Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([O:13][CH2:14][CH2:15][N:16]2C(=O)C3C(=CC=CC=3)C2=O)[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.CN>ClCCl>[C:1]1([O:13][CH2:14][CH2:15][NH2:16])[CH:2]=[CH:3][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:5][CH:6]=1
Reactant: O=C1c2ccccc2C(=O)N1CCOc1ccc(-c2ccccc2)cc1
Agent: CN
Solvent: ClCCl
Product: NCCOc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Yield: 53.8 %

Procedure:
To a solution of 2-([biphen-4-yloxy]ethyl)isoindoline-1,3-dione (1.5 g, 4.4 mmol) in dichloromethane (30 ml) was added methylarnine (33% solution in ethanol, 50 ml) and the solution was heated to reflux under an atmosphere of nitrogen for 2 hours. The mixture was cooled to ambient temperature, and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (dichloromethane/methanol/aqueous ammonium solution 95:5:0 to 94:5:1 as eluent) to give the title compound as a colourless solid (505 mg).
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH:4]1[CH2:13][CH2:12][C:7]2([O:11][CH2:10][CH2:9][O:8]2)[CH2:6][CH2:5]1.[CH2:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][NH:15]1.FC(F)(F)S([O-])(=O)=O.[Ca+2].FC(F)(F)S([O-])(=O)=O>C(#N)C>[CH2:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][N:15]1[CH2:3][CH:2]([CH:4]1[CH2:13][CH2:12][C:7]2([O:11][CH2:10][CH2:9][O:8]2)[CH2:6][CH2:5]1)[OH:1]
Reactant: c1ccc2c(c1)CNC2
Reactant: C1COC2(CCC(C3CO3)CC2)O1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Ca+2]
Solvent: CC#N
Product: OC(CN1Cc2ccccc2C1)C1CCC2(CC1)OCCO2

Procedure:
A solution of 8-oxiranyl-1,4-dioxaspiro[4.5]decane (1.41 g, 7.66 mmol), isoindoline (1.00 g, 8.43 mmol) and calcium trifluoromethanesulfonate (1.29 g, 3.8 mmol) in anhydrous acetonitrile (60 ml) was stirred at room temperature overnight. The solvent was then concentrated in vacuo. The residue was taken up in ethyl acetate (50 ml) and the solution was washed with 25% potassium carbonate solution (3×50 ml). The aqueous phase was extracted with ethyl acetate (3×40 ml) and the combined organic phases were dried with sodium sulfate and concentrated in vacuo.
Reaction SMILES: [C:1]([CH2:5][C:6]1([CH2:16][CH3:17])[CH2:11][CH2:10][CH:9]([CH:12]2[CH2:14][CH2:13]2)[CH2:8][C:7]1=O)([O:3][CH3:4])=[O:2].[CH2:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[NH:26]N)[CH3:19].C(Cl)(C)=O>CO>[CH3:4][O:3][C:1](=[O:2])[CH2:5][C:6]1([CH2:16][CH3:17])[C:7]2[NH:26][C:21]3[C:22](=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:18][CH3:19])[C:8]=2[CH:9]([CH:12]2[CH2:14][CH2:13]2)[CH2:10][CH2:11]1
Reactant: CCC1(CC(=O)OC)CCC(C2CC2)CC1=O
Reactant: CCc1ccccc1NN
Solvent: CC(=O)Cl
Solvent: CO
Product: CCc1cccc2c3c([nH]c12)C(CC)(CC(=O)OC)CCC3C1CC1
Temperature: 0 °C
Yield: 33.8 %

