Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@:9]2([OH:17])[O:14][CH2:13][C@@H:12]([CH3:15])[NH:11][C@H:10]2[CH3:16])[CH:5]=[C:6]([F:8])[CH:7]=1.C(N(CC)CC)C.[NH2:25][S:26]([C:29]1[C:30]([Cl:53])=[CH:31][C:32]([NH:46][CH2:47][C:48]2[O:49][CH:50]=[CH:51][CH:52]=2)=[C:33]([CH:45]=1)[C:34]([O:36][CH2:37][CH2:38][CH2:39][C:40]([O:42][CH2:43]Cl)=[O:41])=[O:35])(=[O:28])=[O:27]>C(#N)C>[NH2:25][S:26]([C:29]1[C:30]([Cl:53])=[CH:31][C:32]([NH:46][CH2:47][C:48]2[O:49][CH:50]=[CH:51][CH:52]=2)=[C:33]([CH:45]=1)[C:34]([O:36][CH2:37][CH2:38][CH2:39][C:40]([O:42][CH2:43][N:11]1[C@H:12]([CH3:15])[CH2:13][O:14][C@:9]([C:4]2[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=2)([OH:17])[C@@H:10]1[CH3:16])=[O:41])=[O:35])(=[O:27])=[O:28]
Reactant: C[C@@H]1CO[C@@](O)(c2cc(F)cc(F)c2)[C@H](C)N1
Reactant: NS(=O)(=O)c1cc(C(=O)OCCCC(=O)OCCl)c(NCc2ccco2)cc1Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C[C@@H]1CO[C@@](O)(c2cc(F)cc(F)c2)[C@H](C)N1COC(=O)CCCOC(=O)c1cc(S(N)(=O)=O)c(Cl)cc1NCc1ccco1

Procedure:
A solution of the free base of (2S,3S,5R)-2-(3,5-difluorophenyl)-3,5-dimethyl-2-morpholinol (20a (0.023 mole) (U.S. Pat. No. 5,104,870), triethylamine (0.025 mole) and acetonitrile (30 mL) is stirred with cooling on an ice bath. A solution of chloromethyl 4-(5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoyloxy)butanoate (315) (0.025 mole) in acetonitrile (30 mL) is added dropwise. After the addition is complete, the reaction is heated to reflux for 2 hours. The reaction is cooled, the volatiles removed by spin evaporation, and the residue partitioned between dichloromethane and 5% aqueous sodium bicarbonate. The organic layer is washed with water, and then with a saturated sodium chloride solution. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo to give crude product, which may be purified by column chromatography on silica gel with hexanes/ethyl acetate as eluent. The fractions that contain pure product may be combined and spin evaporated in vacuo to give a solid that may be recrystallized to give (2S,3S,5R)-4-[4-(5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoyloxy)butanoyloxymethyl]-2-(3,5-difluorophenyl)-3,5-dimethyl-2-morpholinol (620). See eg., U.S. Pat. No. 5,104,870 and Sandler, et al., Organic Functional Group Preparations, p. 324 (1968).
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([C:13]3[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=3)=[CH:10][C:9]=2[CH:21]=1)[CH:2]([CH3:4])[CH3:3].C(O)(=O)C.[NH:26]1[CH2:29][CH:28]([C:30]([OH:32])=[O:31])[CH2:27]1.C([BH3-])#N.[Na+]>C(Cl)Cl.CO.CS(C)=O>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([C:13]3[CH:14]=[CH:15][C:16]([CH2:17][N:26]4[CH2:29][CH:28]([C:30]([OH:32])=[O:31])[CH2:27]4)=[CH:19][CH:20]=3)=[CH:10][C:9]=2[CH:21]=1)[CH:2]([CH3:3])[CH3:4]
Reactant: CC(C)Cc1ccc2oc(-c3ccc(C=O)cc3)cc2c1
Reactant: O=C(O)C1CNC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)Cc1ccc2oc(-c3ccc(CN4CC(C(=O)O)C4)cc3)cc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
A mixture of 4-(5-isobutylbenzofuran-2-yl)benzaldehyde (30 mg, 0.11 mmol), acetic acid (10 μL, 0.15 mmol) and azetidine-3-carboxylic acid (16 mg, 0.16 mmol) in DCM/MeOH (1:1, 2 mL) was stirred at room temperature for 1 h. Sodium cyanoborohydride (3.4 mg, 0.054 mmol) was added and the reaction mixture was stirred for 3 h at room temperature. After concentration of solvent under reduced pressure, the resulting residue was dissolved in an aliquot of DMSO and purified by reverse phase preparative HPLC (Phenomenex reverse phase Luna 5μ C18(2) column, 60×21.2 mm ID) to yield the desired final product (25.6 mg, 65% yield) as a colorless film: >95% purity by LCMS, ESI-MS: 364.0 (M+H)+, 1H NMR (400 MHz, CD3OD) δ 7.99 (d, 2H), 7.55 (d, 2H), 7.42 (d, 1H), 7.39 (s, 1H), 7.24 (s, 1H), 7.12 (dd, 1H), 4.44 (s, 2H), 4.33(d, 4H), 3.68 (m, 1H), 2.57 (d, 2H), 1.90 (m, 1H), 0.92 (d, 6H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10](I)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([NH:24][C:21]2[CH:22]=[CH:23][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COc1ccc(N)cc1
Reactant: COC(=O)c1cccc(I)c1C(=O)OC
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(Nc2ccc(OC)cc2)c1C(=O)OC
Yield: 82 %

