Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH3:13])=[CH:7][CH:6]=1)=O.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][N:16]=1>C(#N)C>[CH2:12]([O:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:14]=[C:15]3[CH:20]=[CH:19][C:18]([I:21])=[CH:17][N:16]3[CH:2]=2)=[CH:6][CH:7]=1)[CH3:13]
Reactant: CCOc1ccc(C(=O)CBr)cc1
Reactant: Nc1ccc(I)cn1
Solvent: CC#N
Product: CCOc1ccc(-c2cn3cc(I)ccc3n2)cc1
Temperature: 110 °C
Yield: 91.1 %

Procedure:
1.20 g (corresponding to 4.94 mmol) of 2-bromo-4′-ethoxyacetophenone and 1.09 g (corresponding to 4.95 mmol) of 2-amino-5-iodopyridine were dissolved in 20 mL of acetonitrile. The resulting solution was refluxed in an oil bath at 110° C. for 1.5 hours. After the completion of the reaction, the reaction solution was cooled down to room temperature, and precipitates were filtered. Then, the precipitates were washed with acetonitrile and dried under reduced pressure. The resulting crude crystals were suspended in a mixed solution of 10 mL of water and 5 mL of methanol. Then, about 20 mL of a saturated sodium hydrogencarbonate solution was added thereto, and the mixture was sonicated for 10 minutes using an ultrasonic washing machine. Precipitates were filtered and recovered from the resulting mixture, sufficiently washed with water, and dried under reduced pressure, to obtain 1.64 g (corresponding to 4.50 mmol) of 2-(4′-ethoxyphenyl)-6-iodoimidazo[1,2-a]pyridine (FIG. 2-3, Step 2).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8](OCC)=O)[CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH2:19]>O1CCCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([OH:19])[CH3:8])[CH:2]=1
Reactant: CCOC(=O)Cc1cccnc1
Reactant: O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(O)c1cccnc1
Reaction time: 0.5 h

Procedure:
Ethyl 3-pyridylacetate (2.0 ml) was dissolved in tetrahydrofuran (66 ml). Under ice cooling, lithium aluminum hydride (0.5 g) was added thereto followed by stirring for 30 min. After adding water (0.5 ml), a 5 N aqueous solution of sodium hydroxide (0.5 ml) and further water (1.5 ml), the resulting precipitate was filtered off and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to give the title compound (1.636 g) as a pale yellow oil (1.636 g) (yield: quantitative).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]2[CH2:15][CH:14]3[N:16](C)[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)=[CH:4][CH:3]=1.Cl[C:19]([O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[O:20].C(=O)([O-])[O-].[K+].[K+]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][CH:9]2[CH2:15][CH:14]3[N:16]([C:19]([O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[O:20])[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)=[CH:6][CH:7]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CN1C2CCC1CC(Sc1ccc(Cl)cc1)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: O=C(OCC(Cl)(Cl)Cl)N1C2CCC1CC(Sc1ccc(Cl)cc1)C2

Procedure:
A mixture of 3-(4-chlorophenylsulfanyl)-8-methyl-8-azabicyclo-(3.2.1)-octane (8.06 g, 30.12 mmol), 2,2,2-trichloroethyl chloroformate (4.56 mL, 33.13 mmol), and potassium carbonate (4.58 g, 33.13 mmol) in benzene (150 mL) was refluxed overnight. The solvent was removed at reduced pressure and the residue was taken up in ethyl acetate. The organic phase was washed with aqueous bicarbonate and brine, dried over calcium sulfate and concentrated. The residue was flash chromatographed on silica gel (3×4 inches) with elution proceeding as follows: hexane (350 mL), nil; 10% ethyl acetate/hexane (500 mL), discarded forerun; 10% ethyl acetate/hexane (500 mL), 20% ethyl acetate/hexane (500 mL), and 30% ethyl acetate/hexane (250 mL), 9.26 g (72%) of 3-(4-chlorophenylsulfanyl)-8-(2,2,2-trichloroethoxycarbonyl)-8-azabicyclo-(3.2.1)-octane as a yellow solid which had: mp 70-71.5° C.; NMR δ 7.33 (long range coupled d, J=8.5 Hz, 2 H), 7.26 (long range coupled 6, J=8.5 Hz, 2 H), 4.73 (ABq, Δv1-3 =58 Hz, J=12 Hz, 2 H), 4.43-4.30 (m, 2 H), 3.40 (septet, J=6 Hz, 1 H), 2.10-1.56 (m, 8 H).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Cl.[CH2:13]([O:15][C:16](=[O:19])[CH2:17][NH2:18])[CH3:14].C(N(C(C)C)CC)(C)C>C(#N)C>[CH2:13]([O:15][C:16](=[O:19])[CH2:17][NH:18][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10])[CH3:14]
Reactant: CCOC(=O)CN
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)CNc1cc(F)ccc1[N+](=O)[O-]

