Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:28])[NH:10][C@@H:11]([CH3:27])[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]3[O:24][C:23]([CH2:25]O)=[CH:22][C:20]3=2)[CH:15]=[N:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[C-:33]#[N:34].[Na+].C(=O)(O)[O-].[Na+]>ClCCl.CS(C)=O>[CH2:1]([O:8][C:9](=[O:28])[NH:10][C@@H:11]([CH3:27])[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]3[O:24][C:23]([CH2:25][C:33]#[N:34])=[CH:22][C:20]3=2)[CH:15]=[N:14]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [C-]#N
Reactant: C[C@@H](Cn1ncc2ccc3oc(CO)cc3c21)NC(=O)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: C[C@@H](Cn1ncc2ccc3oc(CC#N)cc3c21)NC(=O)OCc1ccccc1

Procedure:
A solution of the product from Example 2, Step B (0.55 g, 1.45 mmol) in dichloromethane (20 mL) was cooled (ice bath), thionyl chloride (0.16 mL, 2.18 mmol) was added, and the mixture was stirred for thirty minutes. The reaction mixture was evaporated to a residue which was dissolved in dichloromethane (20 mL) and evaporated. A solution of sodium cyanide (0.29 g, 5.8 mmol) in DMSO (10 mL) was added to this residue and the mixture was stirred at room temperature for one hour. Saturated aqueous sodium bicarbonate (100 mL) was added and the mixture was extracted with ethyl acetate (3×100 mL). The combined extracts were washed with saturated aqueous sodium bicarbonate (2×150 mL), dried (MgSO4) and evaporated to a tan solid (0.49 g, 87%): LC/MS m/z 389 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)(=[O:15])=[O:14])[C:11]([CH3:22])=[C:10]([CH:23]=O)[CH:9]=2)=[CH:4][CH:3]=1.[Cl-:25].C[NH3+].[C:28]([BH3-])#[N:29].[Na+]>CO>[ClH:25].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)(=[O:15])=[O:14])[C:11]([CH3:22])=[C:10]([CH2:23][NH:29][CH3:28])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: [Cl-]
Reactant: [BH3-]C#N
Reactant: Cc1c(C=O)cc(-c2ccc(F)cc2)n1S(=O)(=O)c1ccccc1
Agent: C[NH3+]
Agent: [Na+]
Solvent: CO
Product: CNCc1cc(-c2ccc(F)cc2)n(S(=O)(=O)c2ccccc2)c1C
Product: Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 65.2 %

Procedure:
To a solution (20 mL) of 5-(4-fluorophenyl)-2-methyl-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde (0.40 g) in methanol were added methylammonium chloride (0.95 g) and sodium cyanoborohydride (0.30 g), and the mixture was stirred at room temperature for 20 hr. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=1:0→1:2) to give free base of the title compound as an oil (0.30 g). The obtained oil (0.30 g) was dissolved in ethyl acetate (6 mL), and a 4 mol/L hydrogen chloride-ethyl acetate solution (3 mL) was added. The mixture was concentrated under reduced pressure, and the residue was crystallized from ethyl acetate to give the title compound as colorless crystals (yield 0.31 g, 92%).
Reaction SMILES: [CH3:1][C:2]1[O:3][CH2:4][CH2:5][N:6]=1.[CH2:7](Br)[CH:8]=[C:9]([CH3:11])[CH3:10].[CH3:13][CH2:14][O-:15].[Na+]>CCCCCC.C(O)C>[CH2:14]([O:15][C:2]1([CH3:1])[N:6]([CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])[CH2:5][CH2:4][O:3]1)[CH3:13]
Reactant: CC[O-]
Reactant: CC1=NCCO1
Reactant: CC(C)=CCBr
Agent: [Na+]
Solvent: CCO
Solvent: CCCCCC
Product: CCOC1(C)OCCN1CC=C(C)C
Temperature: 40 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
8.5 g (0.1 mol) of 2-methyloxazoline and 14.9 g (0.1 mol) of prenyl bromide were stirred in 50 ml of n-hexane at 40° C. for 1 hour, whereupon a suspension formed, which, after adding 0.11 mol of a sodium ethylate solution in ethanol, was again stirred at 40° C. for 1 hour. The solution was filtered, the filtrate was concentrated on a rotary evaporator and the residue was distilled using an oil pump. 12.3 g (0.062 mol, 62%) of 2-ethoxy-2-methyl-3-(3-methyl-2-butenyl)-oxazolidine were isolated at a boiling point 67° C./0.1 mm Hg.
Reaction SMILES: [O:1]=[C:2]1[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][N:3]1[CH2:19][C:20]([OH:22])=O.CN(C)C=O.C(Cl)(=O)C([Cl:31])=O>ClCCl>[O:1]=[C:2]1[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][N:3]1[CH2:19][C:20]([Cl:31])=[O:22]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Reaction time: 1 h