Procedure:
A mixture of 3-iodophthalic acid dimethyl ester (1.0 g, 3.1 mmol), p-anisidine (0.38 g, 3.1 mmol), Pd2(dba)3 (0.13 g, 0.14 mmol), rac-BINAP (0.058 g, 0.093 mmol), and cesium carbonate (1.4 g, 4.3 mmol), in 6 mL toluene was heated to reflux under nitrogen for 24 hours. The reaction mixture was cooled, diluted with CH2Cl2 (10 mL), and filtered through Celite, and the filter was washed with additional CH2Cl2 (30 mL). The filtrate was evaporated, and the residue was chromatographed using a hexanes-ethyl acetate gradient, eluting 0.80 g of the product at 70:30 hexanes-ethyl acetate, in 82% yield: 1H NMR (CDCl3) δ 3.81 (s, 3H), 3.87 (s, 3H), 3.88 (s, 3H), 6.86-6.96 (m, 3H), 7.05-7.12 (m, 3H), 7.23 (t, J=7.6 Hz, 1H), 8.11 (br, 1H).
Reaction SMILES: [H-].[Na+].Br[CH2:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=1[CH3:13].[S:14]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C@H:15]1[O:23][C@@H:22]([CH3:24])[C@@H:20]([OH:21])[C@@H:18]([OH:19])[C@@H:16]1[OH:17]>CN(C=O)C>[CH3:13][C:6]1[CH:7]=[C:8]([CH3:12])[CH:9]=[C:10]([CH3:11])[C:5]=1[CH2:4][O:17][C@H:16]1[C@H:18]([O:19][CH2:4][C:5]2[C:10]([CH3:11])=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=2[CH3:13])[C@H:20]([O:21][CH2:4][C:5]2[C:10]([CH3:11])=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=2[CH3:13])[C@H:22]([CH3:24])[O:23][C@@H:15]1[S:14][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: C[C@@H]1O[C@H](Sc2ccccc2)[C@@H](O)[C@H](O)[C@@H]1O
Reactant: Cc1cc(C)c(CBr)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C)c(CO[C@@H]2[C@H](OCc3c(C)cc(C)cc3C)[C@H](C)O[C@H](Sc3ccccc3)[C@H]2OCc2c(C)cc(C)cc2C)c(C)c1
Temperature: 0 °C
Reaction time: 21 h

Procedure:
A dry 250 ml flask is filled with 6.6 g (152 mmol) of sodium hydride in mineral oil emulsion (55%). Dry dimethylformamide (10 ml) is added and the mixture is cooled to 0° C. To this mixture bromomethylmesitylene (32.4 g, 152 mmol) in dry DMF (20 ml) is added. Compound of example 9 (10 g, 39 mmol) is dissolved in dry DMF (20 mL) and added very to the above mixture over 40 minutes. After an additional hour the ice-bath is removed and the reaction is stirred at room temperature for 21 hours. Methanol (15 ml) is added to quench and the reaction mixture is stirred for another hour, then it is diluted with ethyl acetate (200 ml) and extracted with sat. NaHCO3 (200 ml), 1N HCl (200 ml), water (200 ml) and brine (200 ml). The title compound is obtained after column chromatography purification and crystallization.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]2[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=2[CH3:25])=[O:16])[C:5]2[C:6]([CH3:14])=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[F:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C(=O)(O)[O-].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH3:25][C:24]1[CH:23]=[C:22]([CH3:26])[NH:21][C:20](=[O:27])[C:19]=1[CH2:18][NH:17][C:15]([C:4]1[C:5]2[C:6]([CH3:14])=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=[C:2]([C:32]2[CH:33]=[CH:34][C:29]([F:28])=[CH:30][CH:31]=2)[CH:3]=1)=[O:16]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2c(C)nn3C(C)C)c(=O)[nH]1
Reactant: OB(O)c1ccc(F)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(F)cc3)cc3c2c(C)nn3C(C)C)c(=O)[nH]1
Temperature: 100 °C
Yield: 77.9 %