Procedure:
To a mixture of 2,4-difluoronitrobenzene (VII, 19.20 g), glycine ethyl ester hydrochloride (XII, 16.52 g), and acetonitrile (50 ml) is added diisopropylethylamine (42 ml). A mild exotherm ensues. The reaction is stirred (without cooling) for two hours. The acetonitrile is removed under reduced pressure and the residue is partitioned between dichloromethane and water. The organic layers are dried over sodium sulfate and concentrated to give the produce as a solid (single spot by TLC), mp 194°-195°; NMR (CDCl3) 1.33, 4.05, 4.30, 6.35, 6.45, 8.26 and 8.56 δ.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[NH2:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]([CH3:26])[C:13]2[CH:14]=[C:15]([NH:19][C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])[CH:16]=[CH:17][CH:18]=2)=[N:10][CH:11]=1.BrBr>C(O)(=O)C>[NH2:3][C:2]1[S:1][C:11]2[C:6]([N:5]=1)=[CH:7][CH:8]=[C:9]([N:12]([CH3:26])[C:13]1[CH:14]=[C:15]([NH:19][C:20](=[O:25])[C:21]([F:24])([F:22])[F:23])[CH:16]=[CH:17][CH:18]=1)[N:10]=2
Reactant: CN(c1cccc(NC(=O)C(F)(F)F)c1)c1ccc(N)cn1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: CN(c1cccc(NC(=O)C(F)(F)F)c1)c1ccc2nc(N)sc2n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 20.3 %

Procedure:
To a solution of potassium thiocyanate (4.31 g, 44.4 mmol) in acetic acid (15 ml) was added a solution of N-[3-[(5-aminopyridin-2-yl)(methyl)amino]phenyl]-2,2,2-trifluoroacetamide (3.46 g, 11.1 mmol) in acetic acid (10 mL), and the mixture was stirred at room temperature for 20 min. To this solution was added dropwise a solution of bromine (1.95 g, 12.2 mmol) in acetic acid (10 mL), and the mixture was stirred at room temperature for 16 hr. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (140 mL)/tetrahydrofuran (70 mL), and washed with aqueous sodium hydrogen carbonate solution (70 mL) and saturated brine (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20→0/100) to give the title compound (829 mg, 20%) as a violet powder.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH3:7])[C:2]=1[CH3:8].[Br:9]Br.[OH-].[Na+]>S(=O)(=O)(O)O>[Br:9][C:5]1[CH:4]=[C:3]([CH3:7])[C:2]([CH3:8])=[N:1][CH:6]=1
Reactant: Cc1cccnc1C
Reactant: BrBr
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(Br)cnc1C
Temperature: 155 °C

