Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)=[O:2].C1(C)C=CC(S([CH2:22][N:23]=[C:24]=O)(=O)=O)=CC=1>>[O:2]1[C:1]([C:3]2[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=2)=[CH:24][N:23]=[CH:22]1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: Cc1ccc(S(=O)(=O)CN=C=O)cc1
Product: COC(=O)c1ccc(-c2cnco2)cc1
Yield: 86.7 %

Procedure:
The procedure of Example 1 was repeated, except that methyl 4-formylbenzoate (4.92 g) and p-toluenesulfonylmethylisocyanate (7.03 g) were used, to thereby yield the title compound (5.28 g).
Reaction SMILES: [C:1]1([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[C:1]1([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccncc1
Reactant: BrC(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: c1ccc(C(Nc2ccncc2)c2ccccc2)cc1
Reaction time: 20 h
Yield: 30.8 %

Procedure:
24.7 Grams (0.1 mole) of diphenylbromomethane and 29.4 grams (0.3 mole) of 4-aminopyridine in 500 milliliters of toluene were heated under reflux with stirring for 20 hours. The solid formed was filtered off and the toluene was extracted with 2 N hydrochloric acid. The acid extracts were combined with the solid material and the solid was taken into solution by the addition of water and methanol. The alcoholic solution was basified with 5 N sodium hydroxide and extracted with toluene. After drying over magnesium sulphate, the solvent was removed and 8.01 grams of the title compound were obtained as the crude crystalline base, m.p. 148°-50° C. The base was converted into its hydrochloride by solution in the minimum quantity of 2-propanol and addition of a solution of hydrogen chloride in dry ether. The hydrochloride was obtained as a colourless solid, m.p. 237°-9° C.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:7][CH:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4]1.[OH-].[Na+].[C:13]([O:17][C:18](F)=[O:19])([CH3:16])([CH3:15])[CH3:14].Cl>O.O1CCOCC1.C(OCC)C>[C:18]([C:3]1([NH2:2])[CH2:7][CH:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4]1)([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:19]
Reactant: NC1C=CC(C(=O)O)C1
Reactant: CC(C)(C)OC(=O)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)OC(=O)C1(N)C=CC(C(=O)O)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 63 %

Procedure:
16.4 g of crude (±)-1-amino-2-cyclopentene-4-carboxylic acid hydrochloride (prepared as in J. Org. Chem. 1981, 46, 3268) were dissolved in a mixture of 80 ml of water and 80 ml of dioxane at room temperature under nitrogen. The mixture was then adjusted to pH 14 with 1 N NaOH, and a diethyl ether solution of tert-butyloxycarbonyl fluoride (BOC-F, 20% excess) was added (BOC-F prepared as in Synthesis 1975, 599). .The mixture was stirred for a further 5 h at room temperature. The pH was adjusted to 2 with conc. HCl. After distillation of the organic solvents, 50 ml of water were added to the residue, and the mixture was extracted 3 times with 100 ml of ethyl acetate. The organic phase was evaporated to 50 ml and diluted with 25 ml of toluene. After cooling (0-10° C.), the title compound was filtered and dried. 14.3 g of product were obtained. The yield was 63%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:17].[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>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.C1(C)C=CC=CC=1.CCO>[C:18]1([C:16]([C:3]2[CH:4]=[N:5][C:6]3[C:11]([C:2]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:10][CH:9]=[CH:8][C:7]=3[C:12]([F:13])([F:15])[F:14])=[O:17])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1Cl
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: Cc1ccccc1
Solvent: CCO
Product: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1ccccc1
Temperature: 90 °C