Procedure:
To a suspension of 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (1.477 g, 5.0 mmol; Example 1C) in dichloromethane (20 mL) was added catalytic amount of N,N-dimethylformamide followed by oxalyl dichloride (2.0 Min dichloromethane, 3.75 mL, 7.5 mmol). After stirring for 60 minutes, the reaction was concentrated, dried under high vacuum overnight. The resulting material was taken for further reactions without additional purification.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[CH:10][N:9]=[C:8]([NH2:12])[CH:7]=2)[CH2:3][CH2:2]1.[CH:13]1(CO)CCC[CH2:14]1>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[CH:10][N:9]=[C:8]([NH2:12])[CH:7]=2)[CH2:3][CH2:2][CH2:14][CH2:13]1
Reactant: OCC1CCCC1
Reactant: Nc1cc(OCC2CC2)ncn1
Product: Nc1cc(OCC2CCCC2)ncn1
Yield: 89 %

Procedure:
This was prepared in a manner analogous to 6-(cyclopropylmethoxy)pyrimidin-4-amine, where cyclopentylmethanol was used as the alcohol. 6-(cyclopentylmethoxy)pyrimidin-4-amine (0.266 g, 1.376 mmol, 89% yield) was obtained as a white solid. m/z (ESI) 194.2 (M+H)+.
Reaction SMILES: B(F)(F)F.CCOCC.[N+:10](=[CH:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[N-].[Cl:19][CH2:20][C:21]#N>>[Cl:19][CH2:20][C:21]1[O:18][C:13]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:12][N:10]=1
Reactant: N#CCCl
Reactant: CC(C)(C)C(=O)C=[N+]=[N-]
Agent: FB(F)F
Solvent: CCOCC
Product: CC(C)(C)c1cnc(CCl)o1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of chloroacetonitrile (40 mL) and boron trifluoride etherate (20 mL, 0.16 mmol) at 0° C. was added 1-diazo-3,3-dimethyl-2-butanone in chloroacetonitrile (40 mL) dropwise over a period of 20 minutes. After addition was complete, the mixture was stirred at 0° C. for one hour and then partitioned between saturated NaHCO3 solution (700 mL) and CH2Cl2 (500 mL). The aqueous solution was. extracted with CH2Cl2 (500 mL) and the combined organic layers were washed with brine (400 mL) and dried over MgSO4. After filtration, the solution was concentrated and then distilled under vacuum using an oil bath temperature of 40° C. The 2-(chloromethyl)-5-t-butyloxazole (9.2 g, 44% overall from the acid chloride, C8H12CINO, MS m/e 174 (M+H)+) was obtained as a light yellow oil.
Reaction SMILES: [CH2:1]([N:8]1[C:16](=[O:17])[C:15]2[N:14]=[C:13](Br)[N:12]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26]([O:28][CH:29]=[CH:30][Sn](CCCC)(CCCC)CCCC)[CH3:27]>CN(C=O)C>[CH2:1]([N:8]1[C:16](=[O:17])[C:15]2[N:14]=[C:13]([CH:27]=[CH:26][O:28][CH2:29][CH3:30])[N:12]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1c2nc(Br)n(Cc3ccccc3)c2ncn1Cc1ccccc1
Reactant: CCCC[Sn](C=COCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: CCOC=Cc1nc2c(=O)n(Cc3ccccc3)cnc2n1Cc1ccccc1
Temperature: 70 °C

