Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH:10]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[CH2:11]>CCCCCC>[Cl:8][C:6]1[CH:7]=[C:2](/[CH:11]=[CH:10]/[CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:3]([NH2:9])=[N:4][CH:5]=1
Reactant: Nc1ncc(Cl)cc1Br
Reactant: C=CC1CCCCC1
Solvent: CCCCCC
Product: Nc1ncc(Cl)cc1/C=C/C1CCCCC1

Procedure:
The title compound was prepared from 3-bromo-5-chloro-2-pyridinamine and vinylcyclohexane. Purification by column chromatography on silica gel eluting with hexane—EtOAc (80:20) gave a pale yellow oil. An analytical sample was prepared by crystallisation from hexane:
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][CH2:14][C:15]1([C:29]([O:31]CC)=[O:30])[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][S:23][C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)[CH2:17][CH2:16]1)=[CH:9][C:8]([O:34][CH3:35])=[CH:7][CH:6]=2.Cl>O1CCOCC1>[F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][CH2:14][C:15]1([C:29]([OH:31])=[O:30])[CH2:16][CH2:17][N:18]([CH2:21][CH2:22][S:23][C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)[CH2:19][CH2:20]1)=[CH:9][C:8]([O:34][CH3:35])=[CH:7][CH:6]=2
Reactant: CCOC(=O)C1(CCCc2c(F)cnc3ccc(OC)cc23)CCN(CCSc2cccs2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc2ncc(F)c(CCCC3(C(=O)O)CCN(CCSc4cccs4)CC3)c2c1
Temperature: 100 °C
Reaction time: 20 h
Yield: 68.7 %

Procedure:
A mixture of 0.4 g of ethyl 4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(thien-2-yl)thioethyl]-piperidine-4-carboxylate in 5 cm3 of aqueous 5N hydrochloric acid and 3 cm3 of dioxane was maintained at a temperature in t h e region of 100° C. with stirring and under an inert atmosphere for 20 hours. After cooling to about 20° C., the reaction mixture was concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The mixture was filtered and then chromatographed, under atmospheric pressure, on a column of silica gel (particle size 40-63μ; diameter 1.5 cm; mass 55 g), eluting with a mixture of chloroform/methanol/aqueous ammonia (12/3/0.5 by volume) and collecting 15-cm3 fractions. Fractions 5 to 12 were combined and then concentrated to dryness under the above conditions. 0.26 g of 4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(thien-2-yl)thioethyl]piperidine-4-carboxylic acid was obtained in the form of a white crystalline solid melting at 180° C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18](O)=[O:19])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH3:23][O:24][CH2:25][CH2:26][NH:27][CH3:28]>>[CH3:23][O:24][CH2:25][CH2:26][N:27]([CH3:28])[C:18]([C:12]1[S:13][C:14]2[CH2:15][CH2:16][O:17][C:8]3[CH:7]=[C:6]([C:4]4[CH:3]=[N:2][NH:1][CH:5]=4)[CH:22]=[CH:21][C:9]=3[C:10]=2[N:11]=1)=[O:19]
Reactant: CNCCOC
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Product: COCCN(C)C(=O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with 2-methoxy-N-methylethanamine (1.2 equiv) to give 182 (15.1 mg, M+1 385.1)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[NH2:19][C:20]1[CH:21]=[C:22]([CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH:23]=[CH:24][CH:25]=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([C:7]([NH:19][C:20]2[CH:21]=[C:22]([CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH:23]=[CH:24][CH:25]=2)=[O:9])[CH:10]=1
Reactant: O=C(O)c1cc(Cl)ccc1OCc1ccccc1
Reactant: COC(=O)Cc1cccc(N)c1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Cc1cccc(NC(=O)c2cc(Cl)ccc2OCc2ccccc2)c1
Temperature: 60 °C