Procedure:
The mixture of diastereomeric ketones (40 mmol, 9.52 g) prepared in Step (d) and 2-ethylphenylhydrazine (40 mmol, 5.45 g) were heated at reflux in 172 ml of MeOH for 60 hours, cooled to 0° C. and treated with 80 mmol (6.28 g, 5.7 ml) of AcCl. The reaction was refluxed an additional 45 minutes followed by removal of solvent in vacuo. Flash chromatography afforded 4.58 g (13.5 mmol, 34%) of orange oil containing a mixture of diastereomers.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.CCN(C(C)C)C(C)C.[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[O:31][C:32]3[CH:41]=[C:40]([NH:42][S:43]([CH3:46])(=[O:45])=[O:44])[C:39]([O:47][CH:48]([CH3:50])[CH3:49])=[CH:38][C:33]=3[C:34]=2[C:35]([NH2:37])=O)=[CH:26][CH:25]=1>C(Cl)Cl.C1COCC1.CCOC(C)=O>[C:35]([C:34]1[C:33]2[CH:38]=[C:39]([O:47][CH:48]([CH3:50])[CH3:49])[C:40]([NH:42][S:43]([CH3:46])(=[O:45])=[O:44])=[CH:41][C:32]=2[O:31][C:30]=1[C:27]1[CH:26]=[CH:25][C:24]([F:23])=[CH:29][CH:28]=1)#[N:37]
Reactant: CC(C)Oc1cc2c(C(N)=O)c(-c3ccc(F)cc3)oc2cc1NS(C)(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)Oc1cc2c(C#N)c(-c3ccc(F)cc3)oc2cc1NS(C)(=O)=O
Yield: 49.9 %

Procedure:
Trifluoroacetic anhydride (375 μL, 2.66 mmol) was added to a stirring solution of DIEA (928 μL, 5.31 mmol), 2-(4-fluorophenyl)-5-isopropoxy-6 (methylsulfonamido)benzofuran-3-carboxamide (300 mg, 0.738 mmol) in CH2Cl2 (4 mL) and THF (4 mL) at 0° C. for 1 hour. The mixture was diluted with EtOAc and washed with sat NaHCO3, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated. The crude residue was purified by on silica gel (Biotage, gradient EtOAc/hexanes, fraction collection at λ=254 nm) to give the title compound (143 mg, 50%). 1H NMR (300 MHz, DMSO-D6) δ ppm 1.28-1.41 (m, 6 H) 3.01 (s, 3 H) 4.77-4.95 (m, 1 H) 7.35 (s, 1 H) 7.44-7.57 (m, 2H) 7.68 (s, 1 H) 8.04-8.20 (m, 2 H) 9.01 (s, 1 H). LC-MS retention time: 1.65 min; m/z (MH−): 387. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5 u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:16]N1C(=O)CCC1=O>>[Br:16][C:11]1[NH:10][CH:9]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1c[nH]cc1-c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Product: COC(=O)c1c[nH]c(Br)c1-c1ccccc1
Yield: 70.4 %

Procedure:
Using methyl 4-phenyl-1H-pyrrole-3-carboxylate (2.01 g) and N-bromosuccinimide (1.85 g), a procedure as in Reference Example 40 was performed to give the title compound as white crystals (yield 1.97 g, 70%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[CH2:11][C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[N:9]1.CO[CH:23](OC)[N:24]([CH3:26])[CH3:25]>CO>[CH3:23][N:24](/[CH:26]=[C:11]1\[C:12](=[O:13])[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[N:9]=[C:10]\1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20])[CH3:25]
Reactant: O=C1CC(c2ccccc2F)=NN1c1ccccc1F
Reactant: COC(OC)N(C)C
Solvent: CO
Product: CN(C)/C=C1\C(=O)N(c2ccccc2F)N=C1c1ccccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,5-Bis(2-fluorophenyl)-2,4-dihydro-3H-pyrazol-3-one (2.5 g, 8.1 mmol) was dissolved in methanol (3 mL), treated with N,N-dimethylformamide dimethylacetal (1.2 g, 9.7 mmol, 1.2 equiv) and placed into a preheated oil bath at 60° C. for 1 hour. The mixture was cooled to ambient temperature and concentrated in vacuo, providing the titled compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([CH3:16])[N:13]=[C:12]([O:14][CH3:15])[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.[Cl:47][C:48]1[CH:49]=[C:50]([CH:53]=[CH:54][CH:55]=1)[CH2:51][NH2:52]>C1(C)C=CC=CC=1>[Cl:47][C:48]1[CH:49]=[C:50]([CH:53]=[CH:54][CH:55]=1)[CH2:51][NH:52][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2([CH3:16])[N:13]=[C:12]([O:14][CH3:15])[CH2:11][O:10][CH2:9]2)[CH:3]=1
Reactant: COC1=NC(C)(c2cccc(Br)c2)COC1
Reactant: NCc1cccc(Cl)c1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: COC1=NC(C)(c2cccc(NCc3cccc(Cl)c3)c2)COC1
Temperature: 100 °C
Yield: 49.3 %