Procedure:
To a solution of 2,3-lutidine (0.51 mL) in fuming sulfuric acid (10 mL) at 155° C. was added bromine (0.3 mL) dropwise over 2 h. The reaction mixture was then heated at 155° C. for 16 h. After cooling to room temperature, the mixture was poured onto ice and the ph adjusted to 10 with aqueous sodium hydroxide solution. The product was extracted into ethylacetate (3×40 mL) and the organic layers were dried (MgSO4), reduced in vacuo and purified on silica to give 5-bromo-2,3-dimethyl-pyridine as a yellow oil.
Reaction SMILES: P([O-])(O)(O)=O.[Na+].Cl([O-])=O.[Na+].[OH:11]O.[CH3:13][O:14][C:15]1[C:16]([CH3:44])=[C:17]([C:35]([O:42][CH3:43])=[C:36]([O:40][CH3:41])[C:37]=1[O:38][CH3:39])[CH2:18][C:19]1[C:24]([CH:25]=[O:26])=[C:23]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:22]=[CH:21][CH:20]=1>O.C(#N)C>[CH3:13][O:14][C:15]1[C:16]([CH3:44])=[C:17]([C:35]([O:42][CH3:43])=[C:36]([O:40][CH3:41])[C:37]=1[O:38][CH3:39])[CH2:18][C:19]1[C:24]([C:25]([OH:11])=[O:26])=[C:23]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: COc1c(C)c(Cc2cccc(OCc3ccccc3)c2C=O)c(OC)c(OC)c1OC
Reactant: OO
Agent: O=P([O-])(O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC#N
Solvent: O
Product: COc1c(C)c(Cc2cccc(OCc3ccccc3)c2C(=O)O)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 91 %

Procedure:
An aqueous solution (1 ml) of sodium dihydrogenphosphate (24 mg, 0.20 mmol), an aqueous solution (3.5 ml) of sodium chlorite (123 mg, 80%, 1.09 mmol) and aqueous hydrogen peroxide (0.08 ml, 30%) were added to an acetonitrile solution (2.5 ml) of 6-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-benzyloxybenzaldehyde (112 mg, 0.26 mmol) and the resulting solution was stirred at room temperature for 16 hours. The reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with an aqueous 10% sodium hydrosulfite (Na2S2O4) solution and saturated brine, then dried and concentrated to obtain the titled compound (106 mg, 0.23 mmol, 91%).
Reaction SMILES: [NH:1]1[C:5]2=[N+:6]([O-:10])[CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.S(=O)(=O)(O)O.O.[N+:17]([O-])([OH:19])=[O:18]>>[N+:17]([C:9]1[CH:8]=[CH:7][N+:6]([O-:10])=[C:5]2[NH:1][CH:2]=[CH:3][C:4]=12)([O-:19])=[O:18]
Reactant: [O-][n+]1cccc2cc[nH]c21
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=[N+]([O-])c1cc[n+]([O-])c2[nH]ccc12
Temperature: 70 °C

Procedure:
4-Nitro-1H-pyrrolo[2,3-b]pyridine 7-oxide 508 is prepared by dissolving 1H-Pyrrolo[2,3-b]pyridine 7-oxide 507 in nitric acid, followed by the addition of sulfuric acid. Heating (e.g. 70° C.) for one hour, followed by pouring into water provides compound 508, which is isolated by filtration. (Schneller et. al., J. Org. Chem. 1980, 45:4045)
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[N:6]=[N:5][N:4]=1.FC(F)(F)[C:19](O)=[O:20].C1N2CN3CN(C2)CN1C3.OS(O)(=O)=O>O>[OH:14][C:11]1[CH:10]=[CH:9][C:8]([N:7]2[C:3]([C:2]([F:1])([F:15])[F:16])=[N:4][N:5]=[N:6]2)=[CH:13][C:12]=1[CH:19]=[O:20]
Reactant: O=C(O)C(F)(F)F
Reactant: Oc1ccc(-n2nnnc2C(F)(F)F)cc1
Agent: C1N2CN3CN1CN(C2)C3
Agent: O=S(=O)(O)O
Solvent: O
Product: O=Cc1cc(-n2nnnc2C(F)(F)F)ccc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.4 %