Procedure:
A mixture of 1,9-dibenzyl-6,9-dihydro-6-oxo-8-bromopurine (20) (1.20 g, 3.04 mmol) bis(triphenylphosphine)palladium(II)chloride (0.213 g, 0.3 mmol) and ethoxyvinyl(tributyl)tin (2.19 g, 6.07 mmol) in dry DMF (50 mL) was heated under N2 at 70° C. for 22 h. DMF was distilled off and the resulting residue dissolved in EtOAc (100 mL) and filtered through a pad of celite. The solvent was distilled off and the residue was purified by flash chromatography (EtOAc:hexane, 6:4). Yield 0.989 g (88%). Mp 167-168° C. 1H NMR (CDCl3) δ 1.26 (t, 3H, CH3, J=7.5 Hz), 3.86 (q, 2H, CH2, J=7 Hz), 4.46 (d, 1H, CH, J=2.5 Hz), 5.26 (s, 2H, benzylic CH2), 5.32 (d, 1H, CH2 J=3 Hz), 5.60 (s, 2H, benzylic CH2), 7.10-7.37 (m, 10H, Ar—H), 7.99(s, 1H, purine C2—H). 13C NMR (CDCl3) δ 14.1, 47.8, 49.1, 63.8, 90.2, 123.5, 126.6, 126.6, 127.5, 127.5, 128.2, 128.7, 128.7, 128.9, 129.1, 129.1, 136.2, 136.7, 146.2, 146.9, 148.9, 151.9, and 156.6. FAB-HRMS: [M+H]+ calcd. for C23H23N4O2 387.1821, found 387.1815.
Reaction SMILES: [I-].C(OC([NH:9][C@H:10]([C:18]([O:20][CH3:21])=[O:19])[CH2:11][CH2:12][CH2:13][N+:14]([CH3:17])([CH3:16])[CH3:15])=O)(C)(C)C.[ClH:22]>O1CCOCC1>[ClH:22].[Cl-:22].[NH2:9][C@H:10]([C:18]([O:20][CH3:21])=[O:19])[CH2:11][CH2:12][CH2:13][N+:14]([CH3:16])([CH3:15])[CH3:17]
Reactant: COC(=O)[C@H](CCC[N+](C)(C)C)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [I-]
Solvent: C1COCCO1
Product: COC(=O)[C@@H](N)CCC[N+](C)(C)C
Product: [Cl-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 106.1 %

Procedure:
To a solution of (S)-4-(tert-butoxycarbonylamino)-5-methoxy-N,N,N-trimethyl-5-oxopentan-1-aminium iodide (20.5 mmol, 1.0 eq) in anhyd dioxane (10 mL), was added HCl (51 mL, 205 mmol, 10 eq, 4M in dioxane). The orange slurry was stirred at room temperature for 1 h, the solids were broken up, then stirred vigorously for another 1 h. The suspension was allowed to settle before cannulating off the dioxane layer. The remaining yellow slurry was rinsed with Et2O, stirred and cannulated out the ether layer (4×). The solids were dried under high vacuum to give the title compound (5.68 g) as a light yellow powder. 1H NMR (400 MHz, DMSO) δ 8.75 (s, 3H), 4.03-3.93 (m, 1H), 3.68 (s, 3H), 3.30-3.20 (m, 2H), 2.98 (s, 9H), 1.89-1.69 (m, 4H); MS (EI) m/z 189 (M+).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[C:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1.[H-].[Na+].Cl[CH2:20][S:21][CH3:22]>CN(C=O)C>[CH3:20][S:21][CH2:22][N:1]1[C:9]2[CH:8]=[C:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1
Reactant: CSCCl
Reactant: CC(C)(C)OC(=O)c1cc2[nH]ccc2cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSCn1ccc2cnc(C(=O)OC(C)(C)C)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.7 %