Procedure:
[4-Chloro-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone (compound of formula (VII)), 0.050 g, 0.15 mmol) was taken into toluene/EtOH (3 mL/0.5 mL). Then phenylboronic acid (0.30 mmol) was added followed by 2 M Na2CO3 (0.25 mL, 0.5 mmol) and finally Pd(PPh3)4 (0.009 g, 0.0075 mmol). The reaction was heated at 90° C. for 4 hours. The solvent was removed and the resulting material was purified via column chromatography using 5% ethyl acetate in hexane to elute out 0.043 g of the title compound: MS (ESI) m/z 378 ([M+H]+); Anal. Calcd for C23H14F3NO: C, 73.21; H, 3.74; N, 3.71. Found: C, 72.16; H, 3.77; N, 3.69.
Reaction SMILES: Cl.Br[CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.Cl[C:15]([O:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)=[O:16].[CH2:25]([NH:27][CH2:28][CH2:29][OH:30])[CH3:26]>>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][C:15]([N:11]2[CH2:12][CH2:13][CH:8]([O:7][CH2:6][CH2:5][CH2:4][CH2:3][N:27]([CH2:25][CH3:26])[CH2:28][CH2:29][OH:30])[CH2:9][CH2:10]2)=[O:16])=[CH:19][CH:20]=1
Reactant: CCNCCO
Reactant: BrCCCCOC1CCNCC1
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Agent: Cl
Product: CCN(CCO)CCCCOC1CCN(C(=O)Oc2ccc(Cl)cc2)CC1

Procedure:
In analogy to example 1.4 and 1.5, reaction of 4-(4-Brom-butoxy)-piperidine hydrogen chloride with 4-chlorophenyl chloroformate and 2-ethylamino-ethanol yielded 4-{4-[Ethyl-(2-hydroxy-ethyl)-amino]-butoxy}-piperidine-1-carboxylic acid 4-chlorophenyl ester, MS: 399 (MH+).
Reaction SMILES: Cl[C:2](=[N:9][N:10]=[C:11](Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl>CN(C)C1C=CC=CC=1>[CH3:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:11]1[N:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[N:9][N:10]=1
Reactant: Cc1ccccc1C(Cl)=NN=C(Cl)c1ccccc1
Reactant: Nc1ccccc1
Agent: Cl
Solvent: CN(C)c1ccccc1
Product: Cc1ccccc1-c1nnc(-c2ccccc2)n1-c1ccccc1
Temperature: 120 °C
Reaction time: 7 h
Yield: 62 %

Procedure:
Then, 5.1 g (17.6 mmol) of [chloro(2-methylphenyl)methanone][chloro(phenyl)methylidene]hydrazone obtained in Step 2, 60 ml of dimethylaniline, and 4.9 g (52.8 mmol) of aniline were put into a 500-ml recovery flask and heated and stirred at 120° C. for 7 hours. After the stirring, the reacted solution was added to 1N hydrochloric acid and the mixture was stirred for 30 minutes. Then, an organic layer was extracted with dichloromethane. This organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated brine. Purification by column chromatography was then performed. A mixed solvent of toluene and ethyl acetate in a ratio of 1:1 was used as a developing solvent. The obtained fraction was concentrated to give 3.4 g of a white solid of Hmpptz in a yield of 63%. A synthesis scheme of Step 3 is shown in (a-3).
Reaction SMILES: [Br:1][C:2]1[C:3]([S:12]C(C)(C)C)=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[CH:5]=[N:6]O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)CCC>[Br:1][C:2]1[C:3]2[S:12][N:6]=[CH:5][C:4]=2[CH:8]=[C:9]([F:11])[CH:10]=1
Reactant: CC(C)(C)Sc1c(Br)cc(F)cc1C=NO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCO
Product: Fc1cc(Br)c2sncc2c1
Yield: 32.3 %