Procedure:
To a 2 L nitrogen purged round bottom flask fitted with a condenser was charged 67.7 g (0.29 mol) of 4-(5-trifluoromethyl-tetrazol-1-yl)-phenol, 540 mL trifluoroacetic acid, and 86.3 g (0.62 mol, 2.1 eq) of hexamethylenetetramine. The solution was heated to reflux and refluxed for 4 h. An additional 10 g (0.07 mol, 0.24 equiv) of hexamethylenetetramine was added and the solution refluxed overnight. The reaction was cooled and poured slowly into 3 L of 1N H2SO4. The suspension was diluted with an additional 500 mL of water and aged at room temperature for 30 min and at 0° C. and for additional 30 min. The yellow suspension was filtered and the cake washed with water until the filtrate was neutral. The cake was dissolved in methylene chloride and filtered through 300 g of Silica Gel 60 (70-230 mesh) and flushed with 6 L of methylene chloride. The solvent was removed in vacuo and the residue flushed with hexanes. The resulting slurry was cooled to room temperature and filtered. The white crystalline product that was obtained was dried yielding 50.4 g (66.4% yield) of the title compound. An additional 6.9 g (9.1%, for a combined yield of 57.3 g, 75.5% yield) was obtained by extracting the aqueous filtrate with ether and chromatographing (Silica Gel 60, methylene chloride): 1H NMR (CDCI3) δ 7.23 (d, J=9 Hz, 1H), 7.62 (dd, J=9, 2 Hz, 1H), 7.73 (d, J=2.5 Hz, 1H), 9.96 (s, 1H). MS (EI) m/z 258. Anal. Calcd for C9H5F3N4O2: C, 41.87; H, 1.95; F, 22.08; N, 21.70. Found: C, 41.87; H, 1.98; F, 22.61; N, 21.74.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2O.O=P(Cl)(Cl)[Cl:15]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[Cl:15]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncnc2ccc(Br)cc12
Product: Clc1ncnc2ccc(Br)cc12
Temperature: 110 °C

Procedure:
A solution of 6-bromoquinazolin-4-ol (1.0 g, 4.44 mmol) in POCl3 (10 mL) was stirred and heated at 110° C. in a sealed tube overnight. The solution was cooled to room temperature and poured onto ice (200 g.) The solution was extracted with DCM (300 mL), washed with water (200 mL), dried over Na2SO4 and concentrated in vacuo to give the impure 6-bromo-4-chloroquinazoline as a brown solid that was not purified further (1.5 g.) MS (APCI+) [M+H]+ 243.1.
Reaction SMILES: [CH2:1]([N:8]1[CH2:26][CH2:25][C:11]2[N:12]=[C:13]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)[N:14]=[C:15]([OH:16])[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:27][C:28]([F:38])([F:37])[C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=1>>[CH2:1]([N:8]1[CH2:26][CH2:25][C:11]2[N:12]=[C:13]([C:17]3[CH:18]=[C:19]([Cl:24])[CH:20]=[C:21]([Cl:23])[CH:22]=3)[N:14]=[C:15]([O:16][CH2:33][C:32]3[CH:31]=[CH:30][C:29]([C:28]([F:27])([F:37])[F:38])=[CH:36][CH:35]=3)[C:10]=2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: Oc1nc(-c2cc(Cl)cc(Cl)c2)nc2c1CN(Cc1ccccc1)CC2
Product: FC(F)(F)c1ccc(COc2nc(-c3cc(Cl)cc(Cl)c3)nc3c2CN(Cc2ccccc2)CC3)cc1

Procedure:
The title compound was prepared from 6-benzyl-2-(3,5-dichloro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ol (which was obtained in Intermediate 7) and 4-(trifluoromethyl)benzyl bromide according to Method A; LC retention time 3.49 min; MS: m/z (ESI) 544 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1.[CH3:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[CH3:21])[CH:16]=O.Cl.O>CO>[CH3:12][C:13]1[CH:14]=[C:15]([CH:16]=[C:7]2[C:6](=[O:9])[C:5]3[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][C:4]=3[O:8]2)[CH:18]=[CH:19][C:20]=1[CH3:21]
Reactant: Cc1ccc(C=O)cc1C
Reactant: O=C1COc2cc(O)ccc21
Agent: Cl
Solvent: CO
Solvent: O
Product: Cc1ccc(C=C2Oc3cc(O)ccc3C2=O)cc1C
Temperature: 25 °C
Yield: 68.2 %