Procedure:
To a mixture of tert-butyl 1H-pyrrolo[3,2-c]pyridine-6-carboxylate (1.0 g, 4.6 mmol) in DMF (20 ml) was added sodium hydride (60% in oil) (0.41 g, 10 mmol) and stirred at room temperature for 3 h. To the mixture, (chloromethyl)(methyl)sulfane (0.89 g, 9.2 mmol) was added and stirred at room temperature for 2 h. The reaction mixture was extracted with EtOAc/H2O. The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The crude mixture was purified by chromatography (SiO2, hexanes:EtOAc=50:50) to give tert-butyl 1-(methylthiomethyl)-1H-pyrrolo[3,2-c]pyridine-6-carboxylate (8A, 920 mg, 3.3 mmol, 72% yield) as a yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.61 (s, 9H) 1.94 (s, 3H) 5.15 (s, 2H) 6.64 (d, J=3.28 Hz, 1H) 7.34 (d, J=3.28 Hz, 1H) 8.15 (s, 1H) 8.93 (d, J=1.01 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[N:11]2[CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH:13]3[C:9]3[C:10]2=[C:5]([CH:6]=[CH:7][CH:8]=3)[N:4]([CH3:18])[CH2:3]1.Cl[CH2:21][CH2:22][CH2:23][C:24]([C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)=[O:25].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[F:32][C:29]1[CH:28]=[CH:27][C:26]([C:24](=[O:25])[CH2:23][CH2:22][CH2:21][N:15]2[CH2:16][CH2:17][CH:12]3[N:11]4[C:10]5[C:9]([CH:13]3[CH2:14]2)=[CH:8][CH:7]=[CH:6][C:5]=5[N:4]([CH3:18])[CH2:3][C:2]4([CH3:19])[CH3:1])=[CH:31][CH:30]=1
Reactant: O=C(CCCCl)c1ccc(F)cc1
Reactant: CN1CC(C)(C)N2c3c(cccc31)C1CNCCC12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CN1CC(C)(C)N2c3c(cccc31)C1CN(CCCC(=O)c3ccc(F)cc3)CCC12
Temperature: 25 °C
Reaction time: 24 h
Yield: 43 %

Procedure:
To a solution of 1,1,3-trimethyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline (from Example 283) (82 mg, 0.32 mmol) in dioxane (10 mL) at rt was added 4-chloro-1-(4-fluorophenyl)butan-1-one (83 mg, 0.42 mmol), K2CO3 (100 mg), KI (30 mg) and stirred at 25° C. for 24 hours. The solution was diluted with water (30 mL) and extracted with EtOAc (2×30 mL). The combined extracts were dried over magnesium sulfate, concentrated, and purified by flash chromatography to afford the title compound (58 mg, 43%). MS [M+H]+422. 1H NMR (CDCl3, 300 MHz): δ 8.01 (m, 2H), 7.15 (t, 2H, J=7.7 Hz), 6.65 (t, 1H, J=7.7 Hz), 6.51 (d, 1H, J=7.0 Hz), 6.43 (d, 1H, J=7.0 Hz), 3.63 (m, 1H), 3.25 (d, 1H, J=11 Hz), 3.09 (m, 2H), 2.89 (s, 3H), 2.63 (m, 2H), 2.25 (m, 2H), 2.17 (m, 2H), 1.31 (s, 3H), 1.12 (s, 3H) ppm. This racemate was then separated into its corresponding enantiomers by HPLC utilizing a Chiralcel AD column with 50% Ethanol/Methanol solvent system.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([Cl:11])[C:3]=1[S:12][C:13]1[S:14][C:15]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:16]=2[N:17]=1.O.O.[Sn](Cl)(Cl)(Cl)Cl.[OH-].[Na+]>CCOC(C)=O>[Cl:11][C:4]1[CH:5]=[C:6]([NH2:8])[CH:7]=[C:2]([Cl:1])[C:3]=1[S:12][C:13]1[S:14][C:15]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:23])[F:24])=[CH:18][C:16]=2[N:17]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(Sc2nc3cc(C(F)(F)F)ccc3s2)c(Cl)c1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1cc(Cl)c(Sc2nc3cc(C(F)(F)F)ccc3s2)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 96.5 %

