Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=CC(C2C(COC3C=CC(Cl)=CN=3)CCN(C(C3C=CC(C4ON=C(C)N=4)=CC=3)=O)C2)=CC=1.[Cl:37][C:38]1[CH:43]=[CH:42][C:41]([C@@H:44]2[C@@H:49]([CH:50]([NH:52][C:53]3[CH:60]=[CH:59][C:56]([C:57]#[N:58])=[CH:55][N:54]=3)[CH3:51])[CH2:48][CH2:47][NH:46][CH2:45]2)=[CH:40][CH:39]=1.[C:61]([C:63]1[CH:64]=[CH:65][C:66]([N:69]2[CH2:74][CH2:73][CH:72]([C:75](O)=[O:76])[CH2:71][CH2:70]2)=[N:67][CH:68]=1)#[N:62]>>[Cl:37][C:38]1[CH:43]=[CH:42][C:41]([C@@H:44]2[C@@H:49]([CH:50]([NH:52][C:53]3[CH:60]=[CH:59][C:56]([C:57]#[N:58])=[CH:55][N:54]=3)[CH3:51])[CH2:48][CH2:47][N:46]([C:75]([CH:72]3[CH2:71][CH2:70][N:69]([C:66]4[CH:65]=[CH:64][C:63]([C:61]#[N:62])=[CH:68][N:67]=4)[CH2:74][CH2:73]3)=[O:76])[CH2:45]2)=[CH:40][CH:39]=1
Reactant: N#Cc1ccc(N2CCC(C(=O)O)CC2)nc1
Reactant: CC(Nc1ccc(C#N)cn1)[C@H]1CCNC[C@@H]1c1ccc(Cl)cc1
Agent: Cc1noc(-c2ccc(C(=O)N3CCC(COc4ccc(Cl)cn4)C(c4ccc(Cl)cc4)C3)cc2)n1
Product: CC(Nc1ccc(C#N)cn1)[C@H]1CCN(C(=O)C2CCN(c3ccc(C#N)cn3)CC2)C[C@@H]1c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described for the synthesis of [(3RS, 4RS)-3-(4-chloro-phenyl)-4-(5-chloro-pyridin-2-yloxymethyl)-piperidin-1-yl]-[4-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-methanone (example 1, step i) the title compounds were prepared from 6-{1-[(3S,4S)-3-(4-Chloro-phenyl)-piperidin-4-yl]-ethylamino}-nicotinonitrile and 5′-Cyano-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid (commercially available) with subsequent separation via preparative HPLC on chiral pak AD eluting with heptane/ethanol to yield 4-{(3S,4S)-3-(4-Chloro-phenyl)-4-[(SR)-1-(5-cyano-pyridin-2-ylamino)-ethyl]-piperidine-1-carbonyl}-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carbonitrile as off-white solid. MS (m/e): 554.4 [(M+H)+] and 4-{(3S,45)-3-(4-Chloro-phenyl)-4-[(RS)-1-(5-cyano-pyridin-2-ylamino)-ethyl]-piperidine-1-carbonyl}-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carbonitrile as off-white solid. MS (m/e): 554.4 [(M+H)+]
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([OH:23])=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C.[I:54][C:55]1[CH:61]=[CH:60][C:58]([NH2:59])=[CH:57][CH:56]=1.Cl>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([NH:59][C:58]2[CH:60]=[CH:61][C:55]([I:54])=[CH:56][CH:57]=2)=[O:23])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11]
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Reactant: Nc1ccc(I)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(CC(=O)Nc2ccc(I)cc2)ccc1NC(=O)Nc1ccccc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.2 %

Procedure:
A mixture of 3-methoxy-4-[3-(2-methylphenyl)ureido]phenylacetic acid (2.9 g, Reference Example 31), 1-hydroxybenzotriazole (2.13 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (2.67 g) and diisopropylethylamine (3.6 g) in anhydrous dimethylformamide (30 ml) was treated with 4-iodoaniline (2.43 g). After stirring at ambient temperature for 18 hours the reaction mixture was poured into a mixture of ethyl acetate (50 ml) and hydrochloric acid (50 ml, 1M). The resultant solid was filtered and then washed sequentially with 50 ml portions of saturated aqueous sodium bicarbonate solution, water and diethyl ether. The residue was dried under vacuum to give the title compound (4.05 g) as a light brown solid, m.p. >200° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[CH3:10][S-:11].[Na+].C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1>[CH3:10][S:11][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1
Reactant: N#Cc1ccc(Br)cn1
Reactant: C[S-]
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CSc1ccc(C#N)nc1
Yield: 97.2 %