Procedure:
A mixture of 5-chloro-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 45; 50 mg, 0.19 mmol), methyl (3-aminophenyl)acetate (may be prepared as described in Description 44; 48 mg, 0.29 mmol), EDAC (56 mg, 0.29 mmol), and dichloromethane (3 ml) was heated in the microwave at 60° C. for 40 minutes. DIPEA (53 μl, 0.3 mmol) was added and the mixture was heated at 60° C. in the microwave for another 20 minutes. The reaction mixture was purified by SCX cartridge, eluting with methanol. The fractions were combined and evaporated to give the title compound as an off-white solid. 35 mg.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]2[O:16][C:17]([CH3:20])=[CH:18][N:19]=2)[CH:12]=[C:11]([O:21]C)[C:10]=1[C:23]1[S:27][C:26]([N:28]([CH3:39])[CH:29]2[CH2:34][C:33]([CH3:36])([CH3:35])[NH:32][C:31]([CH3:38])([CH3:37])[CH2:30]2)=[N:25][N:24]=1)C1C=CC=CC=1.CCOC(C)=O>[Pd].CO>[CH3:1][O:8][C:9]1[C:10]([C:23]2[S:27][C:26]([N:28]([CH3:39])[CH:29]3[CH2:34][C:33]([CH3:35])([CH3:36])[NH:32][C:31]([CH3:38])([CH3:37])[CH2:30]3)=[N:25][N:24]=2)=[C:11]([OH:21])[CH:12]=[C:13]([C:15]2[O:16][C:17]([CH3:20])=[CH:18][N:19]=2)[CH:14]=1
Reactant: COc1cc(-c2ncc(C)o2)cc(OCc2ccccc2)c1-c1nnc(N(C)C2CC(C)(C)NC(C)(C)C2)s1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc(-c2ncc(C)o2)cc(O)c1-c1nnc(N(C)C2CC(C)(C)NC(C)(C)C2)s1
Temperature: 25 °C
Reaction time: 72 h
Yield: 37.1 %

Procedure:
A solution of 5-(2-(benzyloxy)-6-methoxy-4-(5-methyloxazol-2-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine (28.9 mg, 0.053 mmol) in 1:1 EtOAc:MeOH (5 mL) was added to a nitrogen flushed flask containing 10% Pd/C (2.9 mg, 10% by weight) and the resulting mixture placed under a hydrogen atmosphere and left to stir at room temperature for 72 hours. The reaction mixture was purged with nitrogen, diluted with EtOAc (10 mL), filtered through celite, then rinsed with EtOAc (50 mL). The filtrate was concentrated in vacuo to afford the crude product as a pale yellow solid. The crude material was purified by preparative HPLC under acidic conditions running a gradient from 20-95% MeCN/water (+0.1% TFA) over 15 minutes. The product containing fractions were loaded directly onto a 1 g SCX cartridge (pre-wet with MeOH) and the cartridge was washed with MeOH (10 mL) then flushed with 7M NH3 in MeOH (10 mL). The MeOH/NH3 was removed in vacuo to afford the title compound as an off-white/pale brown solid (9 mg, 39% yield). LC-MS: Rt 2.08 min; MS m/z 458.4 [M+H]+ [Method B]. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.74 (br. s., 1H), 7.15 (s, 2H), 7.05 (d, J=1.01 Hz, 1H), 4.42-4.33 (m, 1H), 4.04 (s, 3H), 3.03 (s, 3H), 2.41 (d, J=1.01 Hz, 3H), 1.64 (dd, J=11.87, 3.28 Hz, 2H), 1.44 (t, J=12.13 Hz, 2H), 1.22 (s, 6H), 1.09 (s, 6H).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC(=O)[NH:14][C:15]1[C:20]2=[CH:21][N:22]([C:24]3[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:31])[N:23]=[C:19]2[C:18]([F:32])=[CH:17][N:16]=1)(C)(C)C>C(Cl)Cl>[Cl:31][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]([Cl:30])[C:24]=1[N:22]1[CH:21]=[C:20]2[C:15]([NH2:14])=[N:16][CH:17]=[C:18]([F:32])[C:19]2=[N:23]1
Reactant: CC(C)(C)OC(=O)Nc1ncc(F)c2nn(-c3c(Cl)cccc3Cl)cc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncc(F)c2nn(-c3c(Cl)cccc3Cl)cc12
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 76.1 %