Procedure:
A dried pressure tube was charged consecutively under a nitrogen atmosphere with a solution of (RS)-3-(3-bromo-phenyl)-5-methoxy-3-methyl-3,6-dihydro-2H [1,4]oxazine (150 mg, 0.5 mmol) in toluene (5 ml), sodium tert-butylate (157 mg, 1.6 mmol), 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (tert-butyl-x-phos) (23 mg, 0.1 mmol), tris(dibenzylideneacetone)-dipalladium chloroform complex (17 mg), and 3-chlorobenzylamine (154 mg, 1.1 mmol). The sealed pressure tube was heated at 100° C. for 15 hours. After cooling, the reaction mixture was evaporated to dryness and directly purified by chromatography on an Isolute flash NH2 column using a gradient of heptane/ethyl acetate=100/0 to 50/50 as the eluent. 85 mg (47%) of (RS)-(3-chloro-benzyl)-[3-(5-methoxy-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amine were obtained as a yellow oil. Mass (calculated) C19H21ClN2O2 [344.844]; (found) [M+H]+=345.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8]Br)[N:3]=1.C1N2CN3CN(C2)C[N:11]1C3.[OH-].[Na+]>C(Cl)(Cl)Cl>[Br:1][C:2]1[N:3]=[C:4]([CH2:8][NH2:11])[CH:5]=[CH:6][CH:7]=1
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: BrCc1cccc(Br)n1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: NCc1cccc(Br)n1
Temperature: 25 °C

Procedure:
2-Bromo-6-bromomethyl-pyridine (2.67 g, 10.63 mmol) was combined with hexamethylenetetramine (3.00 g, 21.30 mmol) in chloroform (50 ml) and the resulting reaction mixture was stirred at reflux for 14 hours. The reaction mixture was then cooled to room temperature and the white solid was collected by filtration. The white solid was suspended in ethanol (50 ml) and concentrated HCl (12 ml) was added. The resulting reaction mixture was stirred at 90° C. for 14 hours. Adjustment of pH to 12 was done by the addition of aq 5N NaOH. The reaction mixture was extracted with dichloromethane several times. The combined organic layers were concentrated to yield the title compound. Spectroscopic data: 1H NMR (300 MHz, CDCl3) δ 3.95 (s, 2H) 7.19-7.28 (m, 2H) 7.62 (t, J=7.82 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([CH3:18])[NH:15][C:14](=O)[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].O=P(Cl)(Cl)[Cl:22]>>[Cl:22][C:14]1[N:13]=[C:12]([C:4]2[CH:5]=[CH:6][C:7]([C:8]([F:11])([F:10])[F:9])=[C:2]([CH3:1])[CH:3]=2)[CH:17]=[C:16]([CH3:18])[N:15]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(-c2ccc(C(F)(F)F)c(C)c2)nc(=O)[nH]1
Product: Cc1cc(-c2ccc(C(F)(F)F)c(C)c2)nc(Cl)n1