Procedure:
A mixture of 3-bromo-2-tert-butylsulfanyl-5-fluoro-benzaldehyde oxime (3.8 g, 12 mmol) and p-toluenesulfonic acid (1.1 g, 6.2 mmol) in n-butanol (60 mL) was heated to reflux for 16 h. The reaction mixture was then concentrated. The residue was treated with water and saturated aqueous sodium bicarbonate, then extracted with dichloromethane (3×20 mL). The combined organic fractions were washed with water, dried over sodium sulfate, filtered, and concentrated. Purification by column chromatography (100% hexanes) afforded 900 mg (32%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 8.97 (s, 1H), 7.68 (dd, J=2, 6 Hz, 1H), 7.50 (dd, J=2, 6 Hz, 1H).
Reaction SMILES: [I-].C[S+](C)(C)=O.[CH3:7]C(C)([O-])C.[K+].[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([CH:20]2[CH2:22][O:21]2)[CH:19]=1>C(O)(C)(C)C>[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([CH:20]2[CH2:22][CH2:7][O:21]2)[CH:19]=1
Reactant: Brc1cncc(C2CO2)c1
Reactant: CC(C)(C)[O-]
Agent: C[S+](C)(C)=O
Agent: [I-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: Brc1cncc(C2CCO2)c1
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
To a suspension of trimethylsulfoxonium iodide (CAS#1774-47-6, 6.38 g, 29.0 mmol) in tert-butanol (20 mL), was added potassium tert-butoxide (3.25 g, 29.0 mmol). The reaction was heated to 50° C. and permitted to stir for 15 min. A solution of 3-bromo-5-oxiranyl-pyridine (2.9 g, 14.50 mmol) in tert-butanol (20 mL) was then added slowly to the reaction. The reaction was permitted to stir at 50° C. for 16 hr. The reaction mixture was cooled to 0° C., quenched with brine, and diluted with diethyl ether. The layers were separated and the aqueous layer was extracted with diethyl ether two additional times. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (ethyl acetate-heptane, 0 to 60%) to afford 3-bromo-5-oxetan-2-yl-pyridine; MS: (ES+) m/z 214.3 (M+H)+.
Reaction SMILES: C(O[C:4](=[C:7]([C:10]#[N:11])[C:8]#[N:9])[CH2:5][CH3:6])C.[CH3:12][CH:13]([NH:20][NH2:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].N.[OH:23]O>CO.C(O)C>[NH2:9][C:8]1[N:20]([CH:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH3:12])[N:21]=[C:4]([CH2:5][CH3:6])[C:7]=1[C:10]([NH2:11])=[O:23]
Reactant: OO
Reactant: CCOC(CC)=C(C#N)C#N
Reactant: CCCCCCC(C)NN
Agent: N
Solvent: CO
Solvent: CCO
Product: CCCCCCC(C)n1nc(CC)c(C(N)=O)c1N
Temperature: 25 °C
Reaction time: 48 h

Procedure:
5.21 g (34.66 mmol) of 2-(1-ethoxy-propylidene)-malononitrile and 5.00 g (34.66 mmol) of (1-methyl-heptyl)-hydrazine are refluxed for 4 hours in 40 ml of methanol. After the solvent has been removed in vacuo, 8.60 g of a red oil are obtained. The latter is dissolved in 250 ml of ethanol and, after 300 ml of concentrated NH3 solution (25% strength) and 70 ml of hydrogen peroxide solution (30%) have been added, the mixture is stirred for 48 hours at room temperature. After the non-aqueous solvents have been removed, the mixture is extracted three times with dichloromethane, and the organic phase is dried over sodium sulphate and evaporated on a rotary evaporator. This gives 7.45 g (71%) of a red solid.
Reaction SMILES: CCN(CC)CC.C(S)(S)CC.[Cl:13][C:14]1[CH:15]=[C:16]([CH:36]=[C:37]([F:39])[CH:38]=1)[CH2:17][NH:18][C:19]([C:21]1([N:33]=[N+]=[N-])[CH2:25][CH2:24][N:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:22]1=[O:32])=[O:20]>CO>[Cl:13][C:14]1[CH:15]=[C:16]([CH:36]=[C:37]([F:39])[CH:38]=1)[CH2:17][NH:18][C:19]([C:21]1([NH2:33])[CH2:25][CH2:24][N:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:22]1=[O:32])=[O:20]
Reactant: [N-]=[N+]=NC1(C(=O)NCc2cc(F)cc(Cl)c2)CCN(c2ccccc2)C1=O
Agent: CCC(S)S
Solvent: CCN(CC)CC
Solvent: CO
Product: NC1(C(=O)NCc2cc(F)cc(Cl)c2)CCN(c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Et3N (0.1 ml, 0.75 mmol) followed by propanedithiol (0.08 ml, 0.75 mmol) are added to a solution of 3-azido-2-oxo-1-phenylpyrrolidine-3-carboxylic acid (3-chloro-5-fluorobenzyl)amide (100 mg, 0.25 mmol) in 2 ml of methanol. The batch is stirred at RT for 12 hours. When the reaction is complete, all volatile constituents are removed in vacuo, and the residue is purified on silica gel.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][CH2:10][C:11](=[CH2:24])[CH2:12][CH:13]2[O:17][C:16](=[O:18])[CH:15]=[C:14]2N2CCCC2)=[CH:4][CH:3]=1>C(O)(=O)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:10][C:11](=[CH2:24])[CH2:12][CH:13]3[O:17][C:16](=[O:18])[CH:15]=[C:14]23)=[CH:4][CH:3]=1
Reactant: C=C(CNCc1ccc(Cl)nc1)CC1OC(=O)C=C1N1CCCC1
Solvent: CC(=O)O
Product: C=C1CC2OC(=O)C=C2N(Cc2ccc(Cl)nc2)C1
Yield: 94.9 %