Procedure:
TFA (2.0 ml) was added to a mixture of [2-(2,6-dichlorophenyl)-7-fluoro-2H-pyrazolo[4,3-c]pyridin-4-yl]-carbamic acid tert-butyl ester (390 mg, 1 mmol) in DCM (5 mL) and the reaction mixture was stirred at room temperature for 3.5 h. The volatiles were removed under reduced pressure and the resultant residue was dissolved in DCM and washed with saturated aqueous sodium bicarbonate solution (×2) and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound as an off-white solid (226 mg, 74% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.74 (d, J=3.0 Hz, 1H), 7.82-7.78 (m, 2H), 7.72-7.68 (m, 1H), 7.53 (d, J=4.3 Hz, 1H), 6.86 (br s, 2H).
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1.C(OC([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:9]([O:8][C:6]([C:5]1[CH:11]=[CH:12][C:2]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[N:3][CH:4]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(N2CCNCC2)nc1
Temperature: 80 °C
Reaction time: 18 h
Yield: 82.4 %

Procedure:
Ethyl 6-chloronicotinate (1.12 g) was dissolved in DMF (30 mL), and 1-tert-butoxycarbonylpiperazine (1.24 g) and potassium carbonate (1.00 g) were added thereto. The mixture was stirred at 80° C. for 18 hr. Water (100 mL) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogencarbonate solution and brine and dried. The solvent was evaporated under reduced pressure. The residue was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (5 mL) was added thereto at room temperature. The mixture was stirred for 2 hr and the reaction mixture was concentrated under reduced pressure. Water (50 mL) was added to the residue, and the mixture was washed with diethyl ether. The aqueous layer was basified with aqueous sodium hydrogen carbonate solution. The mixture was extracted with chloroform. The extract was dried and the mixture was concentrated under reduced pressure to give 1-(5-ethoxycarbonyl-2-pyridyl)piperazine (1.17 g) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([SH:11])[C:7]=1[C:8]([OH:10])=[O:9].[OH-].[K+].CS([C:18]1[N:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[N:19]=1)(=O)=O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([S:11][C:18]2[N:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[N:19]=2)[C:7]=1[C:8]([OH:10])=[O:9]
Reactant: O=C(O)c1c(S)cccc1Br
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1cc(OC)nc(Sc2cccc(Br)c2C(=O)O)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
7.0 g of 6-bromothiosalicylic acid was dissolved in 20 ml of an aqueous solution of 4.0 g of potassium hydroxide, and then, 6.9 g of 2-methylsulfonyl-4,6-dimethoxypyrimidine and 20 ml of dimethylformamide were added thereto. The mixture was stirred at room temperature for one hour and poured into a large amount of ice water. The aqueous solution was washed with chloroform and then, neutralized with hydrochloric acid. An oily substance thereby released was extracted with diethyl ether. The diethyl ether layer was dried and passed through a FURORIDIL short column. Diethyl ether was distilled off under reduced pressure to obtain 3.9 g of the desired compound as white powder.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:5]=[C:4]([CH3:18])[N:3]=1.[I-:19].[Na+].CNCCNC>O1CCOCC1.[Cu]I>[I:19][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:5]=[C:4]([CH3:18])[N:3]=1
Reactant: [I-]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(Br)n1
Agent: [Cu]I
Agent: CNCCNC
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(I)n1