Procedure:
The title compound was prepared from 4-(3-methyl-4-trifluoromethyl-phenyl)-6-methyl-1H-pyrimidin-2-one (1.73 g, 6.45 mmol) and phosphoroxychloride (20 mL) according to the general procedure I. Obtained as a brown solid (1.4 g, 76%). MS (EI) 286.1 [(M)+]; mp 101° C.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[S-:10][C:11]#[N:12].[K+].BrBr.C(#N)C1C=CC=CC=1>C(O)(=O)C.O>[NH2:12][C:11]1[S:10][C:3]2[CH:4]=[C:5]([C:6]#[N:7])[CH:8]=[CH:9][C:2]=2[N:1]=1
Reactant: N#C[S-]
Reactant: N#Cc1ccc(N)cc1
Agent: BrBr
Agent: [K+]
Solvent: O
Solvent: N#Cc1ccccc1
Solvent: CC(=O)O
Product: N#Cc1ccc2nc(N)sc2c1
Reaction time: 16 h

Procedure:
4-Aminobenzonitrile is dissolved in acetic acid (or a weak protic acid) and the solution is cooled to about 16–30° C., preferably 16–18° C. Potassium thiocyanate is added and the flask is then equipped with an addition funnel. The addition funnel is charged with bromine and acetic acid. This dark solution is then added to the benzonitrile solution in a dropwise fashion under good agitation and allowed to stir for about 12–20 hours, preferrably about 16 hours. The slurry is then drowned into water and filtered. The presscake is washed well with water, reslurried in dilute aqueous alkali and filtered. Again the presscake is washed well with water to obtain the title compound.
Reaction SMILES: [Na].[N:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.Cl[CH2:18][CH2:19][CH2:20][S:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24]([OH:26])=[O:25]>CC(O)C>[N:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:18][CH2:19][CH2:20][S:21][C:22]3[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=3[C:24]([OH:26])=[O:25])=[CH:14][CH:15]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(CCc2ccncc2)cc1
Reactant: O=C(O)c1ccccc1SCCCCl
Agent: [Na]
Solvent: CC(C)O
Product: O=C(O)c1ccccc1SCCCOc1ccc(CCc2ccncc2)cc1
Yield: 18.4 %

Procedure:
To the solution of 1.3 g (58 mmol) sodium in 100 ml ethanol one adds 5.7 g (29 mmol) 4-[2-(4-pyridinyl)-ethyl]-phenol, stirs for 10 min at room temperature, adds thereto 6.7 g (29 mmol) 2-(3-chloropropylthio)-benzoic acid and heats under reflux for 12 h. One allows to cool, filters, evaporates the filtrate, takes up in water, washes with ether, adjusts the aqueous phase to pH 5 and extracts with dichloromethane. After chromatography of the extract on silica gel and trituration with ligroin, one isolates 2.1 g of title compound (19% of theory) of the m.p. 151°-153° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=O)[C:6]([CH3:14])([CH3:13])[N:5]2[C:15]([N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:16].[N+:22]([CH2:24][C:25]1[N:29]=[C:28]([CH:30]([CH3:32])[CH3:31])[O:27][N:26]=1)#[C-:23]>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:23]=[N:22][C:24]([C:25]3[N:29]=[C:28]([CH:30]([CH3:32])[CH3:31])[O:27][N:26]=3)=[C:7]1[C:6]([CH3:14])([CH3:13])[N:5]2[C:15]([N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:16]
Reactant: CC1(C)C(=O)Nc2ccc(F)cc2N1C(=O)N1CCCC1
Reactant: [C-]#[N+]Cc1noc(C(C)C)n1
Product: CC(C)c1nc(-c2ncn3c2C(C)(C)N(C(=O)N2CCCC2)c2cc(F)ccc2-3)no1

Procedure:
Following the general procedure for EXAMPLE 30 and making non-critical variation but starting with 6-fluoro-1,2,3,4-tetrahydro-3,3-dimethyl-4-[(pyrrolidino)carbonyl]quinoxalin-2-one (XXXII, EXAMPLE 32, 0.647 g) and 3-isocyanomethyl-5-isopropyl-1,2,4-oxadiazole (0.403 g) the title compound is obtained which is crystallized from methylene chloride/ethyl ether/hexane, mp 154.5°-155.5°; MS (m/z) at 424; IR (mineral oil) 1527, 1657, 1414, 1172 and 1395 cm-1 ; NMR (CDCl3) 1.45, 1.7-2.0, 3.0, 3.3, 3.33, 3.58, 6.55, 6.74, 7.45 and 8.06 δ.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[N:3]([C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[O:2]2>C(O)(=O)C.O.[Zn]>[OH:2][C@@H:1]1[CH2:6][CH2:5][C@H:4]([NH:3][C:8](=[O:9])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7]1
Reactant: O=C(OCc1ccccc1)N1OC2CCC1C2
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: O=C(N[C@H]1CC[C@@H](O)C1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 7.5 h
Yield: 23.8 %