Procedure:
In a 25 mL sealable tube under nitrogen were combined 6-bromo-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1-(1-methylethyl)-1H-indazole-4-carboxamide (90 mg, 0.21 mmol), (4-fluorophenyl)boronic acid (43.8 mg, 0.31 mmol) in dioxane/water (3 mL:1 mL). PdCl2(dppf)-CH2Cl2 adduct (5.11 mg, 0.006 mmol) was added and the resulting mixture was degassed with nitrogen for 10 min. Sodium bicarbonate (52.6 mg, 0.63 mmol) was added, the vessel was sealed, and the insoluble mixture was heated in a microwave at 100° C. for 20 min. The mixture was evaporated, DCM/MeOH (1:1) was added, the contents pre-absorbed on silica gel and purified by SiO2 chromatography (eluent: gradient 0 to 80:20:2 DCM/MeOH/NH4OH). The collected product was suspended in EtOAc along with some hexanes. The mixture was sonicated, and the solids that precipitated were filtered and dried to afford the title compound as a white solid (73 mg, 77%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.50 (s, 1H) 8.46 (t, J=5.05 Hz, 1H) 7.94 (d, J=1.26 Hz, 1H) 7.83-7.88 (m, 2H) 7.31-7.36 (m, 3H) 5.88 (s, 1H) 5.06 (quin, J=6.63 Hz, 1H) 4.38 (s, 1H) 4.36 (s, 1H) 2.43 (s, 3H) 2.24 (s, 3H) 2.12 (s, 3H) 1.47 (s, 3H) 1.45 (s, 3H). LC-MS (ES) m/z=446.9
Reaction SMILES: N[C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[S:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12].N([O-])=O.[Na+].O.[OH-].[Na+]>[PH2](O)=O>[S:4]1[C:5]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[CH:2]=[C:3]1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1sc2cccnc2c1N
Agent: O=N[O-]
Agent: O=[PH2]O
Agent: [Na+]
Solvent: O
Product: COC(=O)c1cc2ncccc2s1
Reaction time: 3 h

Procedure:
To a solution of methyl 3-aminothieno[3,2-b]pyridine-2-carboxylate (C-2) (930 mg, 4.47 mmol) in hypophosphorous acid (35 mL) chilled in an ice bath was added sodium nitrite (620 mg, 8.98 mmol) in a minimal amount of water. The reaction mixture was stirred for 3 h in an ice bath, and then the pH was adjusted to about 7.0 with 30% aqueous sodium hydroxide solution. The resulting mixture was extracted with EtOAc. The combined organic layers were dried and concentrated to afford the title compound. MS (m/z): 194 (M+1)+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:11][CH2:12][CH2:13][CH2:14]O)[CH:4]=[CH:3][CH:2]=1.[Cl-:16].C(=O)([O-])[O-].[K+].[K+]>C1C=CC=CC=1>[Cl:16][CH2:14][CH2:13][CH2:12][O:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:1]=[CH:2][CH:3]=[CH:4]2
Reactant: [Cl-]
Reactant: OCCCOc1cccc2cccnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: ClCCCOc1cccc2cccnc12
Temperature: 25 °C