Procedure:
Alternatively the title compound was prepared from 2-bromo-6-methyl-4-(4-trifluoromethyl-phenyl)-pyridine (example A.48) (101.0 g, 320 mmol), sodium iodide (91.04 g, 608 mmol), copper(I) iodide (2.89 g, 5 mol %) and N,N′-dimethylethylenediamine (3.31 mL, 11 mol %) in dioxane (304 mL) according to the general procedure Ia to d preparation of iodides. Obtained as a light yellow solid (112.5 g, 100%). MS (ISP) 364.0 [(M+H)+]; mp 91-93° C.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[OH:26][C:27]1([CH2:33][C:34](O)=[O:35])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:34](=[O:35])[CH2:33][C:27]5([OH:26])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]5)[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Reactant: O=C(O)CC1(O)CCOCC1
Agent: Cl
Product: O=C(CC1(O)CCOCC1)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (15.7 mg, 48.8%), MS (ISP) m/z=473.5 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (25.0 mg, 0.0681 mmol) and (4-Hydroxy-tetrahydro-pyran-4-yl)-acetic acid.
Reaction SMILES: N.[C:2]([C:6]1[CH:11]=[CH:10][C:9]([C@@H:12]2[CH2:17][CH2:16][C@H:15]([NH2:18])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3]>>[C:2]([C:6]1[CH:11]=[CH:10][C:9]([C@H:12]2[CH2:13][CH2:14][C@H:15]([NH2:18])[CH2:16][CH2:17]2)=[CH:8][CH:7]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1ccc([C@H]2CC[C@@H](N)CC2)cc1
Agent: N
Product: CC(C)(C)c1ccc([C@H]2CC[C@H](N)CC2)cc1

Procedure:
The free base is obtained therefrom by adding aqueous ammonia solution, extracting the mixture with methyl tert-butyl ether, and drying and evaporating the organic phase to give a colorless oil (cis/trans mixture). Characteristic NMR data (CDCl3): cis-4-(4-tertbutylphenyl)cyclohexylamine: δ1-Heq =3.19; γ C-1=45.3 ppm.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])[CH:2]=C.[O:14]=[O+][O-]>C(Cl)Cl>[O:14]=[CH:2][CH2:1][O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9]
Reactant: O=[O+][O-]
Reactant: C=CCOc1cccc(C(=O)O)c1
Solvent: ClCCl
Product: O=CCOc1cccc(C(=O)O)c1
Yield: 93 %

Procedure:
A solution of 300 mg (1.68 mmol) of 3-(2-propenyloxy)benzoic acid in 5 mL of methylene chloride is cooled to -78° C. Ozone is introduced by bubbling the gas into the solution through a glass tube until a blue color persists. The solution is then purged with a stream of argon and 1 mL of methyl sulfide is added. The solution is diluted with 20 mL of ether and washed with water. The organic layer is separated and allowed to stand over magnesium sulfate then concentrated in vacuo to give 283 mg (93%) of 3-(2-oxoethoxy)benzoic acid as a colorless oil. The product is utilized in the next reaction without further purification: m.p. 120°-130°; the 1H NMR (300 MHz, CDCl3) is consistent with the desired product; IR (KBr) 3400, 3000, 1680, 1590 cm-1 ; MS (CI low res) m/e 181 (M+H), 163, 139, 119.
Reaction SMILES: [CH3:1][P:2]([CH2:6][O:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[Cl:25])[CH:11]=[CH:10][C:9]=1[N+:26]([O-:28])=[O:27])(=O)[O:3]C.S(Cl)([Cl:31])=O>>[CH3:1][P:2]([Cl:31])([CH2:6][O:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[Cl:25])[CH:11]=[CH:10][C:9]=1[N+:26]([O-:28])=[O:27])=[O:3]
Reactant: COP(C)(=O)COc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: O=S(Cl)Cl
Product: CP(=O)(Cl)COc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
Following the procedure of Example 4, methyl P-methyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)-phenoxymethylphosphinate is reacted with thionyl chloride to give P-methyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenoxymethylphosphinic chloride.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:15]=2)[C:10](O)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:24])=O>CN(C=O)C>[C:1]1([C:7]2[CH:8]=[C:9]([CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:15]=2)[C:10]([Cl:24])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(-c2ccccc2)cc(-c2ccccc2)c1
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(-c2ccccc2)cc(-c2ccccc2)c1