Procedure:
A solution 3-aza-2-oxabicyclo[2.2.1]heptane-3-carboxylic acid, (phenylmethyl) ester (0.5 g) in glacial acetic acid (0.5 ml) was added to a stirred suspension of powdered zinc (0.35 g) in a mixture of acetic acid and water (1:1; 4 ml), and the mixture was stirred at 60° for 7.5 h. Additional zinc powder (0.14 g) and acetic acid (1 ml) were added and stirring was continued for a further 16.5 h. After cooling to room temperature, the mixture was filtered and the excess of zinc washed with 2M hydrochloric acid (20 ml). The combined filtrate and washings were neutralised with 8% sodium carbonate and extracted into ethyl acetate (3×30 ml). The combined organic extracts were washed with brine (30 ml), dried and concentrated in vacuo. Purification by FCC eluting with ethyl acetate: cyclohexane (1:1) gave an oil (120 mg) which solidified upon standing and was recrystallised from cyclohexane to give the title compound (70 mg), m.p. 62°-63°.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:10]1[N:14]([CH3:15])[N:13]=[N:12][N:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C1CN2C(=NCCC2)C1.Br.[Br-].[O:27]1[CH2:31][CH2:30][O:29][CH:28]1[C:32]1[N:37]=[C:36]([CH2:38][N+]2C=CC=CC=2)[CH:35]=[CH:34][CH:33]=1>CC#N>[O:27]1[CH2:31][CH2:30][O:29][CH:28]1[C:32]1[N:37]=[C:36]([CH2:38][O:1][N:2]=[C:3]([C:10]2[N:14]([CH3:15])[N:13]=[N:12][N:11]=2)[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:35]=[CH:34][CH:33]=1
Reactant: Cn1nnnc1C(=NO)c1ccccc1
Reactant: c1cc[n+](Cc2cccc(C3OCCO3)n2)cc1
Agent: Br
Agent: C1CN=C2CCCN2C1
Agent: [Br-]
Solvent: CC#N
Product: Cn1nnnc1C(=NOCc1cccc(C2OCCO2)n1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 35 %

Procedure:
To a cooled (0° C.) stirred solution of N-hydroxy-1-(1-methyl-1H-tetrazol-5-yl)-1-phenylmethanimine (12.2 g, 60.03 mmol, 1.0 eq.) in 250 ml of MeCN, was added dropwise DBN (12.30 g, 99.06 mmol, 1.65 eq.). The reaction was stirred for 5 mins before addition of 1-{[6-(1,3-dioxolan-2-yl)pyridin-2-yl]methyl}pyridinium bromide hydrobromide (15.7 g, 39.02 mmol, 0.65 eq.) portionwise. The mixture was stirred for further 5 mins before removal of the cooling bath and continued at ambient temperature. MeCN was evaporated and the residue dissolved in 500 ml of DCM, washed with water (×2), dried over MgSO4 and concentrated. The residue was purified by chromatography on silica gel to yield N-{[6-(1,3-dioxolan-2-yl)pyridin-2-yl]methoxy}-1-(1-methyl-1H-tetrazol-5-yl)-1-phenylmethanimine (5 g, 22% yield) as a pale yellow oil.
Reaction SMILES: C([Li])CCC.[F:6][C:7]([F:27])([F:26])[C:8]([CH2:14][CH:15]1[CH:20]([C:21]([OH:24])([CH3:23])[CH3:22])[CH:19]2[CH2:25][CH:16]1[CH2:17][CH2:18]2)([OH:13])[C:9]([F:12])([F:11])[F:10].[C:28](Cl)(=[O:32])[C:29]([CH3:31])=[CH2:30]>O1CCCC1>[C:28]([O:13][C:8]([CH2:14][CH:15]1[CH:20]([C:21]([OH:24])([CH3:23])[CH3:22])[CH:19]2[CH2:25][CH:16]1[CH2:17][CH2:18]2)([C:9]([F:11])([F:10])[F:12])[C:7]([F:26])([F:27])[F:6])(=[O:32])[C:29]([CH3:31])=[CH2:30]
Reactant: C=C(C)C(=O)Cl
Reactant: CC(C)(O)C1C2CCC(C2)C1CC(O)(C(F)(F)F)C(F)(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=C(C)C(=O)OC(CC1C2CCC(C2)C1C(C)(C)O)(C(F)(F)F)C(F)(F)F
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 30.1 %