Procedure:
At 100° C., 540 mg (1.55 mmol) of 5-[2-({[(6-chloropyridin-3-yl)methyl]amino}methyl)prop-2-en-1-yl]-4-pyrrolidin-1-ylfuran-2(5H)-one (III-1) in 20 ml of acetic acid are stirred for 2 hours. The reaction mixture is concentrated under reduced pressure, the residue is taken up in dichloromethane and the mixture is washed with water. The aqueous phase is extracted twice with dichloromethane. The combined organic phase is washed with 1N aqueous sodium hydroxide solution, and the aqueous phase (sodium hydroxide solution) for its part is extracted twice with dichloromethane. The combined organic phase is dried over sodium sulphate and concentrated under reduced pressure. Purification of the residue by reciystallization from ethyl acetate gives 407 mg (94% of theory) of 4-[(6-chloropyridin-3-yl)methyl]-6-methylene-5,6,7,7a-tetrahydrofuro[3,2-b]pyridin-2(4H)-one.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[OH-].[K+].[CH3:18][N:19]([CH3:28])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]=[CH2:27])[CH:21]=1>CN1C(=O)CCC1.O>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:27][CH2:26][C:22]3[CH:21]=[C:20]([N:19]([CH3:28])[CH3:18])[CH:25]=[CH:24][CH:23]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: C=Cc1cccc(N(C)C)c1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2cccc(N(C)C)c2)CCN(C)C1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
To a solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.5 mmol) was in NMP (1 mL) were added powdered KOH (196 mg, 3.5 mmol) and dimethyl-(3-vinyl-phenyl)-amine (147 mg, 1.0 mmol) and the reaction mixture stirred at 100° C. for 16 h. The progress of reaction was monitored by TLC and LCMS. The reaction mixture was diluted with water (15 mL) and extracted with EtOAc (3×25 mL). The combined organic layer was washed with water (5×20 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (0-3% MeOH-DCM) to yield {3-[2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-ethyl]-phenyl}-dimethyl-amine. 1H NMR (CDCl3, freebase) δ (ppm): 7.21 (m, 2H), 7.18 (dd, 1H), 7.0 (d, 1H), 6.6 (d, 1H), 6.43 (d, 1H), 6.21 (s, 1H), 4.2 (t, 2H), 3.71 (s, 2H), 2.90 (t, 2H), 2.85 (s, 3H), 2.80 (m, 4H), 2.57 (s, 6H), 2.41 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH2:18][C:19]([OH:21])=O)=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CO.ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[N:15][C:14]([O:17][CH2:18][C:19](=[O:21])[NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:13][CH:12]=2)=[O:10])=[CH:6][CH:7]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Solvent: CO
Solvent: ClCCl
Product: O=C(COc1ncc(C(=O)Nc2ccc(F)cc2)cn1)Nc1ccccc1
Yield: 22 %