Procedure:
5-Bromo-pyridine-2-carbonitrile (2.63 g, 13.7 mmol), sodium methanethiolate (1.44 g, 20.5 mmol), potassium carbonate (3.79 g, 27.4 mmol) in NMP (60 ml) were stirred in a sealed flask overnight. The mixture was partitioned between ethyl acetate and water. The organic phase was washed with water several times, brine and dried over sodium sulphate. The solvent was removed in vacuo to afford the title compound as a yellow solid (2.0 g, 99%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]([CH2:9][CH2:10][C:11](=[CH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)[C:12]([OH:14])=[O:13])=[O:8])[CH2:3][CH2:2]1>CO.[H][H].[Pd]>[O:1]1[CH2:6][CH2:5][N:4]([C:7]([CH2:9][CH2:10][CH:11]([CH2:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)[C:12]([OH:14])=[O:13])=[O:8])[CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: O=C(O)C(=Cc1cccc2ccccc12)CCC(=O)N1CCOCC1
Agent: [Pd]
Solvent: CO
Product: O=C(O)C(CCC(=O)N1CCOCC1)Cc1cccc2ccccc12
Yield: 89.1 %

Procedure:
5.0 g (14.8 mmole) of this 4-morpholinocarbonyl-2-(1-naphthylmethylene)butyric acid were dissolved in 50 ml of methanol and hydrogenated in hydrogen at atmospheric pressure in the presence of 1.0 g of a 10% w/w palladium-on-carbon catalyst. The catalyst was then removed by filtration, after which the solvent was removed by distillation under reduced pressure. The residue was triturated with diethyl ether to precipitate crystals, which were collected by filtration to give 4.5 g of 4-morpholinocarbonyl-2-(1-naphthylmethyl)butyric acid, melting at 130°-135° C.
Reaction SMILES: N[CH:2](C1C=CC(OC)=C(OC)C=1)CC(O)=O.[NH2:17][CH:18]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH:30]([CH3:32])[CH3:31])=[C:25]([O:33][CH3:34])[CH:24]=1)[CH2:19][C:20]([OH:22])=[O:21]>>[NH2:17][CH:18]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH:30]([CH3:32])[CH3:31])=[C:25]([O:33][CH3:34])[CH:24]=1)[CH2:19][C:20]([O:22][CH3:2])=[O:21]
Reactant: COc1cc(C(N)CC(=O)O)ccc1OC(C)C
Reactant: COc1ccc(C(N)CC(=O)O)cc1OC
Product: COC(=O)CC(N)c1ccc(OC(C)C)c(OC)c1

Procedure:
The title compound was prepared following the method for preparing Intermediate 6 except that 3-amino-3-(3,4-dimethoxy-phenyl)-propionic acid was substituted with 3-amino-3-(3-methoxy-4-isopropoxy-phenyl)propionic acid. 1H NMR (CDCl3): δ 6.82-6.89 (m, 3H), 4.44-4.51 (m, 1H), 4.35 (t, 1H, J=5 Hz), 3.83 (s, 3H), 3.66 (s, 3H), 2.62 (d, 2H, J=5 Hz), 1.81 (s, 2H), 1.33 (d, 6H, J=5 Hz).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([OH:10])(=O)=[O:8])[CH:2]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:12]>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([Cl:12])(=[O:10])=[O:8])[CH:2]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=S(=O)(O)c1cccnc1
Product: O=S(=O)(Cl)c1cccnc1

Procedure:
A mixture of pyridine-3-sulphonic acid (3.0 g) and PCl5 (7.9 g) was stirred in an oil bath maintained at 150° for 3 hours, in a flask fitted with a reflux condenser. After cooling, the liquid formed set solid. The solid was triturated with xylene (10 cm3) and evaporated at the water pump in an oil-bath maintained at a maximum temperature of 110°, and with a splash-head to reduce frothing. The evaporation was repeated twice more, and the residue was pumped on a rotary evaporator to remove the last traces of xylene. The yellow, semi-crystalline mass (6.87 g) occluded unreacted PCl5.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([N+:8]([O-])=O)[CH:7]=1.[H][H]>CO.[Ni]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:7]=1)[NH2:8]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(Br)ccc1Cl
Agent: [Ni]
Solvent: CO
Product: Nc1cc(Br)ccc1Cl