Procedure:
After 6-hydroxy-2H-benzofuran-3-one 1 g and 3,4-dimethylbenzaldehyde 1.07 g were dissolved in methanol 75 ml, concentrated hydrochloric acid 50 ml was added, and the mixture was refluxed for two hours. The solution was cooled to room temperature, and water 200 ml was added. Precipitated crystals were filtered and dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 1.21 g.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:13])([CH3:12])[C:10]#[N:11])=[CH:5][CH:4]=1)=[O:2].[N+:14]([CH:16](S(C1C=CC(C)=CC=1)(=O)=O)[CH3:17])#[C-:15].C([O-])([O-])=O.[K+].[K+]>CO>[CH3:12][C:9]([C:6]1[CH:7]=[CH:8][C:3]([C:1]2[O:2][CH:15]=[N:14][C:16]=2[CH3:17])=[CH:4][CH:5]=1)([CH3:13])[C:10]#[N:11]
Reactant: [C-]#[N+]C(C)S(=O)(=O)c1ccc(C)cc1
Reactant: CC(C)(C#N)c1ccc(C=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cc1ncoc1-c1ccc(C(C)(C)C#N)cc1
Temperature: 25 °C
Yield: 80.5 %

Procedure:
A mixture of Example 35B (2.24 g, 12.9 mmol), 1-(1-isocyanoethylsulfonyl)-4-methylbenzene (2.71 g, 12.9 mmol), and K2CO3 (2.15 g, 15.5 mmol) in MeOH (60 mL) was heated at reflux for 2 hr. The reaction was cooled to ambient temperature, and the volatiles removed at reduced pressure. The residue was partitioned between H2O and Et2O. The separated aqueous phase was extracted with Et2O, and the combined organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. Flash chromatography (Analogix® Intelliflash 280™; 15% to 40% EtOAc/hexanes eluant; SF40-150 g column) yielded 2.35 g (80%) of the title compound as a colorless oil. 1H NMR (300 MHz, DMSO-d6) δ 8.35 (s, 1H), 7.71-7.61 (m, 4H), 2.37 (s, 3H), 1.71 (s, 6H). MS (DCI+) m/z 227 (M+H).
Reaction SMILES: [F:1][C:2]([F:32])([O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]#[C:26][CH2:27][CH2:28][CH2:29][CH2:30][OH:31])=[CH:21][CH:20]=1)[C:3]1[C:8]([F:9])=[CH:7][C:6]([C:10]#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])=[CH:5][C:4]=1[F:17]>C1COCC1>[F:32][C:2]([F:1])([O:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][OH:31])=[CH:23][CH:24]=1)[C:3]1[C:4]([F:17])=[CH:5][C:6]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])=[CH:7][C:8]=1[F:9]
Reactant: OCCCCC#Cc1ccc(OC(F)(F)c2c(F)cc(C#CCCCCO)cc2F)cc1
Solvent: C1CCOC1
Product: OCCCCCCc1ccc(OC(F)(F)c2c(F)cc(CCCCCCO)cc2F)cc1

Procedure:
6-(4-{Difluoro-[4-(6-hydroxyhex-1-ynyl)phenoxy]methyl}-3,5-difluorophenyl)hex-5-yn-1-ol is hydrogenated to completion on palladium/active carbon catalystin THF. The catalyst is filtered off, the solvent is removed in vacuo, and the crude product is chromatographed on silica gel with toluene/ethyl acetate (1:2), giving 6-(4-{difluoro-[4-(6-hydroxyhexyl)phenoxy]methyl}-3,5-difluorophenyl)hexan-1-ol as a colourless solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH3:12])=[C:10]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:17]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:12][C:11]1[C:2]([Cl:1])=[C:3]([CH:8]=[CH:9][C:10]=1[S:13]([CH3:16])(=[O:15])=[O:14])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(C)c1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(S(C)(=O)=O)c(CBr)c1Cl