Procedure:
The titled compound was prepared from [5-(4-fluorophenylcarbamoyl)pyrimidin-2-yloxy]acetic acid using aniline (12 mg, 0.13 mmol) as the coupling partner. Chromatography (10% methanol/dichloromethane) through SiO2 yielded 14 mg (22%) of the titled compound. ESI-MS m/z 367 (MH+), 365 (M−H−).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][C@@H:15]2[CH2:21][CH2:20][C@@H:19]3[NH:22][C@@:16]2([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:17][C@@H:18]3[C:23]#[CH:24])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C[Si]([N:37]=[N+:38]=[N-:39])(C)C.[ClH:40]>C1(C)C=CC=CC=1.CCOCC>[ClH:40].[F:11][C:9]([F:12])([F:10])[C:7]1[CH:6]=[C:5]([CH2:13][O:14][C@@H:15]2[CH2:21][CH2:20][C@@H:19]3[NH:22][C@@:16]2([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:17][C@H:18]3[C:23]2[NH:39][N:38]=[N:37][CH:24]=2)[CH:4]=[C:3]([C:2]([F:31])([F:1])[F:32])[CH:8]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: C#C[C@H]1C[C@]2(c3ccccc3)N[C@H]1CC[C@H]2OCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: FC(F)(F)c1cc(CO[C@@H]2CC[C@@H]3N[C@@]2(c2ccccc2)C[C@H]3c2cnn[nH]2)cc(C(F)(F)F)c1

Procedure:
(1R*,2R*,5S*,6R*)-2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-6-ethynyl-1-phenyl-8-azabicyclo[3.2.1]octane (Example 98; 136 mg, 0.3 mmol) and trimethylsilylazide (0.1 ml, 0.8 mmol) in toluene were heated in a sealed tube at 130° C. for 48 hours. The mixture was allowed to cool and quenched with methanol and water. The mixture was concentrated in vacuo, and the residue purified by flash column chromatography, eluting with 5% methanol/dichloromethane. The debenzylated product was treated with 1.0 eq HCl in ether and the title compound isolated as a white crystalline solid (20 mg, 13%).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:4]([CH3:13])[NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:19]N(C=O)C.[H-].[Na+].CI>[Cl-].[Na+].O>[Br:1][C:2]1[C:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:4]([CH3:13])[N:5]([CH3:19])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1c(C)[nH]c(-c2ccccc2)c1Br
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CCOC(=O)c1c(Br)c(-c2ccccc2)n(C)c1C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 115 %

Procedure:
Ethyl 4-bromo-2-methyl-5-phenyl-1H-pyrrole-3-carboxylate (3.31 g, 11.4 mmol) was dissolved into anhydrous DMF (50 mL). After stirring at 0° C. for 15 min, to this solution was added NaH (60%, 0.55 g, 13.7 mmol). The mixture was held at 0° C. for 10 min and then MeI (2.13 mL, 34.2 mmol) was added to the mixture. The reaction mixture was gradually warmed to RT and stirred overnight. The mixture was poured into brine (100 mL) and extracted with ethyl acetate (200 mL). The organic phase was dried over MgSO4 and evaporated under vacuum. The residue was further purified by flash column chromatography to provide the crude intermediate ethyl 4-bromo-1,2-dimethyl-5-phenyl-1H-pyrrole-3-carboxylate (4.23 g, 13.1 mmol, 115%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([OH:18])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N-]C(C)C)(C)C.[Li+].CON(C)C(=O)[C:31]1[CH:36]=[C:35]([Cl:37])[C:34]([NH2:38])=[CH:33][C:32]=1[O:39][CH3:40]>CN(P(N(C)C)(N(C)C)=O)C.C1COCC1.O>[NH2:38][C:34]1[C:35]([Cl:37])=[CH:36][C:31]([C:16](=[O:18])[CH2:15][CH2:14][CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]2)=[C:32]([O:39][CH3:40])[CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)O)CC1
Reactant: COc1cc(N)c(Cl)cc1C(=O)N(C)OC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(N)c(Cl)cc1C(=O)CCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 21.1 %