Procedure:
90 g of 5-bromo-2-chloronitrobenzene were hydrogenated in 500 ml of methanol at room temperature and under normal pressure with Raney-Nickel as catalyst and hydrogen. Colorless crystals, melting point: 47° C.
Reaction SMILES: [CH:1]1([N:6]2[CH:21]=[C:9]3[CH2:10][N:11](C(OC(C)(C)C)=O)[CH2:12][CH2:13][C:8]3=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:22]>O1CCOCC1>[ClH:22].[CH:1]1([N:6]2[CH:21]=[C:9]3[CH2:10][NH:11][CH2:12][CH2:13][C:8]3=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(C3CCCC3)cc2C1
Agent: Cl
Solvent: C1COCCO1
Product: c1c2c(nn1C1CCCC1)CCNC2

Procedure:
To a solution of tert-butyl 2-cyclopentyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (720 g, 2.47 mmol) in dioxane (5 mL) is added 4N HCl in dioxane
Reaction SMILES: C1(C23CCCC2CNCC3)C=CC=CC=1.C(=O)(O)[O-].[Na+].C(Br)C=C.[Br-].[C:26]1([C:32]23[CH2:40][CH2:39][CH2:38][CH:37]2[CH2:36][NH+:35]([CH2:41][CH:42]=[CH2:43])[CH2:34][CH2:33]3)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C)C=O>[C:26]1([C:32]23[CH2:40][CH2:39][CH2:38][CH:37]2[CH2:36][N:35]([CH2:41][CH:42]=[CH2:43])[CH2:34][CH2:33]3)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: C=CC[NH+]1CCC2(c3ccccc3)CCCC2C1
Agent: O=C([O-])O
Agent: [Br-]
Agent: [Na+]
Solvent: C=CCBr
Solvent: CN(C)C=O
Product: C=CCN1CCC2(c3ccccc3)CCCC2C1
Temperature: 25 °C

Procedure:
A solution of 2 g. of 4a-phenyl-2,3,4,4a,5,6,7,7a-octahydro-1H-2-pyrindine in 30 ml. of N,N-dimethylformamide containing 1.23 g. of sodium bicarbonate was stirred at 25° C. while 1.23 g. of 2-propenyl bromide was added in one portion. The reaction mixture was stirred and heated at reflux for four hours. After being cooled to room temperature, the reaction mixture was filtered and concentrated to an oil under reduced pressure. The residual oil was dissolved in 300 ml. of diethyl ether. The ethereal solution was washed with water, dried, and the solvent was then removed by evaporation under reduced pressure, thus providing 4a-phenyl-2-(2-propenyl)-2,3,4,4a,5,6,7,7a-octahydro-1H-2-pyrindine as an oil. The oil so formed was dissolved in 150 ml. of fresh diethyl ether, and hydrogen bromide gas was bubbled through the ethereal solution. The precipitated salt was collected by filtration and recrystallized from diisopropyl ether and isopropanol to afford 1.3 g. of 4a-phenyl-2-(2-propenyl)-2,3,4,4a,5,6,7,7a-octahydro-1H- 2-pyrindinium bromide. M.P. 185°-187° C.
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](OCC)=[O:29])[N:27]=2)[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:33]([O:50][CH2:51][C@@H:52]([NH2:54])[CH3:53])([C:46]([CH3:49])([CH3:48])[CH3:47])([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C[Al](C)C.C(O)(=O)C.C(OCC)(=O)C>C1C=CC=CC=1>[Si:1]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](=[O:29])[NH:54][C@@H:52]([CH3:53])[CH2:51][O:50][Si:33]([C:46]([CH3:48])([CH3:49])[CH3:47])([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:27]=2)[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[C@H](N)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: CCOC(=O)c1csc(N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Agent: C[Al](C)C
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: C[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)NC(=O)c1csc(N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
Subsequently, to a solution of 3-t-butyldiphenylsilyloxy-1-(4-ethoxycarbonyl-1,3-thiazol-2-yl)azetidine (2.0 g, 4.29 mmol) (obtained as described in Reference Example 2(1)) in benzene (100 ml) was added a solution of 0.67M (1S)-2-(t-butyldiphenylsilyloxy)-1-methylethylamine-trimethylaluminium in benzene (12.9 ml) at room temperature under an atmosphere of nitrogen. The mixture was heated under reflux overnight. After checking the completion of the reaction, 10% aqueous acetic acid solution (100 ml) and ethyl acetate (200 ml) were added to the reaction mixture in an ice bath, and the resulting mixture was stirred at room temperature for 1 hour. After adding ethyl acetate thereto, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (6:1→2:1) as the eluant to afford 3-t-butyldiphenylsilyloxy-1-{4-[(1S)-2-(t-butyldiphenylsilyloxy)-1-methylethylcarbamoyl]-1,3-thiazol-2-yl}azetidine (2.77 g, yield 88%) as a pale brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=O)[CH2:24][O:25][C:26]2[C:31]([O:32][CH3:33])=[CH:30][CH:29]=[CH:28][C:27]=2[O:34][CH3:35])=[CH:18][C:17]=1[CH3:37].Cl.[OH-].[Na+]>O1CCCC1>[CH3:33][O:32][C:31]1[CH:30]=[CH:29][CH:28]=[C:27]([O:34][CH3:35])[C:26]=1[O:25][CH2:24][CH2:23][NH:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[C:17]([CH3:37])[CH:18]=1
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)COc4c(OC)cccc4OC)cc3C)c2cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3ccc(NCCOc4c(OC)cccc4OC)cc3C)c2cc1OC
Temperature: 0 °C
Yield: 80.2 %