Procedure:
44.14 g (0.17 mol) of methyl 2-chloro-3-methyl-4-methylsulfonylbenzoate were dissolved in 600 ml of carbon tetrachloride and treated with 29.91 g (0.17 mol) of N-bromosuccinimide and 0.41 g of dibenzoyl peroxide. The mixture was then refluxed and illuminated with a 300 W lamp. The reaction mixture was filtered, the filtrate was concentrated and the residue was taken up in diethyl ether. The solution was treated with n-heptane, and the precipitated solid was filtered off with suction and dried.
Reaction SMILES: [S:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1.C([Li])CCC.[B:15](OC(C)C)([O:20]C(C)C)[O:16]C(C)C.P(=O)(O)(O)O>O.CCOCC>[S:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[C:2]1[B:15]([OH:20])[OH:16]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: c1cc2sccc2cn1
Agent: O=P(O)(O)O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: OB(O)c1cc2cnccc2s1
Temperature: -44 °C
Reaction time: 1 h

Procedure:
A three neck flask fitted with an internal thermometer containing thieno[3,2-c]pyridine (5.0 g, 37 mmol, 1 equivalent) was evacuated and then filled with a nitrogen gas atmosphere. THF (60 mL) was added and the solution was cooled to −44° C. (CH3CN/dry ice). n-Butyllithium (1.6M/hexane, 25 mL, 41 mmol, 1.1 equivalents) was added over 10 minutes, while maintaining the internal temperature at or below −33° C. The reaction was stirred at −33 to −45° C. for 60 minutes. Triisopropyl borate (10.2 mL, 44 mmol, 1.2 equivalents) was added and the cooling bath removed. The reaction was allowed to proceed for 105 minutes. Then 3.0 mL phosphoric acid (85% aqueous, 3.0 mL, 44 mmol, 1.2 equivalents) was added. A yellow solid formed, which was diluted with water and Et2O (about 150 mL each). A yellow solid was collected by filtration and was dried by suction overnight (5.05 g). Analytical Data: 1H NMR (400 MHz, METHANOL-d4) β ppm 7.95 (1H, s), 8.09 (1H, d, J=5.9 Hz), 8.34 (1H, d, J=6.1 Hz), 9.09 (1H, s). MS (APCI, M+1) 180.1. Microanalysis for C7H6BNSO2.H3PO4: calculated C, 30.35; H, 3.27; N, 5.06; P, 11.18. Found: C, 41.12; H, 3.19; N, 6.53; P, 0.68%.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([NH2:13])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-:3])=[O:2].[CH2:14](Cl)Cl.CO>O=S(Cl)Cl>[N+:1]([C:4]1[CH:12]=[C:11]([NH2:13])[CH:10]=[CH:9][C:5]=1[C:6]([O:8][CH3:14])=[O:7])([O-:3])=[O:2]
Reactant: Nc1ccc(C(=O)O)c([N+](=O)[O-])c1
Reactant: ClCCl
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(N)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Nitro-4-aminobenzoic acid (261 mg, 1.43 mmol) was dissolved in 1 ml of SOCl2. The solution was refluxed for 1 hour. Excess SOCl2 was removed under reduced pressure and 5 ml of CH2Cl2, 1 ml of MeOH and TEA (0.24 ml, 1.7 mmol) were added to the residue. The reaction mixture was stirred at room temperature for 2 hours. Excess MeOH and TEA were removed and the residue was purified by column chromatography with ethyl acetate/hexane (1/3) to yield the title compound as a yellow solid (316 mg). 1H NMR δ 7.69 (d, J=8.5 Hz, 1H), 6.85 (d, J=2.2 Hz, 1H), 6.67 (dd, J=8.3; 2.1 Hz, 1H), 4.31 (b, 2H), 3.94 (s, 3H).
Reaction SMILES: C([N:8]1[C@@H:13]([CH:14]=[CH:15][CH3:16])[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH3:17])(OC(C)(C)C)=O>FC(F)(F)C(O)=O.ClCCl>[CH3:17][C@H:9]1[CH2:10][CH2:11][CH2:12][C@H:13]([CH:14]=[CH:15][CH3:16])[NH:8]1
Reactant: CC=C[C@H]1CCC[C@H](C)N1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC=C[C@H]1CCC[C@H](C)N1