Procedure:
A solution of 3-(8-quinolinyloxy)-1-propanol (32.0 g, 0.158 mole) and thinoyl chloride (24.0 g, 0.203 mole) was heated at reflux for 5 hours in 300 ml of dry benzene (dried over 4A molecular sieves). The reaction mixture was cooled to room temperature and then stripped to dryness. The residue was treated with potassium carbonate solution (30 g in 500 ml of water). The gummy residue was dissolved in chlorofrom and extracted with the potassium carbonate solution. The chloroform layer was dried over anhydrous sodium sulfate, filtered, and solvent removed to give a dark mass which crystallized. The mass was treated with 500 ml of boiling hexane. The hexane layer was decanted off from insoluble oil. A white solid crystallized on cooling, and was collected by filtration. The solid was dried in vacuo at room temperature overnight to give 26.69 g (76.2%) of white, crystalline solid, m.p. 69°-71° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1.FC(F)(F)S(O[CH2:33][CH3:34])(=O)=O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][CH3:34])[C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(CC(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Reactant: CCOS(=O)(=O)C(F)(F)F
Solvent: C1CCOC1
Product: CCC(C(=O)OC(C)(C)C)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Under argon and at −78° C., 14.0 ml (1.0M in THF, 14.0 mmol, 1.05 eq.) of bis(trimethylsilyl)lithium amide were added dropwise to a solution of 5.0 g (13.3 mmol) of tert-butyl [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate in 100 ml of tetrahydrofuran, and the mixture was stirred at −78° C. for 15 min. 2.6 g (14.7 mmol, 1.1 eq.) of neat ethyl trifluoromethanesulphonate were then added dropwise. The cooling bath was removed and the reaction mixture was stirred at RT for another 1 h. The reaction mixture was cooled to 0° C., and saturated aqueous ammonium chloride solution was added. After phase separation, the aqueous phase was extracted twice with methyl tert-butyl ether. The combined organic phases were dried (sodium sulphate), filtered and concentrated under reduced pressure. The crude product was then purified by flash chromatography (340 g of silica gel, mobile phase: cyclohexane/ethyl acetate mixtures 8:1, 4:1). The product-containing fractions were combined and concentrated under reduced pressure. The residue was dissolved in hot methyl tert-butyl ether and the solution was left to stand without any cover, and after 10 min the mixture had crystallized almost completely. The crystals were filtered off and washed twice with methyl tert-butyl ether. The combined filtrates were concentrated under reduced pressure and the residue was re-crystallized as described. The two crystal batches were combined and dried under reduced pressure. Yield: 4.2 g (78% of theory)
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[NH2:8][C:9]1[C:10]([C:17]([NH:19][CH2:20][C@@H:21]([N+:25]([CH2:28][CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37]C)=[CH:33][CH:32]=2)([CH3:27])[CH3:26])[CH2:22][CH2:23][CH3:24])=[O:18])=[N:11][C:12]([Cl:16])=[C:13]([NH2:15])[N:14]=1.B(Br)(Br)Br>C(Cl)Cl.CCCCCCC>[F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[NH2:8][C:9]1[C:10]([C:17]([NH:19][CH2:20][C@@H:21]([N+:25]([CH2:28][CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=2)([CH3:27])[CH3:26])[CH2:22][CH2:23][CH3:24])=[O:18])=[N:11][C:12]([Cl:16])=[C:13]([NH2:15])[N:14]=1
Reactant: CCC[C@@H](CNC(=O)c1nc(Cl)c(N)nc1N)[N+](C)(C)CCCc1ccc(OC)cc1
Agent: BrB(Br)Br
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Solvent: CCCCCCC
Product: CCC[C@@H](CNC(=O)c1nc(Cl)c(N)nc1N)[N+](C)(C)CCCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ((S)-1-{[(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-amino]-methyl}-butyl)-[3-(4-methoxy-phenyl)-propyl]-dimethyl-ammonium trifluoroacetate (Example 120) (313 mg, 0.556 mmol) in DCM (100 mL) is added BBr3 (3.34 mL of a 1M solution in heptane, 3.34 mmol). The reaction mixture is stirred at RT overnight. The reaction mixture is quenched cautiously by the addition of water then the organic solvents are removed in vacuo. Purification by reverse phase column chromatography (Isolute™ C18, 0-50% acetonitrile in water with 0.1% TFA) affords the title compound. M+ 435. 1H NMR (400 MHz, DMSO-d6) δ 8.40 (1H, t), 7.13 (2H, br), 6.89 (2H, d), 6.64 (2H, d), 5.29 (3H, br), 3.79-3.68 (1H, m), 3.57-3.43 (3H, m), 3.37-3.25 (1H, m), 3.04 (3H, s), 3.01 (3H, s), 2.41-2.30 (2H, m), 1.95-1.73 (3H, m), 1.64-1.35 (3H, m), 0.92 (3H, t).
Reaction SMILES: [OH:1][C@H:2]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:3][NH:4][CH2:5][CH2:6][CH2:7][C:8]1[S:12][C:11]([C:13]([NH2:15])=O)=[CH:10][CH:9]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].O>O1CCCC1>[NH2:15][CH2:13][C:11]1[S:12][C:8]([CH2:7][CH2:6][CH2:5][NH:4][CH2:3][C@H:2]([OH:1])[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:9][CH:10]=1
Reactant: NC(=O)c1ccc(CCCNC[C@H](O)c2ccccc2)s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: NCc1ccc(CCCNC[C@H](O)c2ccccc2)s1
Yield: 37.1 %