Procedure:
N1-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-methylphenyl}-2-(2,6-dimethoxyphenoxy)acetamide (200 mg) was dissolved in tetrahydrofuran (10 ml) to prepare a solution. A 1 M solution (1.3 ml) of a borane-tetrahydrofuran complex in tetrahydrofuran was then added to the solution, and the mixture was stirred with heating under reflux for 2 hr. The reaction solution was cooled to 0° C. and was adjusted to pH=1 by the addition of 1 N hydrochloric acid, followed by stirring with heating under reflux for 30 min. The reaction solution was cooled to 0° C., was adjusted to pH=12 by the addition of a 1 N aqueous sodium hydroxide solution, and was extracted with chloroform. After the concentration of the extract, the residue was purified on a column using chloroform/methanol to give the title compound (156 mg, yield 80%).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[Cl:19][C:20]1[CH:21]=[C:22]([C:26]2[O:30][CH:29]=[N:28][C:27]=2[C:31](O)=[O:32])[CH:23]=[CH:24][CH:25]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:31]([C:27]3[N:28]=[CH:29][O:30][C:26]=3[C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([Cl:19])[CH:21]=3)=[O:32])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)c1ncoc1-c1cccc(Cl)c1
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)c3ncoc3-c3cccc(Cl)c3)n2)o1

Procedure:
Following general procedure B followed by T, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-(3-chloro-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 01b: tR=1.0 min; [M+H]+=411.11.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:16]>C(#N)C.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N+:3]=1[O-:16]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1ccc(Cl)[n+]([O-])c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 81 %

Procedure:
Urea hydroperoxid complex (1.19 g, 12.6 mmol) was added to a stirred solution of ethyl 6-chloronicotinate (1.10 g, 6.0 mmol) in acetonitrile (15 mL) at room temperature. This mixture was stirred for 10 min at 0° C. followed by slow addition of an acetonitrile solution (5 mL) of trifluoroacetic anhydride (2.52 g, 12.0 mmol). After the addition the mixture was stirred for 2 h at room temperature. Thereafter, the reaction mixture was diluted with a saturated aqueous NaHCO3 solution and extracted with dichloromethane. The organic phase was dried (Na2SO4) and concentrated to afford 0.98 g (81% yield) of the title compound as a white solid: 1H NMR (DMSO-d6, 400 MHz) δ 8.94 (s, 1H), 7.81 (dd, J=8.4, 1.6 Hz, 1H), 7.60 (d, J=8.4 Hz, 1H), 4.43 (q, J=7.2 Hz, 2H), 1.40 (t, J=7.2 Hz, 3H); MS (EI) m/z 202 and 204 (M++1).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([B:13]2[O:17][C:16]([CH3:19])([CH3:18])[C:15]([CH3:21])([CH3:20])[O:14]2)[CH:8]=[C:9]([O:11]C)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].B(Br)(Br)Br>C(Cl)Cl>[C:1]([C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]([B:13]2[O:14][C:15]([CH3:21])([CH3:20])[C:16]([CH3:19])([CH3:18])[O:17]2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(C(C)(C)C)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)(C)c1cc(O)cc(B2OC(C)(C)C(C)(C)O2)c1
Reaction time: 2 h
Yield: 0.1 %