Procedure:
To a solution of 2-(2,6-dichloro-4-nitro-phenylsulfanyl)-5-trifluoromethyl-benzothiazole (258) (840 mg, 1.98 mmol) in EtOAc (20 mL) was added tin chloride dihydrate (Aldrich, 2.15 g, 9.52 mmol) and the resulting mixture was heated to reflux for 3 hours. After cooled to room temperature, to the mixture was added excess of 4N aqueous NaOH solution and the resulting mixture was stirred for 20 minutes. The mixture was filtered through Celite pad and washed with EtOAc. The organic layer was separated, washed twice with a brine solution, dried over Na2SO4, and concentrated under vacuum to give compound 270 (755 mg, 96%) product as a pale yellow solid, which was used in the next reaction without further purification.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:17]=[C:16]([CH2:18][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[C:15]([C:25]([F:28])([F:27])[F:26])=[CH:14][C:10]=2[C:11]([OH:13])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[N:38]1[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][N:39]=1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CN(C)C=O>[C:1]1([CH2:7][O:8][C:9]2[CH:17]=[C:16]([CH2:18][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[C:15]([C:25]([F:28])([F:27])[F:26])=[CH:14][C:10]=2[C:11]([NH:44][C:41]2[CH:42]=[CH:43][N:38]=[N:39][CH:40]=2)=[O:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ccnnc1
Reactant: O=C(O)c1cc(C(F)(F)F)c(CN2CCCCC2)cc1OCc1ccccc1
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(Nc1ccnnc1)c1cc(C(F)(F)F)c(CN2CCCCC2)cc1OCc1ccccc1
Reaction time: 18 h