Procedure:
2.58 g of 5-[3-[[(R)-β-hydroxyphenethyl]amino]propyl]-2-thiophenecarboxamide were treated portionwise in 129 ml of tetrahydrofuran under argon with 1.29 g of lithium aluminium hydride and the mixture was boiled at reflux for 3.25 hours. Then, while cooling, there were cautiously added 34 ml of 2N sodium hydroxide solution and subsequently 400 ml of water and the mixture was extracted three times with chloroform. The chloroform solutions were washed neutral with water and dilute sodium chloride solution, dried and evaporated in vacuo. Chromatography on silica gel with methanol and 0.5% concentrated ammonia and crystallization from acetonitrile/ether gave 914 mg of (R)-α-[[[3-[5-(aminomethyl)-2-thienyl]propyl]amino]methyl]benzyl alcohol of melting point 64°-65°. [α]D =-18° (c=0.1% in dioxane); UV: ε240 =9080.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]4[NH:30][N:29]=[N:28][N:27]=4)=[CH:16][CH:15]=3)[C:9]([CH2:11][CH3:12])=[N:10][C:5]2=[C:4]([CH3:31])[CH:3]=1.O.[NH2:33][NH2:34]>>[NH:33]([C:2]1[N:7]=[C:6]2[N:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]4[NH:30][N:29]=[N:28][N:27]=4)=[CH:16][CH:15]=3)[C:9]([CH2:11][CH3:12])=[N:10][C:5]2=[C:4]([CH3:31])[CH:3]=1)[NH2:34]
Reactant: NN
Reactant: CCc1nc2c(C)cc(Br)nc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Solvent: O
Product: CCc1nc2c(C)cc(NN)nc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
A mixture of 5-Bromo-2-ethyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine. (2.0 g), and hydrazine hydrate (15 mL) was heated to 120° C. for 24 hours. Concentration and purification (SiO2, 85/14/2 CH2Cl2 /MeOH/NH4OH) gave 1.80 g of 5-hydrazino-2-ethyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]-pyridine. Reduction in methanol (50 mL) under 1 atm. H2 with W-2 Raney nickle (1 mL, 50% dispersion/water) at RT for 48 hours gave the title compound (1.44 g) after purification (SiO2, 85/14/2 CH2Cl2 /MeOH/NH4OH). 1H NMR (300 MHz, CD3OD) δ 7.60-7.50 (m, 2H), 7.49-7.42 (m, 2H), 7.10-7.00 (m, 4H), 6.38 (s, 1H), 5.39 (s, 2H), 2.79 (q, 2H, J=7.5 Hz), 2.49 (s, 3H), 1.21 (t, 3H, J=7.5 Hz).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([CH2:9][O:10][CH3:11])[C:6]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:5][N:4]=1.Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[F:29]>>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][N:4]2[CH:5]=[C:6]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:7]([CH2:9][O:10][CH3:11])=[CH:8][C:3]2=[O:2])=[C:23]([F:29])[CH:24]=1
Reactant: COCc1cc(OC)ncc1-c1ccc(OC)cc1
Reactant: Fc1cc(Cl)ccc1CBr
Product: COCc1cc(=O)n(Cc2ccc(Cl)cc2F)cc1-c1ccc(OC)cc1
Yield: 0.8 %

Procedure:
According to Scheme 31 Step 4: The title compound was prepared from 2-methoxy-4-(methoxymethyl)-5-(4-methoxyphenyl)pyridine (1 eq, 0.66 mmol, 0.17 g) and 1-(bromomethyl)-4-chloro-2-fluorobenzene (1.5 eq, 0.98 mmol, 0.22 g) according to the procedure described for Example 6 Step 2. Reaction conditions: 12 hours at 80° C. The crude product was purified by silica gel chromatography (AIT Flashsmart prepacked column 25 g SiO2) using CH2Cl2/MeOH 98/2 as the eluent to afford 1-(4-chloro-2-fluorobenzyl)-4-(methoxymethyl)-5-(4-methoxyphenyl)pyridin-2(1H)-one (5 μmol, 2 mg, 1%) as yellow oil.
Reaction SMILES: [N:1]1[NH:2][N:3]=[N:4][C:5]=1[C:6]1[S:10][C:9]([N:11]2[CH2:16][CH2:15][CH:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:26])[F:25])[CH2:13][CH2:12]2)=[N:8][N:7]=1.[H-].[Na+].Br[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33].Cl>CN(C=O)C>[F:25][C:24]([F:27])([F:26])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[O:17][CH:14]1[CH2:13][CH2:12][N:11]([C:9]2[S:10][C:6]([C:5]3[N:1]=[N:2][N:3]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[N:4]=3)=[N:7][N:8]=2)[CH2:16][CH2:15]1
Reactant: FC(F)(F)c1ccccc1OC1CCN(c2nnc(-c3nn[nH]n3)s2)CC1
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1nnc(-c2nnc(N3CCC(Oc4ccccc4C(F)(F)F)CC3)s2)n1
Temperature: 0 °C