Procedure:
To a flame-dried, nitrogen-purged 250 mL 3-neck roundbottom flask with 50 mL pressure-equalizing addition funnel and magnetic stirbar was charged 141 mL n-butyl lithium (65 mmol, 2 equiv., 1.6 M in hexanes). A degassed solution of 1,1,1,3,3,3-hexafluoro-2-((3-(2-hydroxypropan-2-yl)bicyclo[2.2.1]heptan-2-yl)methyl)propan-2-ol (VII) (˜33 mmol, 1 eq.) in 50 mL anhydrous tetrahydrofuran was charged to the addition funnel was added to the reaction mixture dropwise at 0° C. over 30 minutes. The reaction mixture was warmed for 15 minutes on an oil bath at 70° C. to ensure the reaction was complete. The reaction vessel was cooled to 0° C. and 3.75 g methacryloyl chloride (36 mmol, 1.1 eq.) was added dropwise and allowed to stir for 15 minutes. The addition funnel was replaced with a reflux condenser and the reaction heated to reflux for 20 hours. After the reaction was complete, it was cooled to 0° C. and quenched with dilute HCl solution until the pH was less than 5.0. The reaction solution was neutralized with saturated aqueous sodium bicarbonate until the pH was greater than 8. The product was extracted into ethyl ether and the organic phase washed sequentially with aqueous sodium bicarbonate, water, and brine and then dried over magnesium sulfate, filtered, concentrated in vacuo, and stored over a small amount of sodium bicarbonate. The crude product mixture was purified via silica gel column chromatography (20:1 hexane:ethyl acetate eluent) to afford 4.0 g (30%) of 1,1,1,3,3,3-hexafluoro-2-((3-(2-hydroxypropan-2-yl)bicyclo[2.2.1]heptan-2-yl)methyl)propan-2-yl methacrylate (VIII) as a colorless liquid (˜1.35:1 isomer ratio).
Reaction SMILES: Br[C@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].C(N(CC)CC)C>C(OCC)(=O)C>[C:3]([OH:5])(=[O:4])[CH:2]=[CH:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C(O)[C@H](Br)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(O)C=Cc1ccccc1

Procedure:
5 g of crude (2R)-2-bromo-3-phenylpropionic acid (HPLC: 92.5%) were dissolved in 20 ml of ethyl acetate and treated at room temperature with 2.7 ml of triethylamine. After a stirring time of about 150 minutes, no precipitation of the product was to be observed. An HPLC analysis of the solution showed that the (2R)-2-bromo-3-phenyl-propionic acid had reacted completely to give cinnamic acid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:20][CH:21]1[CH2:27][CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Cl:49][C:50]1[C:58](O)=[CH:57][CH:56]=[C:55]2[C:51]=1[CH:52]=[N:53][NH:54]2.Cl.O1CCOCC1>O1CCCC1.CO>[NH:24]1[CH:25]=[CH:26][CH:27]=[C:21]([O:20][C:58]2[C:50]([Cl:49])=[C:51]3[C:55](=[CH:56][CH:57]=2)[NH:54][N:53]=[CH:52]3)[CH:22]=[CH:23]1
Reactant: CC(C)(C)OC(=O)N1CCCC(O)CC1
Reactant: Oc1ccc2[nH]ncc2c1Cl
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: CO
Product: Clc1c(OC2=CC=CNC=C2)ccc2[nH]ncc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.4 %