Procedure:
Preparation in accordance with Organikum [Practical Organic Chemistry], VEB Deutscher Verlag der Wissenschaften, Berlin, 5th Edition, 1965, page 409, by boiling 3,5-bisphenylbenzoic acid [99710-75-5] with 2 equivalents of thionyl chloride with addition of 2 drops of DMF. Yield: quantitative. Purity: >98% according to 1H-NMR.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.CCN(CC)CC.[CH3:23][S:24](Cl)(=[O:26])=[O:25].CCOC(C)=O>C1COCC1.O>[CH3:23][S:24]([O:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Yield: 98.9 %

Procedure:
To a mixture of tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (Aldrich) (4.30 g, 20 mmol) and Et3N (5 mL) in THF (60 mL) at 0° C. was added MeSO2Cl (1.6 mL) dropwise with stirring. After 2.5 h EtOAc (160 mL) and water (50 mL) were added to the reaction mixture, the EtOAc layer was separated, washed with 1N HCl (30 mL), dried over MgSO4, concentrated in vacuo to obtain the product (5.8 g, 98.9%) as a low melting white solid. This material was used directly for the next step without any further purification. 1H NMR (CDCl3) δ 4.20 (m, 2H), 4.04 (d, 2H, J=6.1 Hz), 2.99 (s, 3H), 2.68 (m, 2H), 2.01-1.70 (m, 3H), 1.43 (s, 9H), 1.20 (m, 2H).
Reaction SMILES: C(O)(C(F)(F)F)=O.C[O:9][C:10](=[O:24])[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][C:12]=1[C:20](=O)[CH2:21][Br:22].C([SiH](CC)CC)C>C(Cl)Cl>[Br:22][CH2:21][CH:20]1[C:12]2[C:11](=[C:16]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:14][CH:13]=2)[C:10](=[O:9])[O:24]1
Reactant: COC(=O)c1c(C(=O)CBr)cccc1[N+](=O)[O-]
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1OC(CBr)c2cccc([N+](=O)[O-])c21
Temperature: 70 °C
Reaction time: 48 h

Procedure:
TFA (50 mL) was added to a mixture of 2-(2-bromo-acetyl)-6-nitro-benzoic acid methyl ester (3.47 g, 11.5 mmol, Step D) and 20 mL of triethylsilane in 70 mL of anhydrous CH2Cl2. The mixture was stirred at 70° C. for 48 h, the volatiles were removed under reduced pressure, and hexanes were added to the residue. The titled compound was collected by filtration as an off-white solid.
Reaction SMILES: [BH4-].[Na+].[O:3]=[C:4]1[CH2:10][CH:9]2[N:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:6]([CH2:7][CH2:8]2)[CH2:5]1>C(O)C>[OH:3][CH:4]1[CH2:5][CH:6]2[N:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:9]([CH2:8][CH2:7]2)[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(=O)C2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1C2CCC1CC(O)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
Sodium borohydride (178 mg, 4.7 mmol) was added to a solution of tert-butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (0.50 g, 2.2 mmol) in ethanol (10 mL), and the resulting mixture was stirred at room temperature for one hour. The mixture was quenched with saturated ammonium chloride solution (30 mL), and extracted with ethyl acetate (3×20 mL). The combined extract was washed with water then brine, dried over sodium sulfate, filtered and concentrated to give tert-butyl 3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate (463 mg, 92% yield) as a mixture of endo and exo stereoisomers. GC-MS (EI) for C12H21NO3: 227 (M+).
Reaction SMILES: [Mg].[CH2:2](Br)[CH2:3][CH:4]([CH3:6])[CH3:5].[Br:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[C:11](F)[CH:10]=1.Cl>O1CCCC1.O>[Br:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[C:11]([CH2:2][CH2:3][CH:4]([CH3:6])[CH3:5])[CH:10]=1
Reactant: CC(C)CCBr
Reactant: O=C(O)c1ccc(Br)cc1F
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CCc1cc(Br)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.6 %