Procedure:
A solution of 1-[5-(2H-tetrazol-5-yl)-1,3,4-thiadiazol-2-yl]-4-[2-(trifluoromethyl)phenoxy]piperidine (262 mg, 0.66 mmol) in DMF (5 mL) was treated with NaH (60% in oil) (42 mg, 1.05 mmol) at −78° C. The mixture was warmed to 0° C. and, after 10 min, ethyl bromoacetate (150 μL, 1.35 mmol) was added dropwise. The final reaction mixture was warmed and stirred at room temperature until TLC indicated disappearance of the starting material. The reaction mixture was poured into aqueous 1 N HCl, extracted with EtOAc and washed with brine. The organic layer was dried (Na2SO4) and filtered. Solvents were removed in vacuo to afford the crude product, which was purified by column chromatography on silica gel (eluting with 10-50% EtOAc/hexanes) to afford ethyl [5-(5-{4-[2-(trifluoromethyl)phenoxy]piperidin-1-yl}-1,3,4-thiadiazol-2-yl)-2H-tetrazol-2-yl]acetate as the more polar regioisomer, Rf=0.2 (50% EtOAc/hexanes). 1H NMR (400 MHz, acetone-d6): δ7.70-7.61 (m, 2H), 7.40 (d, 1H), 7.14 (t, 1H), 5.81 (s, 2H), 5.10-5.04 (m, 1H), 4.31 (q, 2H), 3.94-3.85 (m, 2H), 3.86-3.77 (m, 2H), 2.29-2.20 (m, 2H), 2.11-2.03 (dd, 2H), 1.31 (t, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[S:15][CH:16]=[C:17]([C:19]([N:21]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[O:20])[CH:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[N:21]1([C:19]([C:17]2[CH:18]=[C:14]([C:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=3)[S:15][CH:16]=2)=[O:20])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc(C(=O)N3CCCCCC3)cs2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1csc(C2=CCNCC2)c1)N1CCCCCC1
Reaction time: 1 h
Yield: 97.3 %

Procedure:
4-[4-(Azepane-1-carbonyl)-thiophen-2-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.094 g) was dissolved in TFA (1 mL) and DCM (1 mL). The mixture was stirred for 1 hour and then the solvent evaporated. The residue was purified using a SCX-2 column. After washing with methanol and acetonitrile, the desired compound was washed from the column with ammonia (2 M in MeOH). Evaporation gave the title compound as a clear colourless oil (0.068 g). LCMS m/z 291.07 [M+H]+ RT=5.14 min (Analytical Method 2).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C(O[CH:13]=[C:14]([C:20]#[N:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])C>C1(C)C=CC=CC=1.CCCCCC>[C:20]([C:14](=[CH:13][NH:1][C:2]1[C:7]([CH2:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16])#[N:21]
Reactant: CCc1cccnc1N
Reactant: CCOC=C(C#N)C(=O)OCC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C#N)=CNc1ncccc1CC

Procedure:
A solution of 2-amino-3-ethylpyridine (13.0 g., 0.1063 mole) and ethyl ethoxymethylenecyanoacetate (18.0 g., 0.1063 mole) in toluene (50 ml.) was heated on a steam bath for 20 minutes. The solution was cooled and the resulting mixture diluted with Skellysolve B. The title compound (19.0 g.), m.p. 122°-125° C., was collected by filtration. From the mother liquors, after recrystallization from cyclohexane, was obtained a further crop (7.0 g.) of product, m.p. 122°-125° C. Total yield of title compound, 26.0 g. (99.6%). The material from cyclohexane was recrystallized twice from methanol to give analytical material, m.p. 123°-125° C.