Procedure:
Under a nitrogen atmosphere, triphenylphosphine (280 mg, 1.07 mmol), the tert-butyl 4-hydroxyazepane-1-carboxylate (192 mg, 0.890 mmol) obtained in Example 322, (c) and diisopropyl azodicarboxylate (193 μl, 0.979 mmol) were added at 0° C. to a solution of the 4-chloro-1H-indazol-5-ol (150 mg, 0.890 mmol) obtained in Example 468 in tetrahydrofuran (6 ml). After 30 minutes, the mixture thus obtained was warmed up to room temperature and stirred overnight. The reaction solution was concentrated under reduced pressure, and the resulting residue was diluted with chloroform (20 ml) and washed with a 1M-aqueous sodium hydroxide solution (10 ml). After the aqueous layer was re-extracted with chloroform (10 ml), the organic layer was dried over anhydrous magnesium sulfate. The organic layer dried was concentrated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate). The oil thus obtained was dissolved in methanol (3 ml) at room temperature and 4N-hydrochloric acid-dioxane (3 ml) was added thereto. After 1 hour, the mixture thus obtained was concentrated under reduced pressure, and the resulting residue was dissolved in methanol (5 ml) and the resulting solution was adjusted to pH 10 by dropwise addition of a 2M-aqueous sodium hydroxide solution. The solution adjusted was concentrated under reduced pressure and the resulting residue was re-dissolved in methanol (5 ml). Silica gel (1 g) was added thereto and the resulting mixture was concentrated under reduced pressure and then dried. The resulting solid was purified by a silica gel column chromatography (eluent: chloroform/methanol→chloroform/methanol (1%-aqueous ammonia)) to obtain 5-(azepin-4-yloxy)-4-chloro-1H-indazole (128.1 mg, 54%).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1.[N-:13]=[N+:14]=[N-:15].[Na+]>CS(C)=O>[N:13]([CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1)=[N+:14]=[N-:15]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)c1ccc(CCBr)cc1
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(=O)c1ccc(CCN=[N+]=[N-])cc1

Procedure:
p-(2-Bromoethyl)-acetophenone (J.A.C.S. 62, 1940, 1435) was reacted with sodium azide in dimethyl sulphoxide to give p-(2-azidoethyl)acetophenone. Oxidation with sodium hypobromide gave p-(2-azidoethyl)benzoic acid (melting point 130°-131°, from acetone/hexane) which was converted with thionyl chloride into the corresponding acid chloride. Treatment of the acid chloride with ammonia gave p-(2-azidoethyl)benzamide. Treatment with triphenylphosphine and hydrolysis gave p-(2-aminoethyl)benzamide of melting point 132°-133° (from ethanol).
Reaction SMILES: [CH3:1][S-:2].[Na+].[Na+].Cl[C:6]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:7]=1[C:8]([O-:10])=[O:9]>CN1CCCC1=O>[CH3:1][S:2][C:6]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: O=C([O-])c1ccc(C(F)(F)F)cc1Cl
Reactant: C[S-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CSc1cc(C(F)(F)F)ccc1C(=O)O
Temperature: 90 °C
Yield: 100.1 %

Procedure:
A mixture of anhydrous sodium thiomethoxide (0.39 g, 0.00525M), 2-chloro-4-trifluoromethylbenzoic acid sodium salt (1.23 g, 0.005M) and anhydrous N-methylpyrrolidinone (10 ml, containing less than 0.01% of water) was heated at 90° C. for 2 hours. The mixture was cooled to 20° C., acidified and extracted (t-butyl methyl ether). The extract was washed (water) and evaporated to give 2-methylthio-4-trifluoromethylbenzoic acid (1.18 g, 100% yield). 1H-nmr 2.40(s,3H). 7.30(1H), 7.38(1H), 8.07(1H). The purity of the product was greater than 95%.