Procedure:
To a solution of 2-[(phenylmethyl)oxy]-4-(1-piperidinylmethyl)-5-(trifluoromethyl)benzoic acid (may be prepared as described in Description 53; 112 mg, 0.29 mmol) in N,N-dimethylformamide (5 ml) was added diisopropylethylamine (0.10 ml, 0.57 mmol), 4-pyridazinamine (40.6 mg, 0.43 mmol), 1-hydroxy-7-azabenzotriazole (50.4 mg, 0.37 mmol) and EDC (109 mg, 0.57 mmol). The reaction was stirred for 18 hours, then the solvent removed in vacuo to give a yellow oil. Purification by MDAP gave the title compound as a white solid. 66 mg.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:27])[NH:10][C@H:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21]([F:24])([F:23])[F:22])[CH:19]=2)[NH:14][C@@H:13]([CH2:25][CH3:26])[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:35]([O:37][CH2:38][CH3:39])=[O:36].[OH-].[K+]>ClCCl>[CH2:38]([O:37][C:35]([N:14]1[C:15]2[C:20](=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=2)[C@H:11]([NH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:27])[CH2:12][C@@H:13]1[CH2:25][CH3:26])=[O:36])[CH3:39]
Reactant: CCOC(=O)Cl
Reactant: CC[C@H]1C[C@@H](NC(=O)OCc2ccccc2)c2cc(C(F)(F)F)ccc2N1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)N1c2ccc(C(F)(F)F)cc2[C@H](NC(=O)OCc2ccccc2)C[C@@H]1CC
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
A solution of cis-(2-ethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-4-yl)-carbamic acid benzyl ester (Example 3B) (37.0 g, 97.9 mmol) and pyridine (23.2 g, 293.7 mmol) in dichloromethane (1 L) was cooled in an ice/water bath as ethyl chloroformate (37.2 g, 342.6 mmol) was added slowly. After stirring at room temperature overnight, the mixture was cooled with an ice/water bath as a 1M potassium hydroxide solution was added to quench the reaction. The organic phase was washed twice with a 2M hydrochloric acid solution, dried over magnesium sulfate, filtered and concentrated in vacuo to afford the crude product which was purified by silica gel chromatography using 10-15% ethyl acetate/hexanes as eluent to afford 40 g of the title product. 1H NMR (CDCl3) δ 0.83 (t, 3H), 1.28 (t, 3H), 1.4-1.6 (m, 3H), 2.53 (m, 1H), 4.23 (m, 2H), 4.47 (m, 1H), 4.80 (m, 1H), 4.94 (m, 1H), 5.18 (s, 2H) 7.3-7.6 (m, 8H).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:20]=[CH:19][C:6]([CH:7]=[N:8][C:9]2[CH:14]=[CH:13][C:12]([S:15](=[O:18])(=[O:17])[NH2:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C[Si]([C:25]#[N:26])(C)C>>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([CH:7]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15](=[O:17])(=[O:18])[NH2:16])=[CH:11][CH:10]=2)[C:25]#[N:26])=[CH:19][CH:20]=1
Reactant: CSc1ccc(C=Nc2ccc(S(N)(=O)=O)cc2)cc1
Reactant: C[Si](C)(C)C#N
Product: CSc1ccc(C(C#N)Nc2ccc(S(N)(=O)=O)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 1(ii), but using N-(4-methylthiobenzylidene)-4-sulfamoylaniline [prepared as described in step (i) above] and trimethylsilyl cyanide as starting materials, the title compound was obtained as a yellow powder (yield 100%).
Reaction SMILES: [CH3:1][N:2]([CH3:32])[CH2:3][CH2:4][CH2:5][NH:6]C(C1C=C(C2C=CC(CSCCOC3C=CC=CC=3)=CC=2)C=CC=1)=O.[O:33]([CH2:40][CH2:41][S:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[C:50]1[CH:55]=[CH:54][CH:53]=[C:52]([C:56](O)=[O:57])[CH:51]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CN(C)CCCN>C1COCC1>[CH3:1][N:2]([CH3:32])[CH2:3][CH2:4][CH2:5][NH:6][C:56]([C:52]1[CH:51]=[C:50]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2[CH2:43][S:42][CH2:41][CH2:40][O:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:55]=[CH:54][CH:53]=1)=[O:57]
Reactant: O=C(O)c1cccc(-c2ccccc2CSCCOc2ccccc2)c1
Reactant: CN(C)CCCNC(=O)c1cccc(-c2ccc(CSCCOc3ccccc3)cc2)c1
Agent: CN(C)CCCN
Solvent: C1CCOC1
Product: CN(C)CCCNC(=O)c1cccc(-c2ccccc2CSCCOc2ccccc2)c1
Yield: 86 %

Procedure:
2′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid (3-dimethylamino-propyl)-amide was synthesized as described for 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid (3-dimethylamino-propyl)-amide. 2′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid (1.0 g, 2.74 mmol, 1 eq.) in anhydrous THF was treated with 1,1-carbonyldiimidazole (0.45 g, 2.79 mmol, 1.02 eq.) followed by 3-(dimethylamino)propylamine (0.34 g, 3.29 mmol, 1.2 eq.) as described. When complete, the reaction was worked up leaving a yellow oil. The oil was purified via silica gel flash chromatography using 10% 2M NH3 in methanol in chloroform as the mobile phase. Fractions containing the product were pooled and the solvent removed in vacuo leaving 2′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid (3-dimethylamino-propyl)-amide (1.06 g, 86% yield). The free base was converted to the oxalate salt by adding oxalic acid (0.26 g, 1.2 eq.) in EtOAc dropwise to an EtOAc solution of the free base. 2′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid (3-dimethylamino-propyl)-amide oxalate (1.08 g) was collected by filtration as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([N:14]3[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][NH:22][C:23](=[O:34])[O:24][C:25]4[CH:30]=[CH:29]C([N+]([O-])=O)=CC=4)[CH2:16][CH2:15]3)=[N:12][CH:13]=2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[S:44]1C=C(CO)[N:46]=[N:45]1>ClCCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([N:14]3[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][NH:22][C:23](=[O:34])[O:24][CH2:25][C:30]4[N:46]=[N:45][S:44][CH:29]=4)[CH2:16][CH2:15]3)=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=C(NCCC1CCN(c2ccc(-c3ccc(F)cc3)cn2)CC1)Oc1ccc([N+](=O)[O-])cc1
Reactant: OCc1csnn1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCC1CCN(c2ccc(-c3ccc(F)cc3)cn2)CC1)OCc1csnn1

