h. The reaction mixture was allowed to cool to RT and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (5% petroleum ether/ethyl acetate) to afford the desired product (173 mg, 25% yield) as an off-white solid. ESI-MS m/z: 198.5[M+H]+.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[C:4](=[O:21])[C@H:5]2[CH2:20][C@:8]3([CH2:19][C:18]4[C:14]5N=C[NH:17][C:13]=5[CH:12]=[CH:11][C:10]=4[C:9]=13)[CH2:7][CH2:6]2.[BH4-].[Na+].[Cl-].[NH4+:27].[CH3:28]CO>>[F:1][C:2]([F:23])([F:22])[C:3]1[C@H:4]([OH:21])[C@H:5]2[CH2:20][C@@:8]3([C:9]=1[C:10]1[CH:11]=[CH:12][C:13]4[NH:17][N:27]=[CH:28][C:14]=4[C:18]=1[CH2:19]3)[CH2:7][CH2:6]2
Reactant: CCO
Reactant: O=C1C(C(F)(F)F)=C2c3ccc4[nH]cnc4c3C[C@@]23CC[C@@H]1C3
Reactant: [NH4+]
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Product: O[C@H]1C(C(F)(F)F)=C2c3ccc4[nH]ncc4c3C[C@@]23CC[C@@H]1C3
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirring solution of (8R,10aS)-6-(trifluoromethyl)-3,9,10,11-tetrahydro-8,10a-methanocyclohepta[1,2]indeno[4,5-d]imidazol-7(8H)-one (5.0 mg, 0.016 mmol) in EtOH (0.5 mL) was added sodium borohydride (2 mg, 0.05 mmol). The reaction mixture was stirred at room temperature for 0.5 hour and then saturated aqueous ammonium chloride was added. The reaction mixture was filtered through a pad of sodium sulfate on top of silica gel, washing with ethyl acetate. The filtrate was concentrated under vacuum and the residue was lyophilized from benzene containing a small amount of methanol to give (7R,8R,10aS)-6-(trifluoromethyl)-3,7,8,9,10,11-hexahydro-8,10a-methanoazuleno[2,1-e]indazol-7-ol.
Reaction SMILES: [CH:1](=[O:4])[CH2:2][CH3:3].[CH:5](=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH-].[Na+]>CO.C(O)(=O)C.O>[CH3:3][C:2](=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:1]=[O:4]
Reactant: O=Cc1ccccc1
Reactant: CCC=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: CC(C=O)=Cc1ccccc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 38.1 %

Procedure:
Propionaldehyde (87 gms 15 moles) was added at 50° C. over a period of 5 hours to a stirred mixture of benzaldehyde (318 gms, 3 moles), methanol (500 mls), water (500 mls) and sodium hydroxide (25 gms). After a further 1 hour stirring at 50° C., the reaction mixture was brought to neutrality with acetic acid and the methanol fractionated out of the reaction. The organic layer was then separated from the aqueous layer and fractionated to recover the excess of benzaldehyde (109 gms, b.pt. 36°-40° C./2 mm Hg) and obtain the -methylcinnamaldehyde (167 gms, b.pt. 100°-102° C./2 mm).
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].C[Al](C)C.[CH3:9][C:10]1[N:11]=[C:12]([CH2:18][CH2:19][C:20]2[C:21]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:22][O:23][C:24]=2[CH3:25])[S:13][C:14]=1[C:15](O)=[O:16]>O1CCOCC1.C1(C)C=CC=CC=1>[CH:1]([NH:4][C:15]([C:14]1[S:13][C:12]([CH2:18][CH2:19][C:20]2[C:21]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:22][O:23][C:24]=2[CH3:25])=[N:11][C:10]=1[CH3:9])=[O:16])([CH3:3])[CH3:2]
Reactant: CC(C)N
Reactant: Cc1nc(CCc2c(-c3ccccc3)noc2C)sc1C(=O)O
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: Cc1nc(CCc2c(-c3ccccc3)noc2C)sc1C(=O)NC(C)C
Temperature: 90 °C
Reaction time: 1 h
Yield: 54.1 %

Procedure:
To a stirred solution of isopropylamine (216 mg, 3.65 mmol) in dioxane (4 mL) under argon and at room temperature was added trimethylaluminium (1.83 mL of a 2M solution in toluene, 3.7 mmol). After 1 h, a solution of 4-methyl-2-[2-(5-methyl-3-phenyl-isoxazol-4-yl)-ethyl]-thiazole-5-carboxylic acid (300 mg, 0.91 mmol) in dioxane (4 mL) was added and the reaction mixture warmed to 90° C. After 4 h, the reaction mixture was cooled, quenched with ice water and extracted with dichloromethane. The combined extracts were washed with Seignette's salt solution then dried, filtered, and concentrated. Purification by chromatography (silica, 0 to 10% methanol in dichloromethane) gave the title compound (182 mg, 54%) as a light yellow gum. MS: m/e=370.1 [M+H]+.
Reaction SMILES: C(OC(=O)C)(=O)C.C([O-])(=O)C.[NH4+:12].[C:13]1([CH2:23][C:24]([OH:26])=O)([CH2:19][C:20](O)=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH2:16]1[CH2:17][CH2:18][C:13]2([CH2:23][C:24](=[O:26])[NH:12][C:20](=[O:21])[CH2:19]2)[CH2:14][CH2:15]1
Reactant: [NH4+]
Reactant: O=C(O)CC1(CC(=O)O)CCCCC1
Agent: CC(=O)[O-]
Solvent: CC(=O)OC(C)=O
Product: O=C1CC2(CCCCC2)CC(=O)N1

Procedure:
Reaction of a mixture of acetic anhydride/ammonium acetate with 1,1-cyclohexane diacetic acid at 160° C.-170° C., followed by precipitation of the product by gradual cooling and treatment with water/secondary butyl alcohol, and subsequent filtration to yield 3,3-pentamethylene glutarimide;
Reaction SMILES: [N+:1]1([O-])[CH:6]=[CH:5][CH:4]=[C:3]([CH3:7])[CH:2]=1.C(I)C.[C-:12]#[N:13].[Na+]>ClCCl.O>[CH3:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][C:4]=1[C:12]#[N:13]
Reactant: Cc1ccc[n+]([O-])c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCI
Solvent: O
Solvent: ClCCl
Product: Cc1cnccc1C#N
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.9 %

Procedure:
To a solution of 3-picoline N-oxide (60 g, 0.55 mol) in dichloromethane (1000 mL) was added ethyl iodide (132 mL, 1.65 mol) and the mixture stirred at room temperature for 16 hours. The precipitate was collected by filtration and washed with diethyl ether (200 mL) to give a white solid. The solid was dissolved in water (600 mL) and warmed to 50° C. Sodium cyanide (50 g, 1.02 mol) was added as a solution in water (180 mL) over 1 hour, keeping the internal temperature below 60° C. and the resulting dark brown solution was stirred at 55° C. for a further 1 hour. The reaction mixture was extracted with diethyl ether (3×600 mL). The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure to give a brown oil. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of n-pentane:dichloromethane (40:60 to 0:100). The product was co-evaporated with dichloromethane (2×300 mL) to give the title compound as a colourless oil (30.5 g, 47%).