Procedure:
To a stirred solution of trans-N-Boc-2-methyl-6-(1-propenyl)piperidine (1.80 g, 7.65 mmol) in 15% trifloroacetic acid (38 mL) in dichloromethane was stirred for 2 h at room temperature, and the reaction mixture was quenched with 90 mL saturated NaHCO3 solution. The mixture was extracted with ether *5 and the combined extracts were dried over K2CO3 and then concentrated to give trans-2-methyl-6-(1-propenyl)piperidine as an oil. The crude oil was immediately dissolved in a small amount of ether, and ether saturated with HCl (g) was added slowly via pipette. This solution was allowed to stand for 10 minutes, and the solvent was evaporated. More ether was added and the flask was swirled constantly until crystallization occured. The solid was collected via filtration, and dried in vacuo to give the piperidinium hydrochloride as a white solid that was homogeneous by TLC analysis. mp 139.5-141.1° C.; 1H NMR (250 MHz) δ9.39 (s, 2H), 5.84-5.86 (m, 2H), 4.23 (s, 1H), 3.54 (s, 1H), 1.9-1.44 (m, 12H); 13C NMR (62.7 MHz) 131 (s), 123 (s), 48 (s), 28.5 (s), 28 (s), 17.6 (s), 17.1 (s), 13.7 (s) ppm. FT-IR (neat ): 3420, 3020, 2944, 1588, 1459, 1434, 1386, 821, 816, 804. Elemental Analysis for C9H18NCl: C, 61.52%; H, 10.35%; N, 7.97%. Found: C, 61.44%; H, 10.29%; N, 7.88%.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([CH3:16])[CH2:13][CH:14]=O)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].[C:17]([O:21][C:22]([N:24]1[CH2:31][CH:30]2[O:32][CH:26]([CH2:27][NH:28][CH2:29]2)[CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].C(O)(=O)C.[BH3-]C#N.[Na+]>ClCCl>[C:17]([O:21][C:22]([N:24]1[CH2:25][CH:26]2[O:32][CH:30]([CH2:29][N:28]([CH2:14][CH2:13][N:12]([S:9]([C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)(=[O:11])=[O:10])[CH3:16])[CH2:27]2)[CH2:31]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CC2CNCC(C1)O2
Reactant: CN(CC=O)S(=O)(=O)c1ccc(C#N)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN(CCN1CC2CN(C(=O)OC(C)(C)C)CC(C1)O2)S(=O)(=O)c1ccc(C#N)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A mixture of step (ii) product 4-Cyano-N-methyl-N-(2-oxo-ethyl)-benzenesulfonamide (4.97 g), and 9-oxa-3,7-diaza-bicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester (4.95 g; see WO 01/28992) and acetic acid (1.7 ml) in dry dichloromethane (50 ml) was stirred at RT for 3 h and then cooled to 0° C. NaBH3CN (1.96 g, 0.0312 mol) was added and stirring continued at RT overnight under nitrogen atmosphere. The reaction mixture was quenched with water, extracted with dichloromethane, washed with water and brine and dried over sodium sulfate. Solvent evaporated under reduced pressure and the residue was purified by column chromatography over silica gel using 28% ethyl acetate in petroleum ether eluent to give the sub-title compound (2.2 g) as a liquid.