Procedure:
Compound 14b (290 mg, 1 mol) was dissolved in DCM (25 mL). To the solution was added BBr3 (4 eq) dropwise at 0° C. under N2. The stirred mixture was then allowed to stand at 0° C. for 2 h, after which it was poured carefully dropwise into icewater and extracted with DCM. The organic phase was dried (MgSO4), evaporated and purified by CC to give compound 14c (220 mg, 80%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=1.C1C=CC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.[CH3:45][O:46][C:47]1[CH:52]=[CH:51][C:50]([CH2:53][CH:54]([NH2:56])[CH3:55])=[CH:49][CH:48]=1>CN(C=O)C>[CH3:45][O:46][C:47]1[CH:52]=[CH:51][C:50]([CH2:53][CH:54]([NH:56][C:20]([C:17]2[CH:18]=[CH:19][C:14]([C:3]3[CH:4]=[C:5]([C:8]4[O:9][C:10]([CH3:13])=[N:11][N:12]=4)[CH:6]=[CH:7][C:2]=3[CH3:1])=[CH:15][CH:16]=2)=[O:22])[CH3:55])=[CH:49][CH:48]=1
Reactant: COc1ccc(CC(C)N)cc1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COc1ccc(CC(C)NC(=O)c2ccc(-c3cc(-c4nnc(C)o4)ccc3C)cc2)cc1
Reaction time: 18 h

Procedure:
2′-Methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid (11.3 mg, 0.034 mmol), HOBT (6.0 mg, 0.044 mmol), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (8.0 mg, 0.042 mmol) and 2-(4-methoxyphenyl)-1-methylethylamine (0.34 mmol) were mixed in DMF (0.7 ml) and the reaction left at room temperature for 18 h. The DMF was evaporated under vacuum and the residue partitioned between DCM (0.4 ml) and water (0.4 ml). The organic phase was washed with aqueous sodium hydroxide (0.5M, 0.2 ml) and the DCM evaporated under vacuum. The residue was purified by mass directed HPLC to give N-[2-(4-methoxyphenyl)-1-methylethyl]-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide. LCMS; retention time 3.41 min, MH+ 442.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl.[BH3-]C#N.[Na+]>ClCl.CO.C(O)(=O)C>[ClH:1].[CH2:10]([NH:17][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NCc1ccccc1
Reactant: O=Cc1ccc(Cl)cc1
Agent: Cl
Agent: ClCl
Agent: [BH3-]C#N
Solvent: CO
Solvent: CC(=O)O
Product: Clc1ccc(CNCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 4-chlorobenzaldehyde (1.5 g, 10.7 mmol) dissolved in 40 mL CH2 Cl2 was added benzylamine (1.15g, 10.7 mmol) followed by 1 mL of 6N HCl. The resulting cloudy solution was stirred overnight at room temperature and then concentrated in vacuo to give a white solid. The solid was immediately dissolved in 50 mL of MeOH and the pH of the solution was adjusted to 6 with glacial acetic acid. To this solution was added NaCNBH3 (0.67 g, 10.7 mol), and the resulting clear solution was stirred three hours at room temperature. The mixture was acidified to pH 2 with 6M HCl whereupon a thick white slurry developed. The solid was stirred for 30 minutes and filtered, yielding the title compound as a white solid. 1H NMR δ(DMSO-d6, 300 MHz) δ4.1-4.2 (broad multiplet, 4H), 7.4-7.6 (m, 9H). MS (DCl/NH3) m/e 232 (M+H)+.
Reaction SMILES: [ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@@H:5]3[NH2:12])[CH2:3]1)[CH2:9]2.[S:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[C:15]([C:22](O)=[O:23])=[CH:14]1.N>>[ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@@H:5]3[NH:12][C:22]([C:15]3[C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[S:13][CH:14]=3)=[O:23])[CH2:3]1)[CH2:9]2
Reactant: NC1C2CC3CC1CN(C3)C2
Reactant: O=C(O)c1csc2ccccc12
Agent: Cl
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1csc2ccccc12