Procedure:
A solution of 0.50 g (0.50 mmol) of 4-nitrophenyl 2-[5′-(4-fluorophenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-ethylcarbamate, prepared in step 1.5., 0.128 g (0.99 mmol) of N,N-diisopropylethylamine, 0.030 g (0.25 mmol) of N,N-dimethylaminopyridine and 0.079 g (0.5 mmol) of [1,2,3]thiadiazol-4-ylmethanol (Acta Pharmaceutica Suecica (1973), 10(4), 285-96) in 5 mL of 1,2-dichloroethane is heated in a reactor tube at 80° C. for 12 hours.
Reaction SMILES: [NH2:1][C:2]1([O:9][CH2:10][CH3:11])[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].Cl[C:19]1C=CC=C[CH:20]=1.[CH2:25](I)[CH3:26]>ClCCl>[CH2:19]([N:1]([CH2:25][CH3:26])[C:2]1([O:9][CH2:10][CH3:11])[CH:3]=[CH:4][C:5]([OH:8])=[CH:6][CH2:7]1)[CH3:20]
Reactant: CCI
Reactant: CCOC1(N)C=CC(O)=CC1
Reactant: Clc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCOC1(N(CC)CC)C=CC(O)=CC1
Temperature: 120 °C

Procedure:
A four-necked flask was charged with 9.6 g (70 mmol) of p-aminophenetyl alcohol, 38.7 g (280 mmol) of potassium carbonate and 100 ml of monochlorobenzene under argon gas atmosphere, and heated at 120° C. with agitation. To the flask was added dropwise 32.8 g (210 mmol) of ethyl iodide over 5 hours, and after addition, heated for 5 hours with agitation. The reaction solution was cooled to room temperature, diluted with dichloromethane, and washed with water three times. The dichloromethane solution was dried with anhydrous magnesium sulfate followed by solvent removal, and purified by column chromatography on silica gel using mixture solvent of toluene/ethyl acetate (2/1) to give 12.1 g of p-diethylaminophenetyl alcohol (yield=89% by mass).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]([CH3:18])([CH3:17])[CH2:15][OH:16])[CH:6]=[C:5]2[CH:19]=[O:20].[CH:21]1([NH:24][C:25](=[O:43])[C:26]2[CH:31]=[C:30](B3OC(C)(C)C(C)(C)O3)[C:29]([CH3:41])=[C:28]([F:42])[CH:27]=2)[CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH:21]1([NH:24][C:25](=[O:43])[C:26]2[CH:31]=[C:30]([C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[C:8](=[O:12])[N:7]([CH2:13][C:14]([CH3:18])([CH3:17])[CH2:15][OH:16])[CH:6]=[C:5]4[CH:19]=[O:20])[C:29]([CH3:41])=[C:28]([F:42])[CH:27]=2)[CH2:22][CH2:23]1
Reactant: CC(C)(CO)Cn1cc(C=O)c2cc(Br)ccc2c1=O
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC(C)(C)CO)cc(C=O)c2c1
Yield: 64.8 %

Procedure:
6-Bromo-2-(3-hydroxy-2,2-dimethylpropyl)-1-oxo-1,2-dihydroisoquinoline-4-carbaldehyde (Example 26d 16.8 g), N-cyclopropyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (20.61 g), Pd-118 (1.619 g) and potassium carbonate (17.16 g) in DMF (140 mL) was heated to 70° C. for 4 h under nitrogen. The mixture was cooled, diluted with water (250 mL), and extracted with ethyl acetate (300 mL). The separated organic layer was dried (MgSO4), filtered and evaporated. The residue was purified (SiO2 chromatography, elution with 50 to 100% ethyl acetate in DCM) to give a solid, which was triturated with isohexane 1:1 diethyl ether (200 mL) for 1 h. The suspension was filtered and dried to give the subtitle compound (14.5 g) as a solid.