Procedure:
3-[1-(tert-Butoxycarbonyl)piperidin-4-yl]propionic acid (4.6 g, 18 mmol), prepared as in Example 1, was dissolved in HMPA (10 mL) and THF (10 mL), and this solution was added to a -20° solution of lithium diisopropylamide (60 mmol). The mixture was warmed to 0° C., stirred for 30 minutes, and then cooled to -40° C. N-Methoxy-N-methyl-4-amino-5-chloro-2-methoxybenzamide (4.9 g, 20 mmol), prepared as in Example 2, was dissolved in HMPA (10 mL) and THF (10 mL) and this solution was added to the mixture. The mixture was allowed to warm to 0° C. over 1 hour, then diluted with water, washed with ether, acidified with hydrochloric acid, and extracted into methylene chloride. The methylene chloride extract was concentrated in vacuo and the residue was heated in an oil bath to 140° C. for 30 minutes. The mixture was cooled, partitioned between water and ethyl acetate. The ethyl acetate layer was separated, washed with 5% sodium hydroxide and then brine, dried over sodium sulfate, and evaporated. Purification by silica gel chromatography (40% ethyl acetate-hexane) gave 1-(4-amino-5-chloro-2-methoxyphenyl)-3-[1-(tert-butoxycarbonyl)piperidin-4-yl]-propan-1-one (1.5 g, 3.8 mmol), m.p. 133°-134° C.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[C:11]([C:14]([F:17])([F:16])[F:15])[C:10]([C:18]#[N:19])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].Cl[CH2:21][C:22]1[N:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)[O:24][N:23]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC#N>CCOC(C)=O>[CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[N:26]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=3)[O:24][N:23]=2)[C:7]2[C:12]([CH:13]=1)=[C:11]([C:14]([F:16])([F:17])[F:15])[C:10]([C:18]#[N:19])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Reactant: FC(F)(F)c1cccc(-c2nc(CCl)no2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cccc(C(F)(F)F)c2)n1
Temperature: 75 °C
Reaction time: 1.5 h
Yield: 74.8 %

Procedure:
A mixture of 2-butyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (0.050 g, 0.19 mmol), 3-(chloromethyl)-5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole (0.054 g, 0.21 mmol), Cs2CO3 (0.067 g, 0.21 mmol) and CH3CN (4 mL) was stirred at 75° C. for 1.5 h. The mixture was diluted with EtOAc (25 mL), washed with water (15 mL), and brine (15 mL). Drying (MgSO4) and filtration was followed by concentration. The resulting material was treated with 10% Et2O in hexanes (10 mL) and stirred for 2 h. The resulting solid was filtered, rinsed with hexanes and dried to afford the title compound (0.070 g, 76%) as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ 8.30 (d, J=7.8 Hz, 1H), 8.23 (s, 1H), 8.06 (d, J=7.8 Hz, 1H), 8.03 (d, J=8.6 Hz, 1H), 7.84 (t, J=7.8 Hz, 1H), 7.75 (d, J=8.6 Hz, 1H), 6.58 (s, 1H), 5.88 (s, 2H), 2.92 (t, J=7.5 Hz, 2H), 1.74-1.66 (m, 2H), 1.44-1.35 (m, 2H), 0.90 (t, J=7.4 Hz, 3H); MS m/z 493 (M+H).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:8]=[CH:7][C:6]=1[CH:15]1[CH2:20][CH2:19][CH2:18][CH:17]([CH2:21][OH:22])[CH2:16]1.CC(C)=[O:25]>S(=O)(=O)(O)O.[O-2].[Cr+6].[O-2].[O-2]>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:8]=[CH:7][C:6]=1[CH:15]1[CH2:20][CH2:19][CH2:18][CH:17]([C:21]([OH:25])=[O:22])[CH2:16]1
Reactant: CC(C)=O
Reactant: COCOc1ccc(C2CCCC(CO)C2)c(OCOC)c1
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Product: COCOc1ccc(C2CCCC(C(=O)O)C2)c(OCOC)c1
Reaction time: 3 h
Yield: 29 %

Procedure:
A solution of (±)-{3-[2,4-bis(methoxymethoxy)phenyl]cyclohexyl}methanol (50 mg) in acetone (1 ml) was added to a stirred solution of chromium (VI) oxide (64 mg) in 2M sulfuric acid (0.64 ml) at 0° C. over 3 hr. After 3 hr at 0° C. and then 16 hr at room temperature, the reaction mixture was partitioned between water (10 ml) and ethyl acetate (20 ml). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×20 ml). The combined organic extracts were washed with water (20 ml), dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, ethyl acetate/petrol, 4:1 v/v) to give the title compound as a colourless oil (15 mg, 29%). Rf (ethyl acetate/petrol, 4:1 v/v) 0.5.