Procedure:
To a mixture of magnesium (1.61 g) in tetrahydrofuran (10 ml) was added a solution of isoamyl bromide (5.0 g) in tetrahydrofuran (23 ml) dropwise at room temperature under nitrogen, and the mixture was refluxed for 0.5 hour and cooled to room temperature. The mixture was transferred via a syringe to a solution of 4-bromo-2-fluorobenzoic acid (2.5 g) in tetrahydrofuran (15 ml) at 4-10° C. The resulting mixture was stirred at room temperature for 16 hours. To the reaction mixture was added water (200 ml) dropwise with ice-cooling. The aqueous solution was acidified with 6N aqueous hydrochloride solution and extracted with ethyl acetate (150 ml×2). The combined organic layers were washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform/methanol=10/1) to give 4-bromo-2-(3-methylbutyl)benzoic acid (1.35 g).
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][C:14]=3[C:21]3C(OC)=NC=[CH:25][CH:26]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C12(C[O:40]C3C=CC(C#N)=CC=3C3CC3)CC3CC(CC(C3)C1)C2>>[C:1]12([CH2:11][O:12][C:13]3[CH:20]=[CH:19][C:16]([C:17]([NH2:18])=[O:40])=[CH:15][C:14]=3[CH:21]3[CH2:26][CH2:25]3)[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: COc1ncccc1-c1cc(C#N)ccc1OCC12CC3CC(CC(C3)C1)C2
Reactant: N#Cc1ccc(OCC23CC4CC(CC(C4)C2)C3)c(C2CC2)c1
Product: NC(=O)c1ccc(OCC23CC4CC(CC(C4)C2)C3)c(C2CC2)c1

Procedure:
Following the procedure as described in Example 38 step 3 and making variations as required to replace 4-(adamantan-1-ylmethoxy)-3-(2-methoxypyridin-3-yl)benzonitrile with 4-(adamantan-1-ylmethoxy)-3-cyclopropylbenzonitrile, the title compound was obtained as a colorless solid (0.48 g, 97%): 1H NMR (300 MHz, CDCl3) δ 7.57-7.53 (m, 1H), 7.37-7.35 (m, 1H), 6.81-6.76 (m, 1H), 5.69 (br s, 2H), 3.55 (s, 2H), 2.19-2.09 (m, 1H), 2.04 (br s, 3H), 1.90-1.67 (m, 12H), 0.98-0.91 (m, 2H), 0.73-0.66 (m, 2H); MS (ES+) m/z: 326.2 (M+1).
Reaction SMILES: [NH:1]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:22][C:23]([CH3:29])([CH3:28])[CH2:24][C:25](Cl)=[O:26]>>[CH3:22][C:23]([CH3:29])([CH3:28])[CH2:24][C:25]([N:1]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:26]
Reactant: C1COCCOCCOCCOCCOCCOCCN1
Reactant: CC(C)(C)CC(=O)Cl
Product: CC(C)(C)CC(=O)N1CCOCCOCCOCCOCCOCCOCC1

Procedure:
Analogously to Example 14 from 1-aza-4,7,10,13,16,19-hexaoxacycloheneicosane and 3,3-dimethylbutyryl chloride.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:5]([OH:7])=[O:6].[CH2:12](O)[CH3:13]>S(=O)(=O)(O)O.C(OCC)C.O>[CH2:12]([O:6][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([CH3:11])[CH:10]=[C:2]([Br:1])[CH:3]=1)[CH3:13]
Reactant: Cc1cc(Br)cc(C(=O)O)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)c1cc(C)cc(Br)c1
Temperature: 90 °C
Yield: 94 %

Procedure:
Sulphuric acid (10 drops) was added to 3-bromo-5-methylbenzoic acid (1.18 g, 5.49 mmol) in ethanol (20 ml) and refluxed at 90° C. for 20 hours. After cooling, the mixture was diluted with diethyl ether/water and the organic phase washed with sodium hydrogen bicarbonate (saturated solution), dried (magnesium sulphate) and evaporated to dryness to give the title compound as a pale yellow oil (1.249 g, 94%).