Procedure:
Prepared from (4s)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine hydrochloride and 1-benzothiophene-3-carboxylic acid (Maybridge) according to methods A and C; yield 58 mg, 0.17 mmol (56%): 1H NMR (300 MHz, methanol-d4) δ 1.98 (d, J=13 Hz, 2H), 2.20 (s, 1H), 2.36 (d, J=14 Hz, 2H), 2.48 (s, 2H), 3.57 (s, 2H), 3.69 (d, J=2 Hz, 4H), 4.47 (s, 1H), 7.38-7.48 (m, 2H), 7.92-7.96 (m, 1H), 8.27 (s, 1H), 8.27-8.32 (m, 1H); MS (DCI/NH3) m/z 313 (M+H)+; Anal. C18H20N2OS HCl 0.13H2O: C, H, N.
Reaction SMILES: CS(OC(CCCCCCCC)C)(=O)=O.IC1C=C(I)C=C(I)C=1O.C(=O)([O-])[O-].[K+].[K+].[I:32][C:33]1[CH:54]=[C:53]([I:55])[CH:52]=[C:51]([I:56])[C:34]=1[O:35][CH:36]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]CCCCC)[CH3:37]>CN(C=O)C>[I:32][C:33]1[CH:54]=[C:53]([I:55])[CH:52]=[C:51]([I:56])[C:34]=1[O:35][CH:36]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH3:37]
Reactant: CCCCCCCCCCCCCC(C)Oc1c(I)cc(I)cc1I
Agent: CCCCCCCCC(C)OS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: Oc1c(I)cc(I)cc1I
Solvent: CN(C)C=O
Product: CCCCCCCCC(C)Oc1c(I)cc(I)cc1I
Yield: 75.9 %

Procedure:
The 2-methanesulfonyloxydecane (14.8 g, 62.6 mmol), 2,4,6-triiodophenol (29.7 g) 62.9 mmol) and potassium carbonate (8.7 g, 63.0 mmol) were reacted in DMF (210 ml) as per 2-(2,4,6-triiodophenoxy)-pentadecane except at an oil bath temperature of 72° C. for 88 hrs. The reaction was processed as for 2-(2,4,6-triiodophenoxy)-pentadecane to provide a light brown residue. Flash column chromatography (silica, hexanes) provided 2-(2,4,6-triiodophenoxy)-decane (29.1 g, 75.9%) as a white solid. Title Compound: 1H (300 MHz) and 13C (75 MHz) NMR spectra were consistent with the desired structure. Calculated for C16H23I3O: C, 31.40; H, 3.79; I, 62.20. Found: C, 31.50, H, 3.75; I, 62.37.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][CH:3]=1.[CH2:13](Br)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>>[CH2:13]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:11][CH:12]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCBr
Reactant: CCOC(=O)c1ccc(O)cc1
Product: CCCCCCCCOc1ccc(C(=O)O)cc1

Procedure:
Using ethyl p-hydroxybenzoate (36.7 g, 0.22 mol) and n-octyl bromide (50 g, 0.26 mol), the reaction was carried out in the same manner as described in Example 13, (1), and then recrystallized from ethanol to give the title compound as a white micro-needles; yield: 43.0 g (71.6%); mp 100.2°-101.4° C. (the 1st mp), 107.0°-107.6° C. (the 2nd mp).
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:26])([CH3:25])[O:6][CH2:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[N:11]=[C:10]([CH2:16][CH2:17][C:18](OCCCC)=[O:19])[CH:9]=1)([CH3:4])[CH3:3].[H-].[H-].[H-].[H-].[Li+].[Al+3].O>C1COCC1>[CH3:4][C:2]([Si:5]([CH3:26])([CH3:25])[O:6][CH2:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[N:11]=[C:10]([CH2:16][CH2:17][CH2:18][OH:19])[CH:9]=1)([CH3:1])[CH3:3]
Reactant: CCCCOC(=O)CCc1cc(CO[Si](C)(C)C(C)(C)C)cc(OC)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(CO[Si](C)(C)C(C)(C)C)cc(CCCO)n1
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 102.3 %

Procedure:
A solution of butyl 3-[4-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-6-(methyloxy)-2-pyridinyl]propanoate (4.76 g, 12.49 mmol) in THF (120 ml) was treated with LiAlH4 soln (1M in THF, 12.49 ml, 12.49 mmol) at −78° C. The reaction mixture was allowed warm to −20° C. and after stirring at −20° C. for 15 min, the mixture was treated with water (9 ml) and allowed to stir for 1 h before being filtered and evaporated to give a slightly impure product (3.98